Trial Outcomes & Findings for Study to Assess the Effect of Treatment With Bendamustine in Combination With Rituximab on QT Interval in Patients With Advanced Indolent Non-Hodgkin's Lymphoma (NHL) or Mantle Cell Lymphoma (MCL) (NCT NCT01073163)

Last Updated: 2014-04-24

Results Overview

On Day 2 of Cycle 1, three electrocardiograms (ECGs) were collected 15 minutes prior to any study drug administration. The baseline ECG interval value was obtained by averaging these 3 ECGs, and was compared to the average of the 3 ECGs taken on treatment with bendamustine at the end of the infusion.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

54 participants

Primary outcome timeframe

Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): at the end of the 30-minute infusion.

Results posted on

2014-04-24

Participant Flow

Sixty-five patients were screened for this study; 8 did not meet eligibility criteria, and 3 were not enrolled for other reasons.

Participant milestones

Participant milestones
Measure	Bendamustine With Rituximab Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Overall Study STARTED	54
Overall Study Enrolled But Not Treated	1
Overall Study Treated With <6 Cycles	4
Overall Study Treated With >=6 Cycles	49
Overall Study COMPLETED	51
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Bendamustine With Rituximab Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Overall Study Adverse Event	1
Overall Study Disease Progression	1
Overall Study Early termination	1

Baseline Characteristics

Study to Assess the Effect of Treatment With Bendamustine in Combination With Rituximab on QT Interval in Patients With Advanced Indolent Non-Hodgkin's Lymphoma (NHL) or Mantle Cell Lymphoma (MCL)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bendamustine With Rituximab n=54 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Age, Continuous AgeContinuous	62.9 years STANDARD_DEVIATION 10.50 • n=5 Participants
Sex: Female, Male Female	21 Participants n=5 Participants
Sex: Female, Male Male	33 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	50 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 participants n=5 Participants
Race/Ethnicity, Customized Asian	1 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	0 participants n=5 Participants
Race/Ethnicity, Customized White	49 participants n=5 Participants
Race/Ethnicity, Customized Other	4 participants n=5 Participants
Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status Score=0	29 participants n=5 Participants
Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status Score=1	20 participants n=5 Participants
Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status Score=2	5 participants n=5 Participants
Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status Score=3	0 participants n=5 Participants
Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status Score=4	0 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): at the end of the 30-minute infusion.

Population: ECG Analysis Set: all enrolled participants in study who received at least 1 dose of study drug and with at least 1 available baseline and 1 on-treatment ECG; n=number of participants with measurement at given time point.

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=53 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Mean Change From Baseline in QT Interval as Corrected by the Fridericia Method (QTcF) at End of Infusion Baseline, n=53	410.4 milliseconds (ms) Standard Deviation 23.6	—	—
Mean Change From Baseline in QT Interval as Corrected by the Fridericia Method (QTcF) at End of Infusion End of Infusion, n=52	6.7 milliseconds (ms) Standard Deviation 10.3 • Interval 9.1 to 4.3	—	—

SECONDARY outcome

Timeframe: Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): 1 hour postinfusion.

Population: ECG Analysis Set: all enrolled participants in study who received at least 1 dose of study drug and with at least 1 available baseline and 1 on-treatment ECG.

On Day 2 of Cycle 1, three ECGs were collected 15 minutes prior to any study drug administration. The baseline ECG interval value was obtained by averaging these 3 ECGs, and was compared to the average of the 3 ECGs taken on treatment with bendamustine 1 hour postinfusion.

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=53 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Mean Change From Baseline in QTcF at 1 Hour Postinfusion Baseline	410.4 ms Standard Deviation 23.6	—	—
Mean Change From Baseline in QTcF at 1 Hour Postinfusion 1 Hour Postinfusion	4.1 ms Standard Deviation 9.8	—	—

SECONDARY outcome

Timeframe: Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): at the end of the 30-minute infusion and 1 hour postinfusion.

