Trial Outcomes & Findings for Study to Assess Safety, Pharmacokinetics, and Efficacy of Oral CC-223 for Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma or Multiple Myeloma (NCT NCT01177397)

NCT ID: NCT01177397

Last Updated: 2022-12-13

Results Overview

A dose-limiting toxicity was defined as: - ≥ Grade 3 (per Common Terminology Criteria for Adverse Events \[CTCAE\] Version 4) clinically relevant adverse event (AE) or laboratory abnormality suspected to be related to CC-223 that commenced within 30 days of first dose, except alopecia, Grade 3 rash of the acneiform or maculopapular type for \< 5 days, Grade 3 diarrhea or vomiting lasting \< 72 hours, repeated occurrence of Grade 3 hyperuricaemia in subjects with Grade 3 hyperuricemia at baseline, hyperglycemia, hematologic and liver function test (LFT) abnormalities due to disease progression. - Grade 2 fasting hyperglycemia lasting \> 14 days or ≥ Grade 3 lasting \> 4 days despite optimal medical treatment. - Hematological toxicities including febrile neutropenia, Grade 4 neutropenia or thrombocytopenia for \> 7 days, or Grade 3/4 thrombocytopenia with clinically significant bleeding. - Grade 4 LTFs - AE suspected to be CC-223 related necessitating dose reduction during cycle 1.

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 226 participants
• Primary outcome timeframe: From first dose up to 30 days after first dose
• Results posted on: 2022-12-13

Participant Flow

Participant milestones

Measure	Part A: CC-223 7.5 mg Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 15 mg Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Glioblastoma Multiforme (GBM) Participants with GBM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Hepatocellular Carcinoma (HCC) Participants with HCC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Neuroendocrine Tumor (NET) Participants with NET received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Diffuse Large B-cell Lymphoma (DLBCL) Participants with DLBCL received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Hormone Receptor Positive Breast Cancer (HRPBC) Participants with HRPBC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Overall Study STARTED	1	2	9	9	7	26	13	53	47	28	14	17
Overall Study COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0
Overall Study NOT COMPLETED	1	2	9	9	7	26	13	53	47	28	14	17

Reasons for withdrawal

Measure	Part A: CC-223 7.5 mg Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 15 mg Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Glioblastoma Multiforme (GBM) Participants with GBM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Hepatocellular Carcinoma (HCC) Participants with HCC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Neuroendocrine Tumor (NET) Participants with NET received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Diffuse Large B-cell Lymphoma (DLBCL) Participants with DLBCL received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Hormone Receptor Positive Breast Cancer (HRPBC) Participants with HRPBC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Overall Study Protocol Violation	0	0	0	0	0	1	0	0	0	0	0	0
Overall Study Lost to Follow-up	0	0	0	0	1	0	0	2	0	0	0	0
Overall Study Death	0	0	1	1	0	0	0	5	2	1	0	0
Overall Study Withdrawal by Subject	0	0	1	1	1	2	0	5	9	1	1	0
Overall Study Adverse Event	0	0	1	2	0	12	1	14	8	6	3	7
Overall Study Disease progression	1	2	5	5	4	10	10	21	18	12	10	8
Overall Study Other reasons	0	0	1	0	1	1	2	6	10	8	0	2

Baseline Characteristics

Study to Assess Safety, Pharmacokinetics, and Efficacy of Oral CC-223 for Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma or Multiple Myeloma

Baseline characteristics by cohort

Measure	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=9 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) n=26 Participants Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Glioblastoma Multiforme (GBM) n=13 Participants Participants with GBM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Hepatocellular Carcinoma (HCC) n=53 Participants Participants with HCC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Neuroendocrine Tumor (NET) n=47 Participants Participants with NET received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Diffuse Large B-cell Lymphoma (DLBCL) n=28 Participants Participants with DLBCL received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) n=14 Participants Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Hormone Receptor Positive Breast Cancer (HRPBC) n=17 Participants Participants with HRPBC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Total n=226 Participants Total of all reporting groups
Age, Continuous	55.0 years STANDARD_DEVIATION NA • n=5 Participants	54.5 years STANDARD_DEVIATION 10.61 • n=7 Participants	53.8 years STANDARD_DEVIATION 11.57 • n=5 Participants	46.0 years STANDARD_DEVIATION 12.86 • n=4 Participants	49.9 years STANDARD_DEVIATION 11.65 • n=21 Participants	62.8 years STANDARD_DEVIATION 10.72 • n=8 Participants	55.6 years STANDARD_DEVIATION 9.46 • n=8 Participants	60.0 years STANDARD_DEVIATION 11.41 • n=24 Participants	62.6 years STANDARD_DEVIATION 9.87 • n=42 Participants	53.9 years STANDARD_DEVIATION 14.51 • n=42 Participants	60.4 years STANDARD_DEVIATION 10.00 • n=42 Participants	53.9 years STANDARD_DEVIATION 7.79 • n=42 Participants	58.2 years STANDARD_DEVIATION 11.77 • n=36 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants	5 Participants n=4 Participants	6 Participants n=21 Participants	12 Participants n=8 Participants	5 Participants n=8 Participants	10 Participants n=24 Participants	28 Participants n=42 Participants	11 Participants n=42 Participants	6 Participants n=42 Participants	17 Participants n=42 Participants	108 Participants n=36 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	4 Participants n=4 Participants	1 Participants n=21 Participants	14 Participants n=8 Participants	8 Participants n=8 Participants	43 Participants n=24 Participants	19 Participants n=42 Participants	17 Participants n=42 Participants	8 Participants n=42 Participants	0 Participants n=42 Participants	118 Participants n=36 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	2 Participants n=8 Participants	1 Participants n=8 Participants	4 Participants n=24 Participants	2 Participants n=42 Participants	4 Participants n=42 Participants	2 Participants n=42 Participants	1 Participants n=42 Participants	16 Participants n=36 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1 Participants n=5 Participants	2 Participants n=7 Participants	9 Participants n=5 Participants	9 Participants n=4 Participants	7 Participants n=21 Participants	20 Participants n=8 Participants	12 Participants n=8 Participants	44 Participants n=24 Participants	45 Participants n=42 Participants	22 Participants n=42 Participants	6 Participants n=42 Participants	11 Participants n=42 Participants	188 Participants n=36 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	4 Participants n=8 Participants	0 Participants n=8 Participants	5 Participants n=24 Participants	0 Participants n=42 Participants	2 Participants n=42 Participants	6 Participants n=42 Participants	5 Participants n=42 Participants	22 Participants n=36 Participants
Race Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	1 Participants n=21 Participants	2 Participants n=8 Participants	1 Participants n=8 Participants	10 Participants n=24 Participants	2 Participants n=42 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants	1 Participants n=42 Participants	20 Participants n=36 Participants
Race Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	5 Participants n=24 Participants	1 Participants n=42 Participants	2 Participants n=42 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants	9 Participants n=36 Participants
Race White	1 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants	7 Participants n=4 Participants	6 Participants n=21 Participants	20 Participants n=8 Participants	12 Participants n=8 Participants	31 Participants n=24 Participants	43 Participants n=42 Participants	24 Participants n=42 Participants	8 Participants n=42 Participants	10 Participants n=42 Participants	171 Participants n=36 Participants
Race Other	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	2 Participants n=24 Participants	1 Participants n=42 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants	1 Participants n=42 Participants	4 Participants n=36 Participants
Race Missing	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	4 Participants n=8 Participants	0 Participants n=8 Participants	5 Participants n=24 Participants	0 Participants n=42 Participants	2 Participants n=42 Participants	6 Participants n=42 Participants	5 Participants n=42 Participants	22 Participants n=36 Participants

PRIMARY outcome

Timeframe: From first dose up to 30 days after first dose

Population: All treated participants in Part A.

