Trial Outcomes & Findings for BYL719 and Nab-Paclitaxel in Locally Recurrent or Metastatic HER-2 Negative Breast Cancer (NCT NCT02379247)

Last Updated: 2022-06-07

Results Overview

Phase I was a 3+3 dose escalation design (three dose levels of alpelisib: 250mg, 300mg, and 350mg orally once daily, continuous dosing) with dose-limiting toxicities (DLT) assessed during the first treatment cycle. If two or more of the six patients experienced a dose-limiting toxicity, dosing escalation would cease and maximum tolerated dose (MTD) would be reached. RP2D was the next lower dose at which \<1/6 subjects experienced a DLT.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

43 participants

Primary outcome timeframe

12 months

Results posted on

2022-06-07

Participant Flow

Participant milestones

Participant milestones
Measure	Dose Level 1 BYL-719/Alpelisib (250mg)+Nab-paclitaxel BYL-719 (alpelisib): 250mg daily on day 1-28 Nab-paclitaxel: 100mg/m2 IV days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane	Dose Level 2 BYL-719 (Alpelisib) (300mg)+Nab-paclitaxel BYL-719 (alpelisib): 300mg by mouth daily on day 1-28 of each 28 day cycle Nab-paclitaxel: 100mg/m2 given IV on days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane	Dose Level 3 BYL-719 (Alpelisib) (350mg)+Nab-paclitaxel BYL-719 (alpelisib): 350mg by mouth daily on day 1-28 of each 28 day cycle Nab-paclitaxel: 100mg/m2 given IV on days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane	BYL-719 (Alpelisib) Dose Expansion BYL-719 (alpelisib): RP2D from Phase I by mouth daily on day 1-28 of each 28 day cycle Nab-paclitaxel: 100mg/m2 given IV on days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane
Overall Study STARTED	3	3	7	30
Overall Study COMPLETED	3	3	7	30
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dose Level 1 BYL-719/Alpelisib (250mg)+Nab-paclitaxel n=3 Participants BYL-719 (alpelisib): 250mg daily on day 1-28 Nab-paclitaxel: 100mg/m2 IV days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane	Dose Level 2 BYL-719/Alpelisib (300mg)+Nab-paclitaxel n=3 Participants BYL-719 (alpelisib): 300mg daily on day 1-28 Nab-paclitaxel: 100mg/m2 IV days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane	Dose Level 3 BYL-719/Alpelisib (350mg)+Nab-paclitaxel n=7 Participants BYL-719 (alpelisib): 350mg daily on day 1-28 Nab-paclitaxel: 100mg/m2 IV days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane	BYL-719/Alpelisib Dose Expansion n=30 Participants BYL-719 (alpelisib): RP2D from Phase I by mouth daily on day 1-28 of each 28 day cycle Nab-paclitaxel: 100mg/m2 IV days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane	Total n=43 Participants Total of all reporting groups
Age, Continuous	61 years n=3 Participants	61 years n=3 Participants	59 years n=7 Participants	54 years n=30 Participants	55 years n=43 Participants
Sex: Female, Male Female	3 Participants n=3 Participants	3 Participants n=3 Participants	7 Participants n=7 Participants	30 Participants n=30 Participants	43 Participants n=43 Participants
Sex: Female, Male Male	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=7 Participants	0 Participants n=30 Participants	0 Participants n=43 Participants
Race and Ethnicity Not Collected	—	—	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment United States	3 Participants n=3 Participants	3 Participants n=3 Participants	7 Participants n=7 Participants	30 Participants n=30 Participants	43 Participants n=43 Participants
Metastatic disease subtype Estrogen receptor and/or progesterone receptor positive	1 Participants n=3 Participants	2 Participants n=3 Participants	4 Participants n=7 Participants	23 Participants n=30 Participants	30 Participants n=43 Participants
Metastatic disease subtype Triple-negative	2 Participants n=3 Participants	1 Participants n=3 Participants	3 Participants n=7 Participants	7 Participants n=30 Participants	13 Participants n=43 Participants
Measurable disease	3 Participants n=3 Participants	3 Participants n=3 Participants	7 Participants n=7 Participants	30 Participants n=30 Participants	43 Participants n=43 Participants
Visceral disease Present	3 Participants n=3 Participants	3 Participants n=3 Participants	6 Participants n=7 Participants	24 Participants n=30 Participants	36 Participants n=43 Participants
Visceral disease Absent	0 Participants n=3 Participants	0 Participants n=3 Participants	1 Participants n=7 Participants	6 Participants n=30 Participants	7 Participants n=43 Participants
Prior lines of chemotherapy for metastatic disease 0	0 Participants n=3 Participants	1 Participants n=3 Participants	2 Participants n=7 Participants	7 Participants n=30 Participants	10 Participants n=43 Participants
Prior lines of chemotherapy for metastatic disease 1	3 Participants n=3 Participants	2 Participants n=3 Participants	3 Participants n=7 Participants	12 Participants n=30 Participants	20 Participants n=43 Participants
Prior lines of chemotherapy for metastatic disease ≥2	0 Participants n=3 Participants	0 Participants n=3 Participants	2 Participants n=7 Participants	11 Participants n=30 Participants	13 Participants n=43 Participants
Prior taxane Neoadjuvant or adjuvant	2 Participants n=3 Participants	2 Participants n=3 Participants	5 Participants n=7 Participants	17 Participants n=30 Participants	26 Participants n=43 Participants
Prior taxane Metastatic only	1 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=7 Participants	6 Participants n=30 Participants	7 Participants n=43 Participants
Prior taxane Neoadjuvant or adjuvant AND metastatic	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=7 Participants	3 Participants n=30 Participants	3 Participants n=43 Participants
Prior taxane None	0 Participants n=3 Participants	1 Participants n=3 Participants	2 Participants n=7 Participants	4 Participants n=30 Participants	7 Participants n=43 Participants
Prior CDK4/6 inhibitor Yes	1 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=7 Participants	11 Participants n=30 Participants	12 Participants n=43 Participants
Prior CDK4/6 inhibitor No	2 Participants n=3 Participants	3 Participants n=3 Participants	7 Participants n=7 Participants	19 Participants n=30 Participants	31 Participants n=43 Participants

