Trial Outcomes & Findings for Entospletinib and Obinutuzumab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma (NCT NCT03010358)

Last Updated: 2023-08-08

Results Overview

The dose of obinutuzumab remains fixed in standard doses while the dose of entospletinib will be escalated. The starting dose of entospletinib will be 200 mg (twice-daily) and escalated to the second dose level 400 mg (twice-daily). MTD is the dose associated with a total of 6 patients treated with less than 2 dose limiting toxicities (DLT), or a total of 3 patients treated with less than 1 DLT. DLT is defined as 1) grade 3 or higher non-hematological toxicity (except grade 3 nausea, vomiting or diarrhea that was reversible within 72 hours with supportive care; grade 3 infusion-related toxicity; asymptomatic grade 3-4 laboratory abnormalities that are reversible to grade 2 or less within 72 hours; grade 3 tumor lysis syndrome or hyponatremia); 2) grade 4 neutropenia lasting \>7 days or febrile neutropenia; or 3) grade 4 thrombocytopenia/anemia or grade 3 thrombocytopenia with bleeding. The dosage follows the 3+3 traditional escalation rules.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

24 participants

Primary outcome timeframe

Up to 28 days

Results posted on

2023-08-08

Participant Flow

One (1) participant was initially enrolled onto the study Dose Escalation phase, but was removed from study due to subsequent discovery of transformed disease at the time of screening. This participant is not included in safety nor efficacy analysis sets.

Participant milestones

Participant milestones
Measure	Phase 1, Dose 1 Received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.	Phase 1, Dose 2 Received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.	Phase 2, MTD Received entospletinib at Maximum Tolerated Dose (MTD) in combination with obinutuzumab during Dose Expansion phase of study. The MTD was determined to be 800 mg daily (400 mg twice daily).
Stage 1 - Dose Escalation STARTED	6	3	0
Stage 1 - Dose Escalation COMPLETED	6	3	0
Stage 1 - Dose Escalation NOT COMPLETED	0	0	0
Stage 2 - Dose Expansion STARTED	0	0	15
Stage 2 - Dose Expansion COMPLETED	0	0	14
Stage 2 - Dose Expansion NOT COMPLETED	0	0	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Entospletinib and Obinutuzumab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1, Dose 1 n=6 Participants Received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.	Phase 1, Dose 2 n=3 Participants Received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.	Phase 2, MTD n=14 Participants Received entospletinib at Maximum Tolerated Dose (MTD) in combination with obinutuzumab during Dose Expansion phase of study. The MTD was determined to be 800 mg daily (400 mg twice daily).	Total n=23 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants	8 Participants n=4 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	3 Participants n=7 Participants	10 Participants n=5 Participants	15 Participants n=4 Participants
Age, Continuous	61.03 years STANDARD_DEVIATION 15.67 • n=5 Participants	68.03 years STANDARD_DEVIATION 3.82 • n=7 Participants	67.07 years STANDARD_DEVIATION 8.22 • n=5 Participants	65.62 years STANDARD_DEVIATION 10.02 • n=4 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	0 Participants n=7 Participants	5 Participants n=5 Participants	6 Participants n=4 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	3 Participants n=7 Participants	9 Participants n=5 Participants	17 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	2 Participants n=7 Participants	10 Participants n=5 Participants	18 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	1 Participants n=7 Participants	12 Participants n=5 Participants	19 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants
Region of Enrollment United States	6 participants n=5 Participants	3 participants n=7 Participants	14 participants n=5 Participants	23 participants n=4 Participants

PRIMARY outcome

Timeframe: Up to 28 days

Outcome measures

Outcome measures
Measure	Phase 1, Dose 1-2 n=9 Participants 2 groups of patients in phase 1 study. Phase 1, Dose 1 received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study. Phase 1, Dose 2 received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.	Phase 2 and MTD (800 mg Entospletinib Daily) Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 2 (400 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8 and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity. Entospletinib is administered PO.
Maximum Tolerated Dose (MTD) of Entospletinib in Combination With Obinutuzumab	400 mg orally twice-daily	—

PRIMARY outcome

Timeframe: Up to 45 months

Population: Efficacy evaluable population: participants with CLL (Phase I/Phase II)

Response for CLL/SLL measured using Modified International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 (IWCLL) guidelines. Response for hairy cell leukemia was measured using Consensus resolution: proposed criteria published in Leukemia 1987.

Outcome measures

Outcome measures
Measure	Phase 1, Dose 1-2 n=21 Participants 2 groups of patients in phase 1 study. Phase 1, Dose 1 received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study. Phase 1, Dose 2 received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.	Phase 2 and MTD (800 mg Entospletinib Daily) Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 2 (400 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8 and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity. Entospletinib is administered PO.
Complete Response (CR) Defined as the Percentage of Subjects Who Achieve CR	14.3 percentage of participants Interval 3.0 to 36.3	—

SECONDARY outcome

Timeframe: Up to 45 months

Population: Efficacy evaluable population: participants with CLL (Phase I/Phase II)

Defined as percentage of participants with complete remission, complete response with incomplete marrow recovery, partial remission and nodular partial response. Response for CLL/SLL measured using Modified International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 (IWCLL) guidelines. Response for hairy cell leukemia was measured using Consensus resolution: proposed criteria published in Leukemia 1987.

Outcome measures

Outcome measures
Measure	Phase 1, Dose 1-2 n=21 Participants 2 groups of patients in phase 1 study. Phase 1, Dose 1 received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study. Phase 1, Dose 2 received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.	Phase 2 and MTD (800 mg Entospletinib Daily) Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 2 (400 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8 and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity. Entospletinib is administered PO.
Objective Response Rate (ORR)	66.7 Percentage of participants Interval 43.0 to 85.4	—

SECONDARY outcome

Timeframe: The interval between the date of first study treatment and the date of objective signs of disease recurrence, subsequent anti leukemic therapy, or death, whichever is first reported, assessed up to 45 months.