A dose-limiting toxicity was defined as: - ≥ Grade 3 (per Common Terminology Criteria for Adverse Events [CTCAE] Version 4) clinically relevant adverse event (AE) or laboratory abnormality suspected to be related to CC-223 that commenced within 30 days of first dose, except alopecia, Grade 3 rash of the acneiform or maculopapular type for < 5 days, Grade 3 diarrhea or vomiting lasting < 72 hours, repeated occurrence of Grade 3 hyperuricaemia in subjects with Grade 3 hyperuricemia at baseline, hyperglycemia, hematologic and liver function test (LFT) abnormalities due to disease progression. - Grade 2 fasting hyperglycemia lasting > 14 days or ≥ Grade 3 lasting > 4 days despite optimal medical treatment. - Hematological toxicities including febrile neutropenia, Grade 4 neutropenia or thrombocytopenia for > 7 days, or Grade 3/4 thrombocytopenia with clinically significant bleeding. - Grade 4 LTFs - AE suspected to be CC-223 related necessitating dose reduction during cycle 1.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=9 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part A: Number of Participants With Dose-limiting Toxicities	0 Participants	1 Participants	1 Participants	2 Participants	0 Participants	—	—

PRIMARY outcome

Timeframe: Cycle 1 Day 1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose

Population: All treated participants with available pharmacokinetic data in Part A.

Cmax is defined as the maximum observed concentration (in plasma), obtained directly from the observed concentration versus time data. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=8 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Maximum Observed Plasma Concentration (Cmax) of CC-223 Day -1	97.4 ng/mL Geometric Coefficient of Variation 57.5	188 ng/mL Geometric Coefficient of Variation 41.8	269 ng/mL Geometric Coefficient of Variation 65.7	319 ng/mL Geometric Coefficient of Variation 70.0	45.8 ng/mL Geometric Coefficient of Variation NA Coefficient of Variation not calculable because data were only collected for 1 participant.	—	—
Maximum Observed Plasma Concentration (Cmax) of CC-223 Day 15	92.0 ng/mL Geometric Coefficient of Variation 162.6	293 ng/mL Geometric Coefficient of Variation 38.8	417 ng/mL Geometric Coefficient of Variation 61.6	480 ng/mL Geometric Coefficient of Variation 88.9	50.8 ng/mL Geometric Coefficient of Variation NA Coefficient of Variation not calculable because data were only collected for 1 participant.	—	—

PRIMARY outcome

Timeframe: Cycle 1 Day 1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose

Population: All treated participants with available pharmacokinetic data in Part A.

Tmax is defined as the time to Cmax, obtained directly from the observed concentration versus time data. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=8 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Time to Maximum Concentration (Tmax) of CC-223 Day -1/1	1.25 Hours Interval 1.0 to 1.5	1.55 Hours Interval 1.0 to 3.2	3.00 Hours Interval 0.967 to 3.0	1.50 Hours Interval 1.0 to 5.0	1.00 Hours Interval 1.0 to 1.0	—	—
Time to Maximum Concentration (Tmax) of CC-223 Day 15	2.00 Hours Interval 1.0 to 3.0	1.28 Hours Interval 0.5 to 3.03	1.63 Hours Interval 0.5 to 8.0	1.58 Hours Interval 1.0 to 3.0	1.50 Hours Interval 1.5 to 1.5	—	—

PRIMARY outcome

Timeframe: Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose

Population: All treated participants with available pharmacokinetic data in Part A.

Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=8 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223 Day -1/Day 1	347 ng*h/mL Geometric Coefficient of Variation 60.2	1204 ng*h/mL Geometric Coefficient of Variation 37.8	1493 ng*h/mL Geometric Coefficient of Variation 54.3	2080 ng*h/mL Geometric Coefficient of Variation 100.8	318 ng*h/mL Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223 Day 15	282 ng*h/mL Geometric Coefficient of Variation 100.7	1016 ng*h/mL Geometric Coefficient of Variation 39.2	1351 ng*h/mL Geometric Coefficient of Variation 45.0	1900 ng*h/mL Geometric Coefficient of Variation 93.5	179 ng*h/mL Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—

PRIMARY outcome

Timeframe: 0 to 24 hours post-dose on Day -1 and Day 15

Population: All treated participants with available pharmacokinetic data in Part A.

AUC0-24 is defined as the area under the concentration-time curve from Time 0 to 24 hours after a dose. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=8 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223 Day 15	383 ng*h/mL Geometric Coefficient of Variation 88.8	1443 ng*h/mL Geometric Coefficient of Variation 41.4	2082 ng*h/mL Geometric Coefficient of Variation 29.3	2954 ng*h/mL Geometric Coefficient of Variation 106.2	299 ng*h/mL Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—
Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223 Day -1	379 ng*h/mL Geometric Coefficient of Variation 45.2	1144 ng*h/mL Geometric Coefficient of Variation 36.5	1497 ng*h/mL Geometric Coefficient of Variation 45.5	2031 ng*h/mL Geometric Coefficient of Variation 96.3	319 ng*h/mL Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—

PRIMARY outcome

Timeframe: Cycle 1 Day 1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose

Population: All treated participants with available pharmacokinetic data in Part A.

AUCinf is defined as the area under the concentration-time curve from Time 0 extrapolated to infinity. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. AUCinf was not assessed following multiple dosing as the blood sampling schedule on Day 15 did not allow robust assessment of the terminal elimination rate constant.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=8 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=8 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=6 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) For CC-223 Day -1/1	378 ng*h/mL Geometric Coefficient of Variation 49.7	1234 ng*h/mL Geometric Coefficient of Variation 38.9	1694 ng*h/mL Geometric Coefficient of Variation 41.8	2074 ng*h/mL Geometric Coefficient of Variation 111.4	353 ng*h/mL Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—

PRIMARY outcome

Timeframe: Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose

Population: All treated participants with available pharmacokinetic data in Part A.

Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. T1/2 was not assessed following multiple dosing as the blood sampling schedule on Day 15 did not allow robust assessment of the terminal elimination rate constant.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=8 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=8 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=6 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part A: Terminal Elimination Phase Half-Life (T1/2) of CC-223	3.35 Hours Geometric Coefficient of Variation 54.1	5.57 Hours Geometric Coefficient of Variation 38.4	4.86 Hours Geometric Coefficient of Variation 25.9	5.64 Hours Geometric Coefficient of Variation 16.7	7.68 Hours Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—

PRIMARY outcome

Timeframe: Cycle 1 Day 1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose

Population: All treated participants with available pharmacokinetic data in Part A.

CL/F is defined as the apparent total body clearance when dosed orally, calculated as Dose/AUCinf. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=8 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=8 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=6 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Apparent Total Body Clearance (CL/F) of CC-223 Day -1/1	39.7 L/h Geometric Coefficient of Variation 49.7	24.3 L/h Geometric Coefficient of Variation 38.9	26.6 L/h Geometric Coefficient of Variation 41.8	28.9 L/h Geometric Coefficient of Variation 111.4	21.2 L/h Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—
Apparent Total Body Clearance (CL/F) of CC-223 Day 15	39.2 L/h Geometric Coefficient of Variation 88.8	20.8 L/h Geometric Coefficient of Variation 41.4	21.6 L/h Geometric Coefficient of Variation 29.3	20.3 L/h Geometric Coefficient of Variation 106.2	25.1 L/h Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—

PRIMARY outcome

Timeframe: Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose

Population: All treated participants with available pharmacokinetic data in Part A.

Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. VZ/F was not assessed following multiple dosing as the blood sampling schedule on Day 15 did not allow robust assessment of the terminal elimination rate constant.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=8 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=8 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=6 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Apparent Volume of Distribution (Vz/F) of CC-223	192 L Geometric Coefficient of Variation 3.70	195 L Geometric Coefficient of Variation 36.7	186 L Geometric Coefficient of Variation 27.1	236 L Geometric Coefficient of Variation 107.5	235 L Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—

PRIMARY outcome

Timeframe: From first dose to 6 months

Population: All treated participants in Part B with GBM without progression per RECIST 1.0 at 6 months

Progression free survival rate of GBM participants at 6 months is defined as the percentage of participants without progressive disease per Evaluation Criteria in Solid Tumors (RECIST) 1.1 6 months after starting study treatment. Progressive disease is defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Outcome measures

Measure	Part A: CC-223 15 mg Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=13 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part B: Progression Free Survival (PFS) Rate at 6 Months for GBM Participants	—	—	—	—	0 Percentage of participants Lower and upper limit not reached to insufficient number of events	—	—

SECONDARY outcome

Timeframe: Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose

Population: All biomarker evaluable participants who received treatment in Part A.

Phosphorylated S6RP is a biomarker for inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Phosphorylated S6RP was measured in stimulated B cells via flow cytometry. The raw measurements were expressed as median fluorescence intensity (MFI). MFI values were normalized against calibration beads using a linear regression transformation carried out on a log-log scale and reported as equivalent reference fluorophores (ERF). The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment. Results were not available for the single subject treated in the 7.5-mg dose group and for one of the two subjects treated in the 15-mg dose group.

Outcome measures

Measure	Part A: CC-223 15 mg n=1 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=6 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=8 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells Day -1 3 hours post-dose	-19.4 Percent change Interval -19.4 to -19.4	-73.6 Percent change Interval -86.1 to -58.5	-79.8 Percent change Interval -87.5 to -34.7	-76.6 Percent change Interval -83.4 to -60.2	—	—	—
Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells Day 15 1.5 hours post-dose	174.0 Percent change Interval 174.0 to 174.0	-59.0 Percent change Interval -77.5 to -41.3	-80.5 Percent change Interval -84.6 to -80.0	-69.3 Percent change Interval -86.2 to -61.7	—	—	—

SECONDARY outcome

Timeframe: Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose

Population: All biomarker evaluable participants who received treatment in Part A.

Phosphorylated 4E-BP1 is a biomarker for inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Phosphorylated 4E-BP1 was measured in stimulated T cells via flow cytometry. The raw measurements were expressed as median fluorescence intensity (MFI). MFI values were normalized against calibration beads using a linear regression transformation carried out on a log-log scale and reported as equivalent reference fluorophores (ERF). The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment. Results were not available for the single subject treated in the 7.5-mg dose group and for one of the two subjects treated in the 15-mg dose group.

Outcome measures

Measure	Part A: CC-223 15 mg n=1 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=9 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=8 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells Day -1 3 hours post-dose	-20.7 Percent change in p4E-BP1 Interval -20.7 to -20.7	-44.0 Percent change in p4E-BP1 Interval -65.1 to -28.7	-55.7 Percent change in p4E-BP1 Interval -71.2 to -26.4	-44.3 Percent change in p4E-BP1 Interval -63.7 to -1.0	—	—	—
Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells Day 15 1.5 hours post-dose	-14.4 Percent change in p4E-BP1 Interval -14.4 to -14.4	-61.1 Percent change in p4E-BP1 Interval -92.8 to -44.5	-54.8 Percent change in p4E-BP1 Interval -61.8 to -34.4	-46.4 Percent change in p4E-BP1 Interval -69.8 to -26.3	—	—	—

SECONDARY outcome

Timeframe: Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose

Population: All biomarker evaluable participants who received treatment in Part A.

Phosphorylated AKT is a biomarker for inhibition of the mammalian target of rapamycin complex 2 (mTORC2). Phosphorylated AKT was measured in stimulated monocytes via flow cytometry. The raw measurements were expressed as median fluorescence intensity (MFI). MFI values were normalized against calibration beads using a linear regression transformation carried out on a log-log scale and reported as equivalent reference fluorophores (ERF). The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment. Results were not available for the single subject treated in the 7.5-mg dose group and for one of the two subjects treated in the 15-mg dose group.

Outcome measures

Measure	Part A: CC-223 15 mg n=1 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=9 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=8 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes Day -1 3 hours post-dose	-26.9 Percent change in pAKT Interval -26.9 to -26.9	-56.5 Percent change in pAKT Interval -72.2 to -31.7	-59.7 Percent change in pAKT Interval -74.6 to -23.0	-48.4 Percent change in pAKT Interval -53.6 to -26.7	—	—	—
Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes Day 15 1.5 hours post-dose	58.3 Percent change in pAKT Interval 58.3 to 58.3	-70.5 Percent change in pAKT Interval -81.1 to -39.6	-55.8 Percent change in pAKT Interval -70.1 to -42.0	-45.7 Percent change in pAKT Interval -56.5 to -31.6	—	—	—

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose

Population: All biomarker evaluable participants who received treatment in Part B.

Phosphorylated 4E-BP1 is a biomarker for inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Phosphorylated 4E-BP1 was measured in stimulated monocytes via flow cytometry. MFI values were determined and converted to molecules of equivalent fluorescence label (MEFL) by normalizing against calibration beads. The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment. Data is reported by T-cell subsets known as clusters of differentiation (CD).