PRIMARY outcome

Timeframe: 12 months

Outcome measures

Outcome measures
Measure	Phase I n=13 Participants All patients in phase I, across all three dose levels of BYL-719 (alpelisib) + nab-paclitaxel	Dose Level 2 Participants assigned to Dose Level 2 BYL-719/Alpelisib (300mg)+Nab-paclitaxel	Dose Level 3 Participants in phase I assigned to dose level 3 BYL-719/Alpelisib (350mg)+Nab-paclitaxel
Phase I: Recommended Phase II Dose (RP2D) of BYL-719 (Alpelisib) + Nab-paclitaxel to be Used in Combination to Treat Advanced HER2-negative Breast Cancer	350 mg	—	—

PRIMARY outcome

Timeframe: 24 months

ORR includes complete response (CR) plus partial response (PR). As evaluated per RECIST version 1.1.

Outcome measures

Outcome measures
Measure	Phase I n=33 Participants All patients in phase I, across all three dose levels of BYL-719 (alpelisib) + nab-paclitaxel	Dose Level 2 Participants assigned to Dose Level 2 BYL-719/Alpelisib (300mg)+Nab-paclitaxel	Dose Level 3 Participants in phase I assigned to dose level 3 BYL-719/Alpelisib (350mg)+Nab-paclitaxel
Phase II: Overall Response Rate (ORR) of Subjects Treated at the Recommended Phase II Dose (RP2D)	17 Participants	—	—

SECONDARY outcome

Timeframe: 16 weeks

Population: Per protocol the endpoint of CBR at 16 weeks is to be reported for all participants in phase I and phase II who were evaluable for response, thus participants from all assigned dose levels are combined for this analysis.

