Trial Outcomes & Findings for Study of Bendamustine Hydrochloride for the Treatment of Pediatric Patients With Relapsed or Refractory Acute Leukemia (NCT NCT01088984)

Last Updated: 2016-05-23

Results Overview

RP2D was determined by a traditional 3+3 dose escalation design, with the following restrictions: only doses of 60, 90, 120, and 150 mg/m\^2 were explored, and escalation to 150 mg/m\^2 would only occur if the 120 mg/m\^2 dose was deemed safe and pharmacokinetic data indicate subtherapeutic exposure as compared with adults. The first cohort was administered bendamustine at the 90 mg/m\^2 dose; de-escalation to the 60 mg/m\^2 dose would only occur if the starting dose led to dose-limiting toxicity (DLT) in 2 or more participants. A DLT was defined as any study drug-related nonhematologic adverse event (AE) that was grade 4 for toxicity by National Cancer Institute's Common Toxicity Criteria for AEs, version 4. In addition, grade 3 or above allergic reaction or skin rash were considered DLTs. Hematologic AEs were not considered DLTs. The dose level at which at least 2 of 3 or 2 of 6 participants had a DLT was considered as exceeding the RP2D. The RP2D was the dose 1 step below that level.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

43 participants

Primary outcome timeframe

Induction Cycle (21- to 35-day cycle)

Results posted on

2016-05-23

Participant Flow

Of the 46 patients screened, 43 patients at 24 centers from the United States, Australia, South Korea, Israel, Mexico, and Brazil met entry criteria and were considered eligible for enrollment. Of the 3 patients who were not enrolled, 2 patients died prior to study enrollment, and 1 patient was ineligible because inclusion criteria were not met.

Participant milestones

Participant milestones
Measure	Bendamustine 90 mg/m^2 Bendamustine 90 mg/m\^2 administered as an intravenous (IV) infusion over 60 minutes on Days 1 and 2 of a 21-day Induction cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Bendamustine 120 mg/m^2 Bendamustine 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Phase 1 STARTED	5	6
Phase 1 COMPLETED	0	0
Phase 1 NOT COMPLETED	5	6
Phase 2 STARTED	0	32
Phase 2 COMPLETED	0	0
Phase 2 NOT COMPLETED	0	32

Reasons for withdrawal

Reasons for withdrawal
Measure	Bendamustine 90 mg/m^2 Bendamustine 90 mg/m\^2 administered as an intravenous (IV) infusion over 60 minutes on Days 1 and 2 of a 21-day Induction cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Bendamustine 120 mg/m^2 Bendamustine 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Phase 1 Death	2	1
Phase 1 Disease Progression	2	4
Phase 1 Other	1	1
Phase 2 Death	0	5
Phase 2 Withdrawal by Subject	0	1
Phase 2 DIsease Progression	0	25
Phase 2 Other	0	1

Baseline Characteristics

Study of Bendamustine Hydrochloride for the Treatment of Pediatric Patients With Relapsed or Refractory Acute Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1: Bendamustine 90 or 120 mg/m^2 n=11 Participants Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of a 21-day Induction Cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Phase 2: Bendamustine 120 mg/m^2 n=32 Participants Bendamustine 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Total n=43 Participants Total of all reporting groups
Age, Continuous	8.7 years STANDARD_DEVIATION 4.31 • n=5 Participants	9.3 years STANDARD_DEVIATION 4.93 • n=7 Participants	9.2 years STANDARD_DEVIATION 4.74 • n=5 Participants
Age, Customized 1 to 6 years	4 participants n=5 Participants	10 participants n=7 Participants	14 participants n=5 Participants
Age, Customized 7 to 11 years	3 participants n=5 Participants	10 participants n=7 Participants	13 participants n=5 Participants
Age, Customized 12 to 20 years	4 participants n=5 Participants	12 participants n=7 Participants	16 participants n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	12 Participants n=7 Participants	13 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	20 Participants n=7 Participants	30 Participants n=5 Participants

PRIMARY outcome

Timeframe: Induction Cycle (21- to 35-day cycle)

Population: All participants enrolled in Phase 1 of the study.