Outcome measures

Measure	Part A: CC-223 15 mg n=44 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=34 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=15 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=6 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=10 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) n=18 Participants Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) n=3 Participants Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort Day 15, 1.5 hours post-dose - CD14+	-58.1 Percent change in p4E-BP1 Interval -91.7 to 528.1	-39.1 Percent change in p4E-BP1 Interval -78.7 to 26.0	-74.1 Percent change in p4E-BP1 Interval -94.1 to 210.2	-35.8 Percent change in p4E-BP1 Interval -70.0 to 154.7	-61.3 Percent change in p4E-BP1 Interval -61.3 to -61.3	—	—
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort Day 15, 1.5 hours post-dose - CD91+	-24.7 Percent change in p4E-BP1 Interval -39.7 to 16.8	—	-6.9 Percent change in p4E-BP1 Interval -6.9 to -6.9	—	-22.4 Percent change in p4E-BP1 Interval -53.7 to 151.3	-24.8 Percent change in p4E-BP1 Interval -38.4 to 77.5	19.6 Percent change in p4E-BP1 Interval -7.9 to 47.2
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort Day 1,1.5 hours post-dose - CD19+	-44.3 Percent change in p4E-BP1 Interval -100.0 to 266.7	-39.4 Percent change in p4E-BP1 Interval -93.7 to 34.3	-44.5 Percent change in p4E-BP1 Interval -71.9 to -36.0	-44.8 Percent change in p4E-BP1 Interval -88.3 to 58.2	-15.3 Percent change in p4E-BP1 Interval -15.3 to -15.3	—	—
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort Day 15, 1.5 hours post-dose - CD19+	-48.0 Percent change in p4E-BP1 Interval -91.0 to 844.4	-51.1 Percent change in p4E-BP1 Interval -86.1 to 18.1	-27.3 Percent change in p4E-BP1 Interval -32.7 to -5.0	-12.0 Percent change in p4E-BP1 Interval -77.2 to 229.7	-0.3 Percent change in p4E-BP1 Interval -0.3 to -0.3	—	—
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort Day 1,1.5 hours post-dose - CD91+	-20.0 Percent change in p4E-BP1 Interval -58.1 to 8.3	-49.4 Percent change in p4E-BP1 Interval -63.7 to -13.2	-24.5 Percent change in p4E-BP1 Interval -32.4 to -16.6	-43.0 Percent change in p4E-BP1 Interval -43.0 to -43.0	-39.4 Percent change in p4E-BP1 Interval -69.2 to 20.1	-24.9 Percent change in p4E-BP1 Interval -57.6 to 28.1	-51.4 Percent change in p4E-BP1 Interval -64.2 to -25.1
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort Day 1,1.5 hours post-dose - CD3+	-23.5 Percent change in p4E-BP1 Interval -100.0 to 157.1	-50.0 Percent change in p4E-BP1 Interval -93.6 to 114.3	-61.6 Percent change in p4E-BP1 Interval -100.0 to 19.8	-63.3 Percent change in p4E-BP1 Interval -93.8 to 122.5	—	—	—
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort Day 15, 1.5 hours post-dose - CD3+	-38.9 Percent change in p4E-BP1 Interval -100.0 to 445.8	-51.8 Percent change in p4E-BP1 Interval -98.9 to 105.0	-58.7 Percent change in p4E-BP1 Interval -100.0 to 42.1	-58.4 Percent change in p4E-BP1 Interval -100.0 to 79.3	—	—	—
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort Day 1,1.5 hours post-dose - CD14+	-17.3 Percent change in p4E-BP1 Interval -87.0 to 66.6	-11.7 Percent change in p4E-BP1 Interval -85.3 to 46.3	-44.5 Percent change in p4E-BP1 Interval -85.1 to 438.9	-49.4 Percent change in p4E-BP1 Interval -68.4 to 31.7	-28.7 Percent change in p4E-BP1 Interval -28.7 to -28.7	—	—

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose

Population: All biomarker evaluable participants who received treatment in Part B.

Phosphorylated 4E-BP1 is a biomarker for inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Phosphorylated 4E-BP1 was measured in stimulated monocytes via flow cytometry. MFI values were determined and converted to molecules of equivalent fluorescence label (MEFL) by normalizing against calibration beads. The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment. Data is reported by T-cell subsets known as clusters of differentiation (CD).

Outcome measures

Measure	Part A: CC-223 15 mg n=6 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=21 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=13 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=20 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose Day 15 1.5 hours post-dose - CD3+	-52.8 Percent change in p4E-BP1 Interval -62.6 to 52.4	-39.7 Percent change in p4E-BP1 Interval -95.7 to 33.8	-70.2 Percent change in p4E-BP1 Interval -98.9 to 105.0	—	-34.0 Percent change in p4E-BP1 Interval -100.0 to 445.8	—	—
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose Day 1 1.5 hours post-dose - CD3+	20.0 Percent change in p4E-BP1 Interval -69.1 to 157.1	-40.4 Percent change in p4E-BP1 Interval -93.6 to 11.6	-70.6 Percent change in p4E-BP1 Interval -90.0 to 114.3	—	-28.3 Percent change in p4E-BP1 Interval -100.0 to 127.6	—	—
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose Day 1 1.5 hours post-dose - CD14+	7.0 Percent change in p4E-BP1 Interval -50.6 to 66.6	-8.7 Percent change in p4E-BP1 Interval -54.7 to 25.8	-36.6 Percent change in p4E-BP1 Interval -85.3 to 46.3	—	-22.1 Percent change in p4E-BP1 Interval -87.0 to 28.9	—	—
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose Day 15 1.5 hours post-dose - CD14+	-28.4 Percent change in p4E-BP1 Interval -67.5 to 111.6	-25.6 Percent change in p4E-BP1 Interval -78.7 to 26.0	-47.4 Percent change in p4E-BP1 Interval -68.3 to 23.2	—	-58.1 Percent change in p4E-BP1 Interval -91.7 to 528.1	—	—

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose

Population: All biomarker evaluable participants who received treatment in Part B.

Phosphorylated AKT is a biomarker for inhibition of the mammalian target of rapamycin complex 2 (mTORC2). Phosphorylated AKT was measured in stimulated monocytes via flow cytometry. MFI values were determined and converted to molecules of equivalent fluorescence label (MEFL) by normalizing against calibration beads. The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment.

Outcome measures

Measure	Part A: CC-223 15 mg n=8 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=16 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=4 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=2 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=16 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) n=4 Participants Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) n=1 Participants Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort Day 15 1.5 hours post-dose	-34.1 Percent change in pAKT Interval -89.8 to 48.6	-84.1 Percent change in pAKT Interval -87.7 to -19.5	-52.2 Percent change in pAKT Interval -52.2 to -52.2	-88.6 Percent change in pAKT Interval -88.6 to -88.6	-76.1 Percent change in pAKT Interval -93.0 to -27.5	-52.9 Percent change in pAKT Interval -77.5 to -28.2	—
Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort Day 1 1.5 hours post-dose	-28.0 Percent change in pAKT Interval -73.0 to 130.1	-55.5 Percent change in pAKT Interval -86.2 to 27.1	-70.3 Percent change in pAKT Interval -83.7 to -51.2	-54.3 Percent change in pAKT Interval -89.0 to -19.6	-68.1 Percent change in pAKT Interval -86.5 to 43.9	-78.8 Percent change in pAKT Interval -86.2 to -27.1	-53.8 Percent change in pAKT Interval -53.8 to -53.8

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose

Population: All biomarker evaluable participants who received treatment in Part B.

Phosphorylated AKT is a biomarker for inhibition of the mammalian target of rapamycin complex 2 (mTORC2). Phosphorylated AKT was measured in stimulated monocytes via flow cytometry. MFI values were determined and converted to molecules of equivalent fluorescence label (MEFL) by normalizing against calibration beads. The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment.

Outcome measures

Measure	Part A: CC-223 15 mg n=16 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=4 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part B: Percent Change From Baseline in Levels of pAKT in Monocytes in the HCC and NET Cohorts by Dose Day 1 1.5 hours post-dose	-55.5 Percent change in pAKT Interval -86.2 to 27.1	—	-70.3 Percent change in pAKT Interval -83.7 to -51.2	—	—	—	—
Part B: Percent Change From Baseline in Levels of pAKT in Monocytes in the HCC and NET Cohorts by Dose Day 15 1.5 hours post-dose	-84.1 Percent change in pAKT Interval -87.7 to -19.5	—	-52.2 Percent change in pAKT Interval -52.2 to -52.2	—	—	—	—

SECONDARY outcome

Timeframe: Up to Cycle 1 Day 15 3 hours post dose

Population: All biomarker evaluable participants who received treatment in Part B.

Tumor tissue biopsies were performed at Baseline and on Day 15 3 hours post dose. Levels of pS6RP were quantified using immunohistochemical (IHC) methods.