CBR includes complete response (CR), partial response (PR), plus stable disease (SD) ≥16 weeks. As evaluated per RECIST version 1.1.

Outcome measures

Outcome measures
Measure	Phase I n=42 Participants All patients in phase I, across all three dose levels of BYL-719 (alpelisib) + nab-paclitaxel	Dose Level 2 Participants assigned to Dose Level 2 BYL-719/Alpelisib (300mg)+Nab-paclitaxel	Dose Level 3 Participants in phase I assigned to dose level 3 BYL-719/Alpelisib (350mg)+Nab-paclitaxel
Clinical Benefit Rate (CBR) at 16 Weeks of Study Treatment	35 Participants	—	—

SECONDARY outcome

Timeframe: In cycle 1 day 1, from prior to alpelisib dosing through 8 hours after alpelisib dosing

Population: Pharmacokinetic measures were assessed only among participants in phase I.

Area under the curve (AUC): sampling pre-dose and 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-alpelisib dose

Outcome measures

Outcome measures
Measure	Phase I n=3 Participants All patients in phase I, across all three dose levels of BYL-719 (alpelisib) + nab-paclitaxel	Dose Level 2 n=3 Participants Participants assigned to Dose Level 2 BYL-719/Alpelisib (300mg)+Nab-paclitaxel	Dose Level 3 n=7 Participants Participants in phase I assigned to dose level 3 BYL-719/Alpelisib (350mg)+Nab-paclitaxel
Pharmacokinetics of BYL-719 (Alpelisib) When Administered With Nab-paclitaxel	6846 h*ng/mL Standard Deviation 3410	12436 h*ng/mL Standard Deviation 6174	13359 h*ng/mL Standard Deviation 5798

SECONDARY outcome

Timeframe: In cycle 1 day 1, from prior to alpelisib dosing through 8 hours after alpelisib dosing

Population: Pharmacokinetic measures were assessed only among participants in phase I. One phase I participant assigned to the 350 mg BYL-719 (alpelisib) dose level did not have an end-of-infusion sample for paclitaxel measurement. Data are based on 12 participants.

Area under the curve (AUC): sampling pre-dose and 1.5, 2, 2.5, 3, 3.5, 4, and 6 hours post-alpelisib dose

Outcome measures

Outcome measures
Measure	Phase I n=3 Participants All patients in phase I, across all three dose levels of BYL-719 (alpelisib) + nab-paclitaxel	Dose Level 2 n=3 Participants Participants assigned to Dose Level 2 BYL-719/Alpelisib (300mg)+Nab-paclitaxel	Dose Level 3 n=6 Participants Participants in phase I assigned to dose level 3 BYL-719/Alpelisib (350mg)+Nab-paclitaxel
Pharmacokinetics of (Total) Nab-paclitaxel When Administered With BYL-719 (Alpelisib)	8488 h*ng/mL Standard Deviation 1537	9938 h*ng/mL Standard Deviation 1735	6979 h*ng/mL Standard Deviation 2492

SECONDARY outcome

Timeframe: 36 months

Population: Per protocol the endpoints of PFS and OS are to be reported for all participants in phase I and phase II who were evaluable for response, thus participants from all assigned dose levels are combined for this analysis.

PFS was defined as the time in months from the date of enrollment to the date of progression or death, whichever was earlier. OS was defined as the time in months from the date of enrollment to death as a result of any cause. Survival curves were assessed by the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Phase I n=42 Participants All patients in phase I, across all three dose levels of BYL-719 (alpelisib) + nab-paclitaxel	Dose Level 2 Participants assigned to Dose Level 2 BYL-719/Alpelisib (300mg)+Nab-paclitaxel	Dose Level 3 Participants in phase I assigned to dose level 3 BYL-719/Alpelisib (350mg)+Nab-paclitaxel
Progression-free Survival (PFS) and Overall Survival (OS) Progression-free survival	8.7 months Interval 5.5 to 11.9	—	—
Progression-free Survival (PFS) and Overall Survival (OS) Overall survival	18.5 months Interval 9.6 to 27.4	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 months