Participants were considered to have an outlier ECG value based on the most extreme value across each of the time points. "New" means not present at baseline and becomes present on at least 1 on-treatment ECG time point. A participant had a new outlier event (500) if the maximum QTcF was \>500 ms while their baseline was \<=500 ms, or had an outlier event (480) if the maximum QTcF was \>480 ms while their baseline was \<= 480 ms. QTcF in the 30-60 ms or \>60 ms categories were also considered outliers.

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=53 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Number of Participants With QTcF New Outlier Events at End of Infusion and 1 Hour Postinfusion QTcF New >500 ms at End of Infusion; n=52	0 participants	—	—
Number of Participants With QTcF New Outlier Events at End of Infusion and 1 Hour Postinfusion QTcF New >500 ms 1 Hour Postinfusion; n=53	0 participants	—	—
Number of Participants With QTcF New Outlier Events at End of Infusion and 1 Hour Postinfusion QTcF New >480 ms at End of Infusion; n=52	1 participants	—	—
Number of Participants With QTcF New Outlier Events at End of Infusion and 1 Hour Postinfusion QTcF New >480 ms 1 Hour Postinfusion; n=53	0 participants	—	—
Number of Participants With QTcF New Outlier Events at End of Infusion and 1 Hour Postinfusion QTcF New >60 ms at End of Infusion; n=52	0 participants	—	—
Number of Participants With QTcF New Outlier Events at End of Infusion and 1 Hour Postinfusion QTcF New >60 ms 1 Hour Postinfusion; n=53	0 participants	—	—
Number of Participants With QTcF New Outlier Events at End of Infusion and 1 Hour Postinfusion QTcF New 30-60 ms at End of Infusion; n=52	0 participants	—	—
Number of Participants With QTcF New Outlier Events at End of Infusion and 1 Hour Postinfusion QTcF New 30-60 ms 1 Hour Postinfusion; n=53	0 participants	—	—

SECONDARY outcome

Timeframe: Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): at the end of the 30-minute infusion and 1 hour postinfusion.

Population: ECG Analysis Set: all enrolled participants in study who received at least 1 dose of study drug and with at least 1 available baseline and 1 on-treatment ECG.

The core ECG laboratory cardiologist assessed all leads in the ECGs and defined morphological changes. Changes from baseline (looking at each of the 3 ECGs at Day 2 Cycle 1 individually and the ECGs at all on-treatment time points individually) were noted for the following events: atrial fibrillation or flutter; second degree heart block; third degree heart block; complete right bundle branch block; complete left bundle branch block; ST segment depression; T wave abnormalities (negative T waves only); myocardial infarction pattern; any new abnormal U waves.

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=53 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Number of Participants With New Onset ECG Waveform Morphological Changes	0 participants	—	—

SECONDARY outcome

Timeframe: Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.

Population: Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.

Number of participants with cardiac disorders overall, with severity from grades 1 (mild) to grade 4 (severe), according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5= death). Participants may have reported more than 1 event.

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=53 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Number of Participants With Treatment-Emergent Cardiac Disorders ECG QT prolonged: Overall	3 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders ECG QT prolonged: Grade >/=3	2 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Blood pressure decreased: Overall	1 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Blood pressure decreased: Grade >/=3	1 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Cardiac murmur: Overall	1 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Cardiac murmur: Grade >/=3	0 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders ECG ST segment abnormal: Overall	1 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders ECG ST segment abnormal: Grade >/=3	0 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Heart rate irregular: Overall	1 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Heart rate irregular: Grade >/=3	0 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Palpitations: Overall	2 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Palpitations: Grade >/=3	0 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Arteriosclerosis coronary artery: Overall	1 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Arteriosclerosis coronary artery: Grade >/=3	0 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Atrial fibrillation: Overall	1 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Atrial fibrillation: Grade >/=3	0 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Cardiac failure congestive: Overall	1 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Cardiac failure congestive: Grade >/=3	0 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Left ventricular dysfunction: Overall	1 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Left ventricular dysfunction: Grade >/=3	1 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Sinus tachycardia: Overall	1 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Sinus tachycardia: Grade >/=3	0 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Tachycardia: Overall	1 participants	—	—
Number of Participants With Treatment-Emergent Cardiac Disorders Tachycardia: Grade >/=3	0 participants	—	—

SECONDARY outcome

Timeframe: Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): at the end of the 30-minute infusion and 1 hour postinfusion.