Outcome measures

Measure	Part A: CC-223 15 mg n=1 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=3 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=1 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=9 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=6 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) n=3 Participants Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part B: Percent Change From Baseline in pS6RP Levels in Tumor Tissue by Tumor Type	-36 Percent change in pS6RP Full Range -36 • Interval -36.0 to -36.0	-19 Percent change in pS6RP Full Range -37 • Interval -37.0 to 24.0	-30 Percent change in pS6RP Full Range -30 • Interval -30.0 to -30.0	-21 Percent change in pS6RP Full Range -43 • Interval -43.0 to 12.0	22 Percent change in pS6RP Full Range -37 • Interval -37.0 to 66.0	—	-15 Percent change in pS6RP Full Range -17 • Interval -17.0 to 6.0

SECONDARY outcome

Timeframe: From first dose up to tumor response (approximately 11 months)

Population: Participants who received treatment in Part A

Tumor response was based on Investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for solid tumors (NSCLC, HCC, NET, and HRPBC), and the International Working Group Criteria (IWC) for DLBCL. Overall Response Rate is defined as the percentage of participants with a best overall response of complete response or partial response. Complete response is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. In Part A, participants with MM and participants with GBM were not evaluated for tumor response.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=9 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part A: Overall Response Rate	0 Percentage of participants Lower and upper limit not calculated due to insufficient number of events	11.1 Percentage of participants Interval 0.6 to 42.9	0 Percentage of participants Lower and upper limit not calculated due to insufficient number of events	0 Percentage of participants Lower and upper limit not calculated due to insufficient number of events	0 Percentage of participants	—	—

SECONDARY outcome

Timeframe: From first dose up to tumor response (approximately 36 months)

Population: Participants who received treatment in Part B reported by tumor cohort

Tumor response was based on Investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for solid tumors (NSCLC, HCC, NET, and HRPBC), International Working Group Criteria (IWC) for DLBCL, and the International Myeloma Working Group (IMWG) criteria for MM. For GBM, Responses Assessment for Neuro-Oncology Working Group (RANO) criteria were used for tumor response, using the post resection MRI scan as the baseline. Overall Response Rate is defined as the percentage of participants with a best overall response of complete response or partial response. Complete response is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Outcome measures

Measure	Part A: CC-223 15 mg n=13 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=53 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=47 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=28 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=26 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) n=14 Participants Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) n=17 Participants Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Part B: Overall Response Rate	0 Percentage of participants Lower and upper limit not calculated due to insufficient number of events	5.7 Percentage of participants Interval 1.2 to 15.7	6.4 Percentage of participants Interval 1.3 to 17.5	10.7 Percentage of participants Interval 2.3 to 28.2	3.8 Percentage of participants Interval 0.1 to 19.6	0 Percentage of participants Lower and upper limit not calculated due to insufficient number of events	11.8 Percentage of participants Interval 1.5 to 36.4

SECONDARY outcome

Timeframe: Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose

Population: All treated participants with available pharmacokinetic data in Part A.

Cmax is defined as the maximum observed concentration (in plasma), obtained directly from the observed concentration versus time data. Plasma metabolite M1 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 10.0 ng/mL.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=8 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Maximum Observed Concentration (Cmax) of Metabolite M1 Day -1	284 ng/mL Geometric Coefficient of Variation 64.6	729 ng/mL Geometric Coefficient of Variation 40.3	1002 ng/mL Geometric Coefficient of Variation 37.2	1174 ng/mL Geometric Coefficient of Variation 86.0	143 ng/mL Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—
Maximum Observed Concentration (Cmax) of Metabolite M1 Day 15	357 ng/mL Geometric Coefficient of Variation 139.8	1681 ng/mL Geometric Coefficient of Variation 34.5	2061 ng/mL Geometric Coefficient of Variation 23.1	1946 ng/mL Geometric Coefficient of Variation 78.9	363 ng/mL Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—

SECONDARY outcome

Timeframe: Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose

Population: All treated participants with available pharmacokinetic data in Part A.

Tmax is defined as the time to Cmax, obtained directly from the observed concentration versus time data. Plasma metabolite M1 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 10.0 ng/mL.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=8 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Time to Maximum Concentration (Tmax) of Metabolite M1 Day 1	2.28 Hours Interval 1.5 to 3.05	6.51 Hours Interval 1.5 to 8.0	5.00 Hours Interval 1.6 to 8.0	5.00 Hours Interval 1.67 to 8.0	8.00 Hours Interval 8.0 to 8.0	—	—
Time to Maximum Concentration (Tmax) of Metabolite M1 Day 15	3.25 Hours Interval 1.5 to 5.0	1.58 Hours Interval 1.0 to 3.03	1.71 Hours Interval 0.0 to 3.2	3.00 Hours Interval 0.0 to 5.0	1.50 Hours Interval 1.5 to 1.5	—	—

SECONDARY outcome

Timeframe: Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose

Population: All treated participants with available pharmacokinetic data in Part A.

AUCt is defined as the area under the concentration-time curve from Time 0 to the time of the last quantifiable concentration. Plasma metabolite M1 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 10.0 ng/mL.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=8 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1 Day 1	3788 ng*h/mL Geometric Coefficient of Variation 121.2	18964 ng*h/mL Geometric Coefficient of Variation 45.1	19938 ng*h/mL Geometric Coefficient of Variation 30.1	23702 ng*h/mL Geometric Coefficient of Variation 98.1	4583 ng*h/mL Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1 Day 15	4388 ng*h/mL Geometric Coefficient of Variation 133.8	27389 ng*h/mL Geometric Coefficient of Variation 48.5	30823 ng*h/mL Geometric Coefficient of Variation 38.3	33070 ng*h/mL Geometric Coefficient of Variation 101.6	6401 ng*h/mL Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—

SECONDARY outcome

Timeframe: 0 to 24 hours post-dose on Day -1 and Day 15

Population: All treated participants with available pharmacokinetic data in Part A.

AUC0-24 is defined as the area under the concentration-time curve from Time 0 to 24 hours after a dose. Plasma metabolite M1 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 10.0 ng/mL.

Outcome measures

Measure	Part A: CC-223 15 mg n=2 Participants Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=8 Participants Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 Participants Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 Participants Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 7.5 mg n=1 Participants Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1 Day 1	3207 ng*h/mL Geometric Coefficient of Variation 82.5	12328 ng*h/mL Geometric Coefficient of Variation 39.4	14107 ng*h/mL Geometric Coefficient of Variation 26.9	16926 ng*h/mL Geometric Coefficient of Variation 89.2	2712 ng*h/mL Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—
Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1 Day 15	4388 ng*h/mL Geometric Coefficient of Variation 133.8	27389 ng*h/mL Geometric Coefficient of Variation 48.5	30823 ng*h/mL Geometric Coefficient of Variation 38.3	33070 ng*h/mL Geometric Coefficient of Variation 101.6	6401 ng*h/mL Geometric Coefficient of Variation NA Insufficient data values to calculate coefficient of variation.	—	—

Adverse Events

Part A: CC-223 7.5 mg

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Part A: CC-223 15 mg

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Part A: CC-223 30 mg

Serious events: 4 serious events

Other events: 8 other events

Deaths: 2 deaths

Part A: CC-223 45 mg

Serious events: 4 serious events

Other events: 9 other events

Deaths: 3 deaths

Part A: CC-223 60 mg

Serious events: 2 serious events

Other events: 7 other events

Deaths: 1 deaths

Part B: Non-small Cell Lung Cancer (NSCLC)