Population: Among 42 participants evaluable for response, 17 had PIK3CA mutation in tumor tissue and/or circulating tumor DNA, while 25 did not. Clinical benefit rate was assessed among participants with PIK3CA mutation separately from participants without PIK3CA mutation for the purpose of correlating clinical benefit rate with PIK3CA mutation status. Per protocol the analysis is reported for all participants evaluable for response, thus participants from all dose levels are combined for this analysis.

Comparison of clinical benefit rate between participants with and without PIK3CA mutation in tumor tissue and/or circulating tumor DNA. Clinical benefit rate includes complete response (CR), partial response (PR), plus stable disease (SD) ≥16 weeks, as evaluated per RECIST version 1.1. Tumor DNA was isolated from archived formalin-fixed, paraffin-embedded tumor tissue (primary or metastatic site) and subjected to next-generation sequencing for assessment of PIK3CA mutation using ONCOReveal Multi-Cancer Panel (Pillar Biosciences). Circulating tumor DNA was isolated from pre-treatment plasma samples and subjected to next-generation sequencing for assessment of PIK3CA mutation using FoundationOne CDx testing or ONCOReveal Multi-Cancer Panel.

Outcome measures

Outcome measures
Measure	Phase I n=42 Participants All patients in phase I, across all three dose levels of BYL-719 (alpelisib) + nab-paclitaxel	Dose Level 2 Participants assigned to Dose Level 2 BYL-719/Alpelisib (300mg)+Nab-paclitaxel	Dose Level 3 Participants in phase I assigned to dose level 3 BYL-719/Alpelisib (350mg)+Nab-paclitaxel
Correlation of PIK3CA Mutation With Clinical Benefit Rate PIK3CA mutation present	17 participants	—	—
Correlation of PIK3CA Mutation With Clinical Benefit Rate PIK3CA mutation absent	17 participants	—	—

Adverse Events

Dose Level 1 BYL-719/Alpelisib (250mg)+Nab-paclitaxel

Serious events: 0 serious events

Other events: 3 other events

Deaths: 3 deaths

Dose Level 2 BYL-719/Alpelisib (300mg)+Nab-paclitaxel

Serious events: 0 serious events

Other events: 3 other events

Deaths: 3 deaths

Dose Level 3 BYL-719/Alpelisib (350mg)+Nab-paclitaxel

Serious events: 0 serious events

Other events: 7 other events

Deaths: 5 deaths

BYL-719 (Alpelisib) Dose Expansion

Serious events: 0 serious events

Other events: 28 other events

Deaths: 19 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr. Priyanka Sharma