Population: Pharmacokinetic-pharmacodynamic Analysis Set: all enrolled participants in study who received at least 1 dose of study drug and with at least 1 available baseline and 1 on-treatment ECG and at least 1 ECG with a time-matched plasma concentration pair.

Results from a pharmacokinetic-pharmacodynamic model to show the relationship of the overall predicted change from Baseline in QTcF at the average Cmax of bendamustine and its metabolites M3 and M4.

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=51 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Change From Baseline in QTcF at Maximum Concentration (Cmax) of Bendamustine and Its Metabolites (M3 and M4) Bendamustine	5.4097 ms Interval to 7.567 One-sided confidence interval was calculated.	—	—
Change From Baseline in QTcF at Maximum Concentration (Cmax) of Bendamustine and Its Metabolites (M3 and M4) Metabolite M3	5.9995 ms Interval to 8.8415 One-sided confidence interval was calculated.	—	—
Change From Baseline in QTcF at Maximum Concentration (Cmax) of Bendamustine and Its Metabolites (M3 and M4) Metabolite M4	7.1390 ms Interval to 10.0904 One-sided confidence interval was calculated.	—	—

SECONDARY outcome

Timeframe: Day 1 of Cycle 1: prior to start of bendamustine infusion, immediately postinfusion, 15 minutes and 30 minutes postinfusion. Day 2 of Cycle 1: 15 minutes prior to start of bendamustine infusion, 15 minutes, 30 minutes, 1, 3, and 5 hours postinfusion.

Population: Pharmacokinetic Analysis Set: all enrolled participants in study who received at least 1 dose of study drug and with at least 1 quantifiable bendamustine plasma concentration.

Boxplots of model-predicted Bayesian bendamustine clearance (CL) values in the presence of rituximab were generated based on the administered bendamustine doses, rate of infusion, and sample times.

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=49 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Model-predicted Bayesian Bendamustine Clearance in the Presence of Rituximab	32.9 L/h Full Range 12.8 • Interval 0.9 to 58.5	—	—

SECONDARY outcome

Timeframe: Day 1 of Cycle 1: prior to start of rituximab infusion, immediately postinfusion. Day 2 of Cycle 1: 15 minutes prior to the start of the bendamustine infusion. Day 7 and Day 14: anytime. Day 1 of Cycle 2: prior to start of rituximab infusion.

Population: Pharmacokinetic Analysis Set: all enrolled participants in study who received at least 1 dose of study drug and with at least 1 quantifiable serum concentration of rituximab.

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=19 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Rituximab Concentrations at 0.5 Hours, 24 Hours, and 7 Days Postinfusion 0.5 Hours Postinfusion; n=19	173.0 mcg/mL Interval 74.5 to 299.0	—	—
Rituximab Concentrations at 0.5 Hours, 24 Hours, and 7 Days Postinfusion 24 Hours Postinfusion; n=19	105.0 mcg/mL Interval 4.62 to 176.0	—	—
Rituximab Concentrations at 0.5 Hours, 24 Hours, and 7 Days Postinfusion 7 Days Postinfusion; n=17	30.5 mcg/mL Interval 0.256 to 73.3	—	—

SECONDARY outcome

Timeframe: The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.

Population: Full Analysis Set: all enrolled participants who received at least 1 dose of both bendamustine and rituximab and who had both a baseline and at least 1 postbaseline tumor response evaluation.