Serious events: 15 serious events

Other events: 26 other events

Deaths: 10 deaths

Part B: Glioblastoma Multiforme (GBM)

Serious events: 6 serious events

Other events: 13 other events

Deaths: 3 deaths

Part B: Hepatocellular Carcinoma (HCC)

Serious events: 29 serious events

Other events: 53 other events

Deaths: 24 deaths

Part B: Neuroendocrine Tumor (NET)

Serious events: 23 serious events

Other events: 47 other events

Deaths: 2 deaths

Part B: Diffuse Large B-cell Lymphoma (DLBCL)

Serious events: 17 serious events

Other events: 28 other events

Deaths: 5 deaths

Part B: Multiple Myeloma (MM)

Serious events: 6 serious events

Other events: 14 other events

Deaths: 2 deaths

Part B: Hormone Receptor Positive Breast Cancer (HRPBC)

Serious events: 11 serious events

Other events: 17 other events

Deaths: 4 deaths

Serious adverse events

Measure	Part A: CC-223 7.5 mg n=1 participants at risk Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 15 mg n=2 participants at risk Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=9 participants at risk Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 participants at risk Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 participants at risk Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) n=26 participants at risk Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Glioblastoma Multiforme (GBM) n=13 participants at risk Participants with GBM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Hepatocellular Carcinoma (HCC) n=53 participants at risk Participants with HCC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Neuroendocrine Tumor (NET) n=47 participants at risk Participants with NET received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Diffuse Large B-cell Lymphoma (DLBCL) n=28 participants at risk Participants with DLBCL received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) n=14 participants at risk Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Hormone Receptor Positive Breast Cancer (HRPBC) n=17 participants at risk Participants with HRPBC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Blood and lymphatic system disorders Lymph node pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Blood and lymphatic system disorders Neutropenia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Atrial thrombosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Left ventricular dysfunction	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Myocardial ischaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Pericardial effusion	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Supraventricular tachycardia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Abdominal pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	4.3% 2/47 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Aphthous ulcer	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Ascites	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Autoimmune pancreatitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Colonic obstruction	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Crohn's disease	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Diarrhoea	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Dysphagia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Nausea	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Pancreatitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Peptic ulcer	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Retroperitoneal haemorrhage	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	4.3% 2/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Vomiting	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	4.3% 2/47 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Asthenia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Fatigue	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders General physical health deterioration	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Impaired healing	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Mucosal inflammation	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Non-cardiac chest pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Pyrexia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 2/53 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Hepatobiliary disorders Bile duct stenosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Hepatobiliary disorders Cholecystitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Hepatobiliary disorders Cholelithiasis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Hepatobiliary disorders Hepatocellular injury	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Immune system disorders Hypersensitivity	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Abdominal sepsis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Abscess	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Brain abscess	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Campylobacter infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Cellulitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Clostridium difficile infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Cystitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Hepatitis B	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Herpes simplex pneumonia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Incision site infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Lower respiratory tract infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Lung infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Meningitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Perihepatic abscess	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Pneumococcal sepsis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Pneumonia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	4.3% 2/47 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Sepsis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Septic shock	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Urinary tract infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	4.3% 2/47 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Urosepsis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Accidental overdose	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Fall	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Overdose	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Ammonia increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Blood creatinine increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Dehydration	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 2/53 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	4.3% 2/47 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hypophosphataemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Metabolic acidosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Myositis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer metastatic	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Encephalopathy	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Hepatic encephalopathy	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Peripheral motor neuropathy	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Spinal cord compression	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Syncope	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Confusional state	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Delusional disorder, persecutory type	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Mania	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Mental status changes	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Acute kidney injury	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Haematuria	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Renal failure	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Renal tubular necrosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Alveolitis allergic	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Dermatitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 2/53 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Dermatitis acneiform	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Rash	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Rash macular	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.6% 1/28 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Rash maculo-papular	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Vascular disorders Deep vein thrombosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	1.9% 1/53 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Vascular disorders Hypotension	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 2/53 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	2.1% 1/47 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Vascular disorders Jugular vein thrombosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	3.8% 1/26 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Vascular disorders Thrombosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.