Population: Efficacy evaluable population: participants with CLL (Phase I/Phase II)

Will be summarized descriptively using the Kaplan-Meier estimate. EFS will be censored if entospletinib is discontinued for other reasons (such as drug is no longer available).

Outcome measures

Outcome measures
Measure	Phase 1, Dose 1-2 n=21 Participants 2 groups of patients in phase 1 study. Phase 1, Dose 1 received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study. Phase 1, Dose 2 received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.	Phase 2 and MTD (800 mg Entospletinib Daily) Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 2 (400 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8 and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity. Entospletinib is administered PO.
Event Free Survival (EFS)	24.0 Months Interval 16.0 to 28.0	—

SECONDARY outcome

Timeframe: Up to 45 months

Will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All adverse events (AEs) will be coded by system organ class, Medical Dictionary for Regulatory Activities (MedDRA) preferred term, and severity grade using NCI CTCAE (version 4.03).

Outcome measures

Outcome measures
Measure	Phase 1, Dose 1-2 n=6 Participants 2 groups of patients in phase 1 study. Phase 1, Dose 1 received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study. Phase 1, Dose 2 received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.	Phase 2 and MTD (800 mg Entospletinib Daily) n=17 Participants Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 2 (400 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8 and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity. Entospletinib is administered PO.
Number of Participants Who Experienced Adverse Events	6 Participants	17 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 45 months

Population: Data for this outcome was not collected due to PI transition.

Will be summarized using descriptive statistics.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 45 months

Pharmacokinetic parameters including peak and trough levels will be determined by noncompartmental method(s) using the pharmacokinetic profile of entospletinib and obinutuzumab.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 45 months

Will be assessed by IgH somatic hypermutation assay version 2.0. Will associate with response (ORR) to entospletinib (ENTO) in combination with obinutuzumab in patients with relapsed/refractory CLL.

Outcome measures

Outcome data not reported

Adverse Events

Phase 1, Dose 1 (400 mg Entospletinib Daily)

Serious events: 3 serious events

Other events: 6 other events

Deaths: 0 deaths

Phase 2 and MTD (800 mg Entospletinib Daily)

Serious events: 5 serious events

Other events: 17 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Phase 1, Dose 1 (400 mg Entospletinib Daily) n=6 participants at risk Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 1 (200 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity.	Phase 2 and MTD (800 mg Entospletinib Daily) n=17 participants at risk Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 2 (400 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8 and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity.
General disorders Infusion Related Reaction	33.3% 2/6 • Number of events 2 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	5.9% 1/17 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Metabolism and nutrition disorders Tumor Lysis Syndrome	16.7% 1/6 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	0.00% 0/17 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Injury, poisoning and procedural complications Interoperative Hemorrhage	16.7% 1/6 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	0.00% 0/17 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Cardiac disorders Acute Coronary Syndrome	0.00% 0/6 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	5.9% 1/17 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Infections and infestations Infections and infestations - Other, specify	0.00% 0/6 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	5.9% 1/17 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Investigations Febrile neutropenia	0.00% 0/6 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	5.9% 1/17 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Infections and infestations Sepsis	0.00% 0/6 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	5.9% 1/17 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.

Other adverse events

Additional Information

Bria Thurlow

OHSU Knight Cancer Institute

Phone: 503-494-4292

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Phase 1, Dose 1 (400 mg Entospletinib Daily) n=6 participants at risk Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 1 (200 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity.	Phase 2 and MTD (800 mg Entospletinib Daily) n=17 participants at risk Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 2 (400 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8 and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity.
Infections and infestations Otitis externa	16.7% 1/6 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	0.00% 0/17 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Investigations Platelet count decreased	16.7% 1/6 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	29.4% 5/17 • Number of events 13 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Infections and infestations Rhinitis infective	0.00% 0/6 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	5.9% 1/17 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Infections and infestations Sinusitis	16.7% 1/6 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	17.6% 3/17 • Number of events 6 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Infections and infestations Tooth infection	0.00% 0/6 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	11.8% 2/17 • Number of events 2 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Metabolism and nutrition disorders Tumor lysis syndrome	0.00% 0/6 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	5.9% 1/17 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Infections and infestations Upper respiratory infection	16.7% 1/6 • Number of events 2 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	41.2% 7/17 • Number of events 17 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Infections and infestations Wound infection	0.00% 0/6 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	5.9% 1/17 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Infections and infestations Urinary tract infection	0.00% 0/6 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	17.6% 3/17 • Number of events 9 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Investigations Alanine aminotransferase increased	33.3% 2/6 • Number of events 3 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	23.5% 4/17 • Number of events 11 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Investigations Aspartate aminotransferase increased	33.3% 2/6 • Number of events 3 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	29.4% 5/17 • Number of events 13 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Infections and infestations Bronchial infection	0.00% 0/6 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	5.9% 1/17 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Blood and lymphatic system disorders Febrile neutropenia	16.7% 1/6 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	5.9% 1/17 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
General disorders Infusion related reaction	16.7% 1/6 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	64.7% 11/17 • Number of events 13 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Infections and infestations Nail infection	0.00% 0/6 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	5.9% 1/17 • Number of events 1 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.
Investigations Neutrophil count decreased	33.3% 2/6 • Number of events 10 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.	58.8% 10/17 • Number of events 45 • Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months. Per protocol; "Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03)." Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.