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)

• Sponsor: Cephalon (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01073163
• Collaborator: (none)
• Enrollment: 54
• Locations: 43
• Arm: 1
• Duration (Months): 28
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The primary objective of this study is to assess the effect of treatment with bendamustine on cardiac repolarization as reflected by the rate-corrected QT interval by the Fridericia method (QTcF).

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkin's Lymphoma; Mantle Cell Lymphoma	Drug: Bendamustine; Drug: Rituximab	Phase 3

Detailed Description

This study was originally conducted as