Other adverse events

Measure	Part A: CC-223 7.5 mg n=1 participants at risk Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 15 mg n=2 participants at risk Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 30 mg n=9 participants at risk Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 45 mg n=9 participants at risk Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part A: CC-223 60 mg n=7 participants at risk Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Non-small Cell Lung Cancer (NSCLC) n=26 participants at risk Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Glioblastoma Multiforme (GBM) n=13 participants at risk Participants with GBM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Hepatocellular Carcinoma (HCC) n=53 participants at risk Participants with HCC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Neuroendocrine Tumor (NET) n=47 participants at risk Participants with NET received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Diffuse Large B-cell Lymphoma (DLBCL) n=28 participants at risk Participants with DLBCL received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Multiple Myeloma (MM) n=14 participants at risk Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.	Part B: Hormone Receptor Positive Breast Cancer (HRPBC) n=17 participants at risk Participants with HRPBC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator.
Nervous system disorders Hemiparesis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	38.5% 5/13 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Hydrocephalus	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Hypoaesthesia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Incoherent	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Lethargy	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Loss of consciousness	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Memory impairment	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Myoclonus	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Neuropathy peripheral	100.0% 1/1 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	8.5% 4/47 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.7% 3/28 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Paraesthesia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Peripheral sensory neuropathy	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Presyncope	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Quadrantanopia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Restless legs syndrome	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Seizure	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Sensory loss	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Somnolence	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Speech disorder	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Syncope	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 2/7 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	8.5% 4/47 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Tremor	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 2/7 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Upper motor neurone lesion	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Visual field defect	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	30.8% 4/13 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders White matter lesion	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Affect lability	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Affective disorder	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Aggression	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Agitation	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.1% 3/13 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Anhedonia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Anxiety	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.7% 3/28 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Confusional state	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.1% 3/13 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Depressed mood	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Depression	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.4% 3/14 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Disorientation	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Hallucination	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Insomnia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	13.2% 7/53 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Mania	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Mental status changes	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Nervousness	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Persistent depressive disorder	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Psychotic disorder	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Psychiatric disorders Substance-induced psychotic disorder	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Acute kidney injury	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Dysuria	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.6% 5/47 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Glycosuria	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Hypertonic bladder	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Micturition urgency	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Nephropathy	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Nocturia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Oliguria	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Pollakiuria	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	8.5% 4/47 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Proteinuria	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	13.2% 7/53 • Number of events 15 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.6% 5/47 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Renal failure	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Renal impairment	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Renal and urinary disorders Urinary incontinence	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	44.4% 4/9 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 2/7 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	19.2% 5/26 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.1% 8/53 • Number of events 11 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	19.1% 9/47 • Number of events 12 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Dysphonia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	33.3% 3/9 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 2/7 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	57.7% 15/26 • Number of events 29 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	18.9% 10/53 • Number of events 13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.3% 10/47 • Number of events 15 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.7% 3/28 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	41.2% 7/17 • Number of events 9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	35.7% 5/14 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Haemoptysis	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Hiccups	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Laryngeal haemorrhage	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Nasal inflammation	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Paranasal sinus hypersecretion	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.6% 5/47 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Productive cough	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 4/26 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Pulmonary congestion	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Sputum discoloured	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Throat irritation	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Upper-airway cough syndrome	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Decubitus ulcer	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Dermatitis acneiform	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	26.9% 7/26 • Number of events 9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.1% 8/53 • Number of events 13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.0% 8/47 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.5% 4/17 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Eczema	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Erythema	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	9.4% 5/53 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Hyperkeratosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Nail disorder	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Night sweats	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	9.4% 5/53 • Number of events 11 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	34.6% 9/26 • Number of events 21 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	34.0% 18/53 • Number of events 41 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	44.7% 21/47 • Number of events 47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.9% 5/28 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	35.3% 6/17 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Psoriasis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Purpura	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Rash	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	42.9% 3/7 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	30.8% 8/26 • Number of events 13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	30.8% 4/13 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.6% 12/53 • Number of events 18 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	38.3% 18/47 • Number of events 39 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.9% 5/28 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.4% 3/14 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.5% 4/17 • Number of events 19 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Rash erythematous	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	8.5% 4/47 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Rash generalised	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Rash macular	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 4/26 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.9% 7/47 • Number of events 26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Rash maculo-papular	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	13.2% 7/53 • Number of events 22 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	25.5% 12/47 • Number of events 22 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Rash papular	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Rash pruritic	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 2/7 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Skin exfoliation	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Skin lesion	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Skin plaque	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Skin and subcutaneous tissue disorders Urticaria	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Vascular disorders Deep vein thrombosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Vascular disorders Flushing	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	12.8% 6/47 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Vascular disorders Haematoma	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Vascular disorders Hypertension	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 15 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Vascular disorders Hypotension	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	9.4% 5/53 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	8.5% 4/47 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Blood and lymphatic system disorders Anaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	30.8% 8/26 • Number of events 12 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	9.4% 5/53 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 8/28 • Number of events 9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 7/14 • Number of events 24 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	29.4% 5/17 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Blood and lymphatic system disorders Eosinophilia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Blood and lymphatic system disorders Iron deficiency anaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Blood and lymphatic system disorders Leukocytosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Blood and lymphatic system disorders Leukopenia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.1% 3/13 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Blood and lymphatic system disorders Lymphopenia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Blood and lymphatic system disorders Neutropenia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.1% 3/13 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.4% 6/28 • Number of events 12 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 4/14 • Number of events 18 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 4/26 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	30.2% 16/53 • Number of events 30 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.6% 5/47 • Number of events 14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	39.3% 11/28 • Number of events 23 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 7/14 • Number of events 29 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	35.3% 6/17 • Number of events 9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Angina pectoris	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Atrial fibrillation	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Cardiomyopathy	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Palpitations	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Pericardial effusion	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Tachycardia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Ventricular arrhythmia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Ventricular extrasystoles	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Cardiac disorders Ventricular tachycardia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Ear and labyrinth disorders Cerumen impaction	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Ear and labyrinth disorders Deafness	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Ear and labyrinth disorders Vertigo	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Endocrine disorders Adrenal insufficiency	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Endocrine disorders Goitre	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Endocrine disorders Hyperthyroidism	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Eye disorders Blindness unilateral	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Eye disorders Eye haemorrhage	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Eye disorders Eye pruritus	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Eye disorders Eyelid oedema	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Eye disorders Periorbital oedema	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Eye disorders Scintillating scotoma	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Eye disorders Vision blurred	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	9.4% 5/53 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Eye disorders Visual acuity reduced	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Eye disorders Visual impairment	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Abdominal discomfort	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Abdominal distension	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	9.4% 5/53 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	8.5% 4/47 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Abdominal hernia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Abdominal pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 2/7 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	26.4% 14/53 • Number of events 20 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	31.9% 15/47 • Number of events 24 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.9% 5/28 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Abdominal pain upper	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	9.4% 5/53 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.9% 7/47 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Abdominal rigidity	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Aphthous ulcer	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 4/14 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Ascites	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.6% 5/47 • Number of events 9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Constipation	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 2/7 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	34.6% 9/26 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.6% 12/53 • Number of events 13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	19.1% 9/47 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 8/28 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.4% 3/14 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	29.4% 5/17 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Diarrhoea	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	44.4% 4/9 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	55.6% 5/9 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	71.4% 5/7 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	61.5% 16/26 • Number of events 41 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	38.5% 5/13 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	60.4% 32/53 • Number of events 55 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	76.6% 36/47 • Number of events 138 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	60.7% 17/28 • Number of events 29 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 7/14 • Number of events 9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	64.7% 11/17 • Number of events 21 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Dry mouth	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	19.2% 5/26 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	19.1% 9/47 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 4/28 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.4% 3/14 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Dyspepsia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Dysphagia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	19.2% 5/26 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Flatulence	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.6% 5/47 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.6% 5/47 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Haematochezia	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Haemorrhoids	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.9% 7/47 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Lip dry	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Mouth haemorrhage	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Mouth ulceration	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Nausea	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	44.4% 4/9 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	66.7% 6/9 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	42.9% 3/7 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	61.5% 16/26 • Number of events 28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	69.2% 9/13 • Number of events 13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.9% 27/53 • Number of events 40 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	46.8% 22/47 • Number of events 34 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	46.4% 13/28 • Number of events 16 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 7/14 • Number of events 12 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	70.6% 12/17 • Number of events 21 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Odynophagia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Oesophagitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Oral pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Proctalgia	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	12.8% 6/47 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Retching	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Stomatitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 13/26 • Number of events 20 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.1% 3/13 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.3% 15/53 • Number of events 30 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	53.2% 25/47 • Number of events 52 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.9% 5/28 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	64.3% 9/14 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	47.1% 8/17 • Number of events 16 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Toothache	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Gastrointestinal disorders Vomiting	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	33.3% 3/9 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	85.7% 6/7 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 13/26 • Number of events 27 