Complete response, as defined by the International Working Group (IWG) Revised Response Criteria For Malignant Lymphoma. Results are presented for participants with non-Hodgkin lymphoma and mantle cell lymphoma as well as all participants.

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=40 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma n=11 Participants Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total n=51 Participants All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Percentage of Participants With Complete Response (CR)	40 percentage of participants Interval 24.9 to 56.7	55 percentage of participants Interval 23.4 to 83.3	43 percentage of participants Interval 29.3 to 57.8

SECONDARY outcome

Timeframe: The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.

Overall Response was comprised of those participants who had Complete Response (CR) plus those who had Partial Response (PR), as defined by the International Working Group (IWG) Revised Response Criteria For Malignant Lymphoma. Results are presented for participants with non-Hodgkin lymphoma and mantle cell lymphoma as well as all participants.

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=40 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma n=11 Participants Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total n=51 Participants All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Percentage of Participants With Overall Response	93 percentage of participants Interval 79.6 to 98.4	100 percentage of participants Interval 71.5 to 100.0	94 percentage of participants Interval 83.8 to 98.8

SECONDARY outcome

Population: Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.

Adverse event (AE)=any untoward medical occurrence in a patient administered study drug that develops or worsens in severity during the conduct of a clinical study of a pharmaceutical product and does not necessarily have a causal relationship to the study drug. Treatment-related AEs=those that began or worsened after treatment with study drug. AE severity was graded according to the National Cancer Institute's Common Terminology Criteria for AEs (grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5= death). Relationship of an AE to study drug was categorized as definite, probable, possible, unlikely, or not related. Serious AE (SAE)=one that occurred at any dose that resulted in any of the following outcomes or actions: death; a life-threatening adverse event; inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant disability/incapacity; a congenital anomaly/birth defect; or an otherwise important medical event.

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=53 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Overview of Adverse Events Any adverse event	53 participants	—	—
Overview of Adverse Events Severe adverse events (grade 3, 4, 5)	33 participants	—	—
Overview of Adverse Events Treatment-related adverse events	52 participants	—	—
Overview of Adverse Events Deaths	1 participants	—	—
Overview of Adverse Events Other serious adverse events	14 participants	—	—
Overview of Adverse Events Withdrawn from study due to adverse events	1 participants	—	—

SECONDARY outcome

Timeframe: End of study. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.

Population: Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.

The investigator assessed each patient's ECOG performance status according to the ECOG scale at screening, on Day 1 of each treatment cycle, and at the end-of-treatment visit. Scale scores were: 0=fully active, able to carry on all pre-disease performance without restriction; 1=restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 2=ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; 5=dead. Any change in score to a higher value signifies worsening, and any change to a lower value signifies improvement.

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=53 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Eastern Cooperative Oncology Group (ECOG) Performance Status at Endpoint Improved	10 participants	—	—
Eastern Cooperative Oncology Group (ECOG) Performance Status at Endpoint Stayed the same	35 participants	—	—
Eastern Cooperative Oncology Group (ECOG) Performance Status at Endpoint Worsened	8 participants	—	—

SECONDARY outcome

Population: Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.

Grade 1=Mild, 2=Moderate, 3=Severe/medically significant, 4=Life-threatening. Overall is defined as the worst postbaseline grade value for each patient and laboratory test across all cycles. Only postbaseline grades are summarized. If absolute neutrophil count (ANC) and neutrophils absolute (ABS) were both measured, the worse grade value from the two was summarized. Otherwise the worst ANC grade value or the worst neutrophils ABS grade value was summarized. WBC=white blood cell; LLN=lower limit of normal