Outcome measures

Outcome measures
Measure	Phase 1: Bendamustine 90 or 120 mg/m^2 n=11 Participants Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of a 21-day Induction Cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Phase 2: Bendamustine 120 mg/m^2 Bendamustine 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Total Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Recommended Phase II Dose (RP2D) of Bendamustine	120 mg/m^2	—	—

PRIMARY outcome

Timeframe: Assessed at each treatment cycle (21 to 35 days), for a maximum of 12 cycles

Population: The primary analysis set for efficacy included all participants treated at the RP2D in Phase 2.

ORR was calculated as follows: number of participants in the primary analysis set achieving a best overall response of complete remission without platelet recovery (CRp) or complete remission (CR), divided by the number of participants in the primary analysis set. The most positive response for each patient during the study was counted. The 95% CI was calculated using binomial parameter exact method. Response was determined by the investigator, and evaluated per Jeha et al, 2006: A CR required no evidence of circulating blasts or extramedullary disease, an M1 marrow (≤ 5% bone marrow blasts), and recovery of peripheral counts (platelets ≥ 100 × 10\^9/L and absolute neutrophil count ≥ 1.0 × 10\^9/L). A CR without platelet recovery (CRp) required all of the criteria for a CR with the exception of platelet recovery.

Outcome measures

Outcome measures
Measure	Phase 1: Bendamustine 90 or 120 mg/m^2 n=32 Participants Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of a 21-day Induction Cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Phase 2: Bendamustine 120 mg/m^2 Bendamustine 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Total Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Overall Response Rate (ORR)	0 percentage of participants Interval 0.0 to 1-sided 95% confidence interval	—	—

SECONDARY outcome

Timeframe: At each treatment cycle (21 to 35 days), for a maximum of 12 cycles

Population: The primary analysis set for efficacy included all participants treated at the RP2D in Phase 2.

Biological activity of bendamustine was defined as achieving a best response of partial response (PR), CRp, or CR. Rate was calculated as follows: number of participants in the primary analysis set achieving a best overall response of PR, CRp, or CR, divided by the number of participants in the primary analysis set. The most positive response for each patient during the study was counted. The 95% CI was calculated using binomial parameter exact method. Response was determined by the investigator, and evaluated per Jeha et al, 2006: A PR had to meet the following criteria: complete disappearance of circulating blasts and an M2 marrow (≥ 5% and ≤ 25% bone marrow blasts) and appearance of normal progenitor cells or an M1 marrow that did not qualify for CR or CRp. See Outcome Measure 2 for full definitions for CRp and CR.

Outcome measures

Outcome measures
Measure	Phase 1: Bendamustine 90 or 120 mg/m^2 n=32 Participants Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of a 21-day Induction Cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Phase 2: Bendamustine 120 mg/m^2 Bendamustine 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Total Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Best Overall Tumor Response Rate	6 percentage of participants Interval 0.77 to 20.81	—	—

SECONDARY outcome

Timeframe: At each treatment cycle (21 to 35 days), for a maximum of 12 cycles

Population: The safety analysis set included all participants treated at any dose of bendamustine.

Outcome measures

Outcome measures
Measure	Phase 1: Bendamustine 90 or 120 mg/m^2 n=11 Participants Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of a 21-day Induction Cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Phase 2: Bendamustine 120 mg/m^2 n=32 Participants Bendamustine 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Total n=43 Participants Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Best Overall Tumor Response Rate, by Phase	18 percentage of participants Interval 2.28 to 51.78	6 percentage of participants Interval 0.77 to 20.81	9 percentage of participants Interval 2.59 to 22.14

SECONDARY outcome

Timeframe: At each treatment cycle (21 to 35 days), for a maximum of 12 cycles

Population: No duration of remission (defined as CR or CRp) analysis was performed for participants in the primary analysis since none achieved remission.

DOR was determined for the participants with CR or CRp in the primary analysis set, defined as the time from first achieving remission to the time when progression was diagnosed, the participant died, or the participant started receiving new antineoplastic therapy. Data from participants who do not progress were censored at the last valid assessments. Median DOR and its 95% confidence interval was determined based on the Kaplan-Meier method. Data from participants who received a transplant were censored at the time of the transplant.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1, Day 1: before infusion, immediately following the infusion, and 3, 6, 10(±2), and 24 hours after the start of infusion. The 24-hour postinfusion sample was obtained before the start of the infusion on Day 2.