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.3% 15/53 • Number of events 21 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.4% 11/47 • Number of events 14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	32.1% 9/28 • Number of events 11 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	57.1% 8/14 • Number of events 11 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	47.1% 8/17 • Number of events 13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Asthenia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	100.0% 2/2 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	33.3% 3/9 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	42.9% 3/7 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	57.7% 15/26 • Number of events 37 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	26.4% 14/53 • Number of events 23 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	38.3% 18/47 • Number of events 31 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	25.0% 7/28 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	57.1% 8/14 • Number of events 13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	29.4% 5/17 • Number of events 14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Chest discomfort	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Chest pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Chills	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	19.2% 5/26 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.3% 6/53 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.6% 5/47 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Discomfort	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Face oedema	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Fatigue	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	44.4% 4/9 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	66.7% 6/9 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	100.0% 7/7 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	65.4% 17/26 • Number of events 38 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	30.8% 4/13 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	60.4% 32/53 • Number of events 63 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	70.2% 33/47 • Number of events 68 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	39.3% 11/28 • Number of events 17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	47.1% 8/17 • Number of events 25 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Feeling cold	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Feeling jittery	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Gait disturbance	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Influenza like illness	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 2/7 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Malaise	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.3% 10/47 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Medical device pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Mucosal inflammation	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	33.3% 3/9 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	71.4% 5/7 • Number of events 9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	13.2% 7/53 • Number of events 11 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	12.8% 6/47 • Number of events 12 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 4/28 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.5% 4/17 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Non-cardiac chest pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	9.4% 5/53 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.6% 5/47 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Oedema	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Oedema peripheral	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	33.3% 3/9 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	19.2% 5/26 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	20.8% 11/53 • Number of events 14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	29.8% 14/47 • Number of events 30 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Peripheral swelling	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Pyrexia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	33.3% 3/9 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	57.1% 4/7 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	19.2% 5/26 • Number of events 9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	30.8% 4/13 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	24.5% 13/53 • Number of events 18 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.0% 8/47 • Number of events 14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.7% 3/28 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Thirst decreased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
General disorders Xerosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Hepatobiliary disorders Hyperbilirubinaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.3% 6/53 • Number of events 11 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Immune system disorders Drug hypersensitivity	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Immune system disorders Hypersensitivity	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Angular cheilitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Candida infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Cellulitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Conjunctivitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Cystitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Ear infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Escherichia urinary tract infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Eyelid infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Folliculitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Fungal infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Fungal skin infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Incision site infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Influenza	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Klebsiella infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Lower respiratory tract infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Oral fungal infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Paronychia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Perineal abscess	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Pharyngitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Pneumonia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Rhinitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Sinusitis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Skin infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Tooth abscess	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Tooth infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Upper respiratory tract infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.9% 7/47 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.7% 3/28 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Infections and infestations Urinary tract infection	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	13.2% 7/53 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	19.1% 9/47 • Number of events 16 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Excoriation	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Fall	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.1% 3/13 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	8.5% 4/47 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Incision site pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Overdose	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Post procedural haematoma	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Post procedural swelling	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Procedural pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Scar	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Traumatic fracture	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Wound complication	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Injury, poisoning and procedural complications Wound dehiscence	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Alanine aminotransferase increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	30.2% 16/53 • Number of events 22 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Ammonia increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Amylase increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Aspartate aminotransferase increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	43.4% 23/53 • Number of events 46 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.6% 5/47 • Number of events 9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Blood alkaline phosphatase increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.6% 12/53 • Number of events 23 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Blood bilirubin increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.3% 6/53 • Number of events 12 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Blood cholesterol increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Blood creatine phosphokinase increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.4% 3/14 • Number of events 11 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Blood creatinine increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	34.6% 9/26 • Number of events 22 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.6% 12/53 • Number of events 35 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	25.5% 12/47 • Number of events 22 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.9% 5/28 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	42.9% 6/14 • Number of events 12 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Blood lactate dehydrogenase increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Blood thyroid stimulating hormone decreased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Blood thyroid stimulating hormone increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Blood urea increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Breath sounds abnormal	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Ejection fraction decreased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Escherichia test positive	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Gamma-glutamyltransferase increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Glycosylated haemoglobin increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 2/7 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Lipase increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Lymphocyte count decreased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Neutrophil count decreased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Platelet count decreased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Pulse pressure increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Tandem gait test abnormal	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Thyroxine free increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Weight decreased	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	34.6% 9/26 • Number of events 12 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	32.1% 17/53 • Number of events 24 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.9% 7/47 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.9% 5/28 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.4% 3/14 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.5% 4/17 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations Weight increased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Investigations White blood cell count decreased	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Cell death	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Decreased appetite	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	44.4% 4/9 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	44.4% 4/9 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 2/7 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	73.1% 19/26 • Number of events 34 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.1% 3/13 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	64.2% 34/53 • Number of events 52 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	44.7% 21/47 • Number of events 33 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	53.6% 15/28 • Number of events 22 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	42.9% 6/14 • Number of events 11 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	64.7% 11/17 • Number of events 22 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Dehydration	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	38.5% 10/26 • Number of events 11 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	24.5% 13/53 • Number of events 18 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	29.8% 14/47 • Number of events 30 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.5% 4/17 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Fluid retention	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hypercholesterolaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	44.4% 4/9 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	44.4% 4/9 • Number of events 11 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	42.9% 3/7 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	53.8% 14/26 • Number of events 37 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.1% 3/13 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	60.4% 32/53 • Number of events 75 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	31.9% 15/47 • Number of events 38 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	35.7% 10/28 • Number of events 22 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	57.1% 8/14 • Number of events 16 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	41.2% 7/17 • Number of events 20 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hyperlipasaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hyperphagia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hypertriglyceridaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hypoalbuminaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hypocalcaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	9.4% 5/53 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.4% 3/14 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.1% 6/26 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.1% 8/53 • Number of events 12 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.4% 11/47 • Number of events 18 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	35.7% 10/28 • Number of events 16 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hypomagnesaemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	9.4% 5/53 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.7% 3/28 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	29.4% 5/17 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	13.2% 7/53 • Number of events 16 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Hypophosphataemia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	26.9% 7/26 • Number of events 12 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	20.8% 11/53 • Number of events 28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.9% 5/28 • Number of events 9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.6% 3/17 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Malnutrition	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Metabolic acidosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Metabolism and nutrition disorders Metabolic alkalosis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 2/7 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	12.8% 6/47 • Number of events 11 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	19.2% 5/26 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.5% 4/53 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.3% 10/47 • Number of events 12 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 4/28 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	28.6% 4/14 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Flank pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Joint stiffness	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Joint swelling	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Muscle atrophy	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.6% 5/47 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 2/14 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Muscle twitching	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	8.5% 4/47 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 2/26 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.7% 3/53 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	6.4% 3/47 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 2/28 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.6% 5/47 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.7% 3/28 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.5% 4/17 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Ageusia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Aphasia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	15.4% 2/13 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Ataxia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Cerebral atrophy	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Cognitive disorder	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Convulsion	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Coordination abnormal	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Dizziness	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.1% 6/26 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	23.1% 3/13 • Number of events 4 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	13.2% 7/53 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	27.7% 13/47 • Number of events 17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	10.7% 3/28 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Dysarthria	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Dysgeusia	100.0% 1/1 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	50.0% 1/2 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	22.2% 2/9 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.5% 3/26 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	20.8% 11/53 • Number of events 14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.0% 8/47 • Number of events 13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.1% 1/14 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.8% 2/17 • Number of events 2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Dystonia	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/13 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	5.9% 1/17 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Facial paralysis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Facial paresis	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Head discomfort	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/9 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/26 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	7.7% 1/13 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/53 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/47 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/28 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/14 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/17 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.
Nervous system disorders Headache	0.00% 0/1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	0.00% 0/2 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	11.1% 1/9 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	14.3% 1/7 • Number of events 1 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	19.2% 5/26 • Number of events 6 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	38.5% 5/13 • Number of events 10 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	20.8% 11/53 • Number of events 11 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	17.0% 8/47 • Number of events 8 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.4% 6/28 • Number of events 7 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	21.4% 3/14 • Number of events 3 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.	29.4% 5/17 • Number of events 5 • All-Cause Mortality: From first dose through the course of the trial (up to approximately 6 years). Part A SAEs and AEs: From first dose to 100 days post last dose (up to approximately 14 months). Part B SAEs and AEs: From first dose to 100 days post last dose (up to approximately 49 months). Although the protocol stated Part B participants would begin treatment at the MTD determined by Part A (45 mg), the conduct of Part B permitted participants to stay in the study even though they had many dose reductions and dosing interruptions. Dosing/exposure for participants varied greatly and there were few participants which remained at any given dose for most of the study. Due to this, there was no analysis of Part B data available according to dose.

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Phone: Please email

Email: Clinical.Trails@bms.com

Results disclosure agreements

• Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
• Publication restrictions are in place

Restriction type: OTHER