Outcome measures

Outcome measures
Measure	Bendamustine With Rituximab n=53 Participants Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Mantle Cell Lymphoma Participants with mantle cell lymphoma were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.	Total All participants administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall ANC, Grade 1: <LLN - 1.5*10^9/L	5 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall ANC, Grade 2: <1.5 - 1.0*10^9/L	12 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall ANC, Grade 3: <1.0 - 0.5*10^9/L	11 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall ANC, Grade 4: <0.5*10^9/L	12 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall ANC, Grade 1-4	40 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Hemoglobin, Grade 1: <LLN - 100 g/L	36 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Hemoglobin, Grade 2: <100 - 80 g/L	12 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Hemoglobin, Grade 3: <80 - 65 g/L	1 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Hemoglobin, Grade 4: <65 g/L	0 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Hemoglobin, Grade 1-4	49 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Lymphocytes ABS, Grade 1: <LLN - 0.8*10^9/L	0 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Lymphocytes ABS, Grade 2: <0.8 - 0.5*10^9/L	2 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Lymphocytes ABS, Grade 3: <0.5 - 0.2*10^9/L	13 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Lymphocytes ABS, Grade 4: <0.2*10^9/L	22 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Lymphocytes ABS, Grade 1-4	37 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Platelets, Grade 1: <LLN - 75.0*10^9/L	19 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Platelets, Grade 2: <75.0 - 50.0*10^9/L	9 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Platelets, Grade 3: <50.0 - 25.0*10^9/L	3 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Platelets, Grade 4: <25.0*10^9 /L	1 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall Platelets, Grade 1-4	32 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall WBC, Grade 1: <LLN - 3.0*10^9/L	9 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall WBC, Grade 2: <3.0 - 2.0*10^9/L	19 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall WBC, Grade 3: <2.0 - 1.0*10^9/L	15 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall WBC, Grade 4: <1.0*10^9/L	5 participants	—	—
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall WBC, Grade 1-4	48 participants	—	—

Adverse Events

Bendamustine With Rituximab

Serious events: 14 serious events

Other events: 53 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Bendamustine With Rituximab n=53 participants at risk Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Blood and lymphatic system disorders Febrile neutropenia	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Blood and lymphatic system disorders Neutropenia	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Cardiac disorders Atrial fibrillation	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Cardiac disorders Left ventricular dysfunction	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Appendix disorder	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Ascites	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Small intestinal obstruction	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
General disorders Asthenia	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
General disorders Chills	1.9% 1/53 • Number of events 2 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
General disorders Pyrexia	3.8% 2/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Infections and infestations Bacteraemia	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Infections and infestations Cellulitis	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Infections and infestations Pneumonia	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Infections and infestations Urinary tract infection	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Injury, poisoning and procedural complications Infusion related reaction	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Metabolism and nutrition disorders Dehydration	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Renal and urinary disorders Haematuria	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Renal and urinary disorders Urinary retention	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Respiratory, thoracic and mediastinal disorders Pleural effusion	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Respiratory, thoracic and mediastinal disorders Pneumonitis	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Skin and subcutaneous tissue disorders Rash	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Skin and subcutaneous tissue disorders Transient acantholytic dermatosis	1.9% 1/53 • Number of events 1 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.