Population: The pharmacokinetic analysis set included all participants who were in the safety analysis set (ie, those treated at any dose of bendamustine) who had valid pharmacokinetic data; n=number of participants with valid data for this assessment.

Outcome measures

Outcome measures
Measure	Phase 1: Bendamustine 90 or 120 mg/m^2 n=5 Participants Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of a 21-day Induction Cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Phase 2: Bendamustine 120 mg/m^2 n=37 Participants Bendamustine 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Total Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4) Bendamustine; n=5, 37	5093.24 ng/mL Geometric Coefficient of Variation 60.39	6401.80 ng/mL Geometric Coefficient of Variation 52.90	—
Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4) Metabolite M3; n=5, 36	311.70 ng/mL Geometric Coefficient of Variation 92.98	403.52 ng/mL Geometric Coefficient of Variation 69.91	—
Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4) Metabolite M4; n=5, 37	37.53 ng/mL Geometric Coefficient of Variation 82.97	48.27 ng/mL Geometric Coefficient of Variation 53.94	—

SECONDARY outcome

Outcome measures

Outcome measures
Measure	Phase 1: Bendamustine 90 or 120 mg/m^2 n=5 Participants Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of a 21-day Induction Cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Phase 2: Bendamustine 120 mg/m^2 n=37 Participants Bendamustine 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Total Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4) Metabolite M3; n=5, 36	1.14 hours Geometric Coefficient of Variation 10.00	1.07 hours Geometric Coefficient of Variation 9.53	—
Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4) Metabolite M4; n=5, 37	1.14 hours Geometric Coefficient of Variation 10.00	1.07 hours Geometric Coefficient of Variation 9.49	—
Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4) Bendamustine; n=5, 37	1.14 hours Geometric Coefficient of Variation 10.00	1.07 hours Geometric Coefficient of Variation 9.49	—

SECONDARY outcome

Outcome measures

Outcome measures
Measure	Phase 1: Bendamustine 90 or 120 mg/m^2 n=5 Participants Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of a 21-day Induction Cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Phase 2: Bendamustine 120 mg/m^2 n=37 Participants Bendamustine 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Total Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Area Under the Plasma Drug Concentration by Time Curve From Time 0 Until the Last Measurable Plasma Concentration (AUC0-t) for Bendamustine and Its Metabolites (M3 and M4) Bendamustine; n=5, 37	11174.86 ng*hr/mL Geometric Coefficient of Variation 51.73	11046.32 ng*hr/mL Geometric Coefficient of Variation 58.58	—
Area Under the Plasma Drug Concentration by Time Curve From Time 0 Until the Last Measurable Plasma Concentration (AUC0-t) for Bendamustine and Its Metabolites (M3 and M4) Metabolite M3; n=5, 36	697.09 ng*hr/mL Geometric Coefficient of Variation 88.37	701.19 ng*hr/mL Geometric Coefficient of Variation 67.38	—
Area Under the Plasma Drug Concentration by Time Curve From Time 0 Until the Last Measurable Plasma Concentration (AUC0-t) for Bendamustine and Its Metabolites (M3 and M4) Metabolite M4; n=5, 37	43.80 ng*hr/mL Geometric Coefficient of Variation 109.72	72.78 ng*hr/mL Geometric Coefficient of Variation 57.11	—

SECONDARY outcome

Outcome measures

Outcome measures
Measure	Phase 1: Bendamustine 90 or 120 mg/m^2 n=5 Participants Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of a 21-day Induction Cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Phase 2: Bendamustine 120 mg/m^2 n=37 Participants Bendamustine 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Total Bendamustine 90 or 120 mg/m\^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Area Under the Plasma Drug Concentration by Time Curve From Time 0 Until 24 Hours After Study Drug Administration (AUC0-24) for Bendamustine and Its Metabolites (M3 and M4) Bendamustine; n=1, 13	14998.00 ng*hr/mL Geometric Coefficient of Variation NA only 1 participant assessed	12929.22 ng*hr/mL Geometric Coefficient of Variation 50.46	—
Area Under the Plasma Drug Concentration by Time Curve From Time 0 Until 24 Hours After Study Drug Administration (AUC0-24) for Bendamustine and Its Metabolites (M3 and M4) Metabolite M3; n=0, 2	NA ng*hr/mL Geometric Coefficient of Variation NA no participants assessed	1336.89 ng*hr/mL Geometric Coefficient of Variation 1.80	—
Area Under the Plasma Drug Concentration by Time Curve From Time 0 Until 24 Hours After Study Drug Administration (AUC0-24) for Bendamustine and Its Metabolites (M3 and M4) Metabolite M4; n=0, 0	NA ng*hr/mL Geometric Coefficient of Variation NA no participants assessed	NA ng*hr/mL Geometric Coefficient of Variation NA no participants assessed	—

Adverse Events

Bendamustine

Serious events: 33 serious events

Other events: 43 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Bendamustine n=43 participants at risk Bendamustine 90 or 120 mg/m\^2 administered as an intravenous (IV) infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Blood and lymphatic system disorders Febrile neutropenia	27.9% 12/43 • Number of events 13 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Blood and lymphatic system disorders Leukocytosis	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Blood and lymphatic system disorders Neutropenia	4.7% 2/43 • Number of events 2 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Blood and lymphatic system disorders Pancytopenia	4.7% 2/43 • Number of events 2 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Blood and lymphatic system disorders Thrombocytopenia	4.7% 2/43 • Number of events 2 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Cardiac disorders Cardiopulmonary failure	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Gastrointestinal disorders Proctitis	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Gastrointestinal disorders Vomiting	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
General disorders Chest pain	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
General disorders Multi-organ failure	2.3% 1/43 • Number of events 2 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
General disorders Pyrexia	9.3% 4/43 • Number of events 7 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Hepatobiliary disorders Portal vein thrombosis	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Aspergillosis	4.7% 2/43 • Number of events 2 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Bacteraemia	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Beta haemolytic streptococcal infection	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Capnocytophagia infection	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Cellulitis	2.3% 1/43 • Number of events 2 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Febrile infection	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Fungal sepsis	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Herpes zoster	4.7% 2/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Pharyngitis	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Pneumonia	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Septic shock	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Staphylococcal infection	2.3% 1/43 • Number of events 2 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Investigations Blood creatinine increased	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Investigations Electrocardiogram QT prolonged	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Hypercalcaemia	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Hyperglycaemia	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Hyperkalaemia	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Tumour lysis syndrome	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Musculoskeletal and connective tissue disorders Back pain	2.3% 1/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Musculoskeletal and connective tissue disorders Pain in extremity	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute lymphocytic leukaemia	9.3% 4/43 • Number of events 4 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute myeloid leukaemia	7.0% 3/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) B precursor type acute leukaemia	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Leukaemia	4.7% 2/43 • Number of events 4 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myeloid leukaemia	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) T-cell type acute leukaemia	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Nervous system disorders Depressed level of consciousness	4.7% 2/43 • Number of events 2 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Nervous system disorders Headache	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Psychiatric disorders Confusional state	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Renal and urinary disorders Renal failure	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Renal and urinary disorders Renal impairment	4.7% 2/43 • Number of events 2 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Respiratory, thoracic and mediastinal disorders Hypoxia	4.7% 2/43 • Number of events 2 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Respiratory, thoracic and mediastinal disorders Respiratory distress	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Respiratory, thoracic and mediastinal disorders Respiratory failure	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Vascular disorders Hypotension	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Vascular disorders Peripheral artery aneurysm	2.3% 1/43 • Number of events 1 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.

Other adverse events

Other adverse events
Measure	Bendamustine n=43 participants at risk Bendamustine 90 or 120 mg/m\^2 administered as an intravenous (IV) infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Blood and lymphatic system disorders Anaemia	65.1% 28/43 • Number of events 92 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Blood and lymphatic system disorders Febrile neutropenia	34.9% 15/43 • Number of events 19 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Blood and lymphatic system disorders Lymphopenia	7.0% 3/43 • Number of events 10 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Blood and lymphatic system disorders Neutropenia	11.6% 5/43 • Number of events 8 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Blood and lymphatic system disorders Pancytopenia	9.3% 4/43 • Number of events 5 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Blood and lymphatic system disorders Thrombocytopenia	32.6% 14/43 • Number of events 74 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Gastrointestinal disorders Abdominal pain	20.9% 9/43 • Number of events 13 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Gastrointestinal disorders Constipation	16.3% 7/43 • Number of events 8 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Gastrointestinal disorders Diarrhoea	32.6% 14/43 • Number of events 28 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Gastrointestinal disorders Gingival bleeding	7.0% 3/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Gastrointestinal disorders Nausea	46.5% 20/43 • Number of events 26 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Gastrointestinal disorders Vomiting	34.9% 15/43 • Number of events 31 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
General disorders Catheter site pain	7.0% 3/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
General disorders Chest pain	9.3% 4/43 • Number of events 4 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
General disorders Chills	7.0% 3/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
General disorders Fatigue	16.3% 7/43 • Number of events 10 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
General disorders Mucosal inflammation	9.3% 4/43 • Number of events 4 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
General disorders Oedema peripheral	9.3% 4/43 • Number of events 10 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
General disorders Pain	7.0% 3/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
General disorders Pyrexia	48.8% 21/43 • Number of events 35 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Infections and infestations Bacteraemia	7.0% 3/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Investigations Alanine aminotransferase increased	11.6% 5/43 • Number of events 9 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Investigations Aspartate aminotransferase increased	14.0% 6/43 • Number of events 11 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Investigations Blood creatinine increased	11.6% 5/43 • Number of events 20 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Investigations Blood potassium decreased	7.0% 3/43 • Number of events 13 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Investigations Platelet count decreased	18.6% 8/43 • Number of events 41 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Investigations Weight decreased	7.0% 3/43 • Number of events 6 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Decreased appetite	20.9% 9/43 • Number of events 12 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Fluid overload	7.0% 3/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Hypercalcaemia	9.3% 4/43 • Number of events 14 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Hyperglycaemia	11.6% 5/43 • Number of events 15 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Hyperkalaemia	7.0% 3/43 • Number of events 5 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Hypocalcaemia	14.0% 6/43 • Number of events 18 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Hypokalaemia	20.9% 9/43 • Number of events 40 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Hypomagnesaemia	18.6% 8/43 • Number of events 10 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Hyponatraemia	14.0% 6/43 • Number of events 11 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Hypophosphataemia	11.6% 5/43 • Number of events 15 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Metabolism and nutrition disorders Tumour lysis syndrome	9.3% 4/43 • Number of events 4 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Musculoskeletal and connective tissue disorders Arthralgia	7.0% 3/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Musculoskeletal and connective tissue disorders Back pain	7.0% 3/43 • Number of events 5 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Musculoskeletal and connective tissue disorders Bone pain	7.0% 3/43 • Number of events 4 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Musculoskeletal and connective tissue disorders Pain in extremity	11.6% 5/43 • Number of events 8 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute lymphocytic leukaemia	9.3% 4/43 • Number of events 4 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute myeloid leukaemia	7.0% 3/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Nervous system disorders Dizziness	7.0% 3/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Nervous system disorders Headache	20.9% 9/43 • Number of events 12 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Psychiatric disorders Anxiety	7.0% 3/43 • Number of events 4 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Respiratory, thoracic and mediastinal disorders Cough	27.9% 12/43 • Number of events 13 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Respiratory, thoracic and mediastinal disorders Dyspnoea	11.6% 5/43 • Number of events 6 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Respiratory, thoracic and mediastinal disorders Epistaxis	14.0% 6/43 • Number of events 6 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Respiratory, thoracic and mediastinal disorders Productive cough	7.0% 3/43 • Number of events 4 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	7.0% 3/43 • Number of events 4 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	7.0% 3/43 • Number of events 3 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Skin and subcutaneous tissue disorders Dry skin	7.0% 3/43 • Number of events 4 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Skin and subcutaneous tissue disorders Pruritus	9.3% 4/43 • Number of events 5 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Skin and subcutaneous tissue disorders Rash	11.6% 5/43 • Number of events 7 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Vascular disorders Hypertension	27.9% 12/43 • Number of events 19 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Vascular disorders Hypotension	18.6% 8/43 • Number of events 18 • Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days. Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.

Additional Information

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Results disclosure agreements

Principal investigator is a sponsor employee Investigator/Institution must submit proposed publication to Sponsor for review within a prespecified number of days before submission for publication. If Sponsor's review shows that potentially patentable subject matter would be disclosed, publication/public disclosure shall be delayed to enable Sponsor, or Sponsor's designees, to file necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
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