University of Kansas Medical Center

Phone: 9135886079

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Other adverse events
Measure	Dose Level 1 BYL-719/Alpelisib (250mg)+Nab-paclitaxel n=3 participants at risk BYL-719 (alpelisib): 250mg daily on day 1-28 of each 28 day cycle Nab-paclitaxel: 100mg/m2 IV days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane	Dose Level 2 BYL-719/Alpelisib (300mg)+Nab-paclitaxel n=3 participants at risk BYL-719 (alpelisib): 300mg daily on day 1-28 of each 28 day cycle Nab-paclitaxel: 100mg/m2 IV days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane	Dose Level 3 BYL-719/Alpelisib (350mg)+Nab-paclitaxel n=7 participants at risk BYL-719 (alpelisib): 350mg daily on day 1-28 of each 28 day cycle Nab-paclitaxel: 100mg/m2 IV days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane	BYL-719 (Alpelisib) Dose Expansion n=30 participants at risk BYL-719 (alpelisib): RP2D from Phase I by mouth daily on day 1-28 of each 28 day cycle Nab-paclitaxel: 100mg/m2 IV days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane
General disorders Fatigue	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	100.0% 3/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	71.4% 5/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	60.0% 18/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Gastrointestinal disorders Diarrhea	66.7% 2/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	100.0% 3/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	85.7% 6/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	63.3% 19/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Metabolism and nutrition disorders Hyperglycemia	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	100.0% 3/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	100.0% 7/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	63.3% 19/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Gastrointestinal disorders Nausea	100.0% 3/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	66.7% 2/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	42.9% 3/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	66.7% 20/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Nervous system disorders Peripheral neuropathy	66.7% 2/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	100.0% 3/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	42.9% 3/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	56.7% 17/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Metabolism and nutrition disorders Anorexia	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	66.7% 2/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	42.9% 3/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	53.3% 16/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Investigations Electrolyte imbalance	66.7% 2/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	100.0% 3/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	71.4% 5/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	40.0% 12/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Blood and lymphatic system disorders Anemia	100.0% 3/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	42.9% 3/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	50.0% 15/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Gastrointestinal disorders Mucositis	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	66.7% 2/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	57.1% 4/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	46.7% 14/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Blood and lymphatic system disorders Neutropenia	66.7% 2/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	42.9% 3/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	46.7% 14/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Nervous system disorders Dysgeusia	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	28.6% 2/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	53.3% 16/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Skin and subcutaneous tissue disorders Rash	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	57.1% 4/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	46.7% 14/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Infections and infestations Infection	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	100.0% 3/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	28.6% 2/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	26.7% 8/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
General disorders Edema	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	66.7% 2/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	42.9% 3/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	23.3% 7/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Gastrointestinal disorders Vomiting	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	42.9% 3/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	23.3% 7/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	28.6% 2/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	26.7% 8/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Skin and subcutaneous tissue disorders Nail changes	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	28.6% 2/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	23.3% 7/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Hepatobiliary disorders Liver enzyme increase	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	14.3% 1/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	20.0% 6/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	28.6% 2/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	20.0% 6/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	28.6% 2/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	20.0% 6/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Skin and subcutaneous tissue disorders Dry skin/mouth	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	28.6% 2/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	16.7% 5/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Gastrointestinal disorders Dyspepsia	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	23.3% 7/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Respiratory, thoracic and mediastinal disorders Dyspnea	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	23.3% 7/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Respiratory, thoracic and mediastinal disorders Cough	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	14.3% 1/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	16.7% 5/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Metabolism and nutrition disorders Weight loss	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	28.6% 2/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	13.3% 4/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Musculoskeletal and connective tissue disorders Musculoskeletal	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	14.3% 1/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	20.0% 6/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Renal and urinary disorders Creatinine imbalance	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	14.3% 1/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	10.0% 3/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Gastrointestinal disorders Flatulence	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	13.3% 4/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Eye disorders Watering eyes	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	10.0% 3/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Eye disorders Blurred vision	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	10.0% 3/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Blood and lymphatic system disorders Decreased lymphocyte count	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	28.6% 2/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	3.3% 1/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Nervous system disorders Dizziness	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	10.0% 3/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Eye disorders Dry eyes	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	10.0% 3/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Infections and infestations Fever	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	10.0% 3/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Nervous system disorders Gait disturbance	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	14.3% 1/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	3.3% 1/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Gastrointestinal disorders Gastrointestinal - other	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	28.6% 2/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	3.3% 1/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Nervous system disorders Headache	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	33.3% 1/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	14.3% 1/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	3.3% 1/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	0.00% 0/3 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	14.3% 1/7 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.	6.7% 2/30 • For each participant, treatment-related adverse events were collected from start of study treatment until 30 days after the participant's last dose of study treatment, assessed up to 174 weeks, whichever came first. All-cause mortality was collected from start of study treatment through October 16, 2019 (data cutoff date). Adverse events (serious and non-serious) of all grades, definitely related/probably related/possibly related to study treatment, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients were systematically evaluated for toxicity at each visit.