Other adverse events

Other adverse events
Measure	Bendamustine With Rituximab n=53 participants at risk Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m\^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m\^2 on Day 1 of each 28-day cycle.
Blood and lymphatic system disorders Anaemia	11.3% 6/53 • Number of events 18 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Blood and lymphatic system disorders Neutropenia	35.8% 19/53 • Number of events 50 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Blood and lymphatic system disorders Thrombocytopenia	20.8% 11/53 • Number of events 18 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Abdominal discomfort	9.4% 5/53 • Number of events 5 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Abdominal pain	9.4% 5/53 • Number of events 9 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Abdominal pain upper	11.3% 6/53 • Number of events 6 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Constipation	41.5% 22/53 • Number of events 28 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Diarrhoea	30.2% 16/53 • Number of events 21 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Dyspepsia	7.5% 4/53 • Number of events 4 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Gastrooesophageal reflux disease	9.4% 5/53 • Number of events 5 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Mouth ulceration	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Nausea	71.7% 38/53 • Number of events 56 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Stomatitis	13.2% 7/53 • Number of events 8 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Gastrointestinal disorders Vomiting	30.2% 16/53 • Number of events 21 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
General disorders Asthenia	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
General disorders Chills	13.2% 7/53 • Number of events 9 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
General disorders Fatigue	50.9% 27/53 • Number of events 38 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
General disorders Feeling cold	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
General disorders Influenza like illness	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
General disorders Oedema peripheral	7.5% 4/53 • Number of events 6 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
General disorders Pain	11.3% 6/53 • Number of events 6 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
General disorders Pyrexia	22.6% 12/53 • Number of events 20 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Immune system disorders Drug hypersensitivity	15.1% 8/53 • Number of events 10 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Infections and infestations Nasopharyngitis	7.5% 4/53 • Number of events 4 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Infections and infestations Oral herpes	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Infections and infestations Upper respiratory tract infection	9.4% 5/53 • Number of events 5 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Infections and infestations Urinary tract infection	9.4% 5/53 • Number of events 9 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Injury, poisoning and procedural complications Contusion	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Injury, poisoning and procedural complications Infusion related reaction	35.8% 19/53 • Number of events 46 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Investigations Electrocardiogram QT prolonged	5.7% 3/53 • Number of events 4 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Investigations Weight decreased	11.3% 6/53 • Number of events 6 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Metabolism and nutrition disorders Decreased appetite	20.8% 11/53 • Number of events 12 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Metabolism and nutrition disorders Dehydration	7.5% 4/53 • Number of events 5 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Metabolism and nutrition disorders Hypokalaemia	9.4% 5/53 • Number of events 6 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Metabolism and nutrition disorders Hypomagnesaemia	5.7% 3/53 • Number of events 5 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Musculoskeletal and connective tissue disorders Back pain	15.1% 8/53 • Number of events 9 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Musculoskeletal and connective tissue disorders Bone pain	11.3% 6/53 • Number of events 7 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Musculoskeletal and connective tissue disorders Flank pain	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Musculoskeletal and connective tissue disorders Myalgia	7.5% 4/53 • Number of events 4 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Nervous system disorders Dizziness	9.4% 5/53 • Number of events 6 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Nervous system disorders Dysgeusia	17.0% 9/53 • Number of events 10 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Nervous system disorders Headache	17.0% 9/53 • Number of events 10 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Psychiatric disorders Anxiety	9.4% 5/53 • Number of events 6 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Psychiatric disorders Depression	7.5% 4/53 • Number of events 4 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Psychiatric disorders Insomnia	22.6% 12/53 • Number of events 13 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Renal and urinary disorders Nocturia	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Renal and urinary disorders Pollakiuria	7.5% 4/53 • Number of events 4 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Respiratory, thoracic and mediastinal disorders Cough	20.8% 11/53 • Number of events 12 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Respiratory, thoracic and mediastinal disorders Dysphonia	7.5% 4/53 • Number of events 4 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	13.2% 7/53 • Number of events 8 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	7.5% 4/53 • Number of events 4 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Respiratory, thoracic and mediastinal disorders Hiccups	5.7% 3/53 • Number of events 4 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Respiratory, thoracic and mediastinal disorders Pleural effusion	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Respiratory, thoracic and mediastinal disorders Productive cough	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Respiratory, thoracic and mediastinal disorders Wheezing	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Skin and subcutaneous tissue disorders Alopecia	7.5% 4/53 • Number of events 4 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Skin and subcutaneous tissue disorders Night sweats	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Skin and subcutaneous tissue disorders Pruritus	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Skin and subcutaneous tissue disorders Rash	13.2% 7/53 • Number of events 9 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Vascular disorders Hot flush	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Vascular disorders Hypotension	5.7% 3/53 • Number of events 3 • Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.

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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Restriction type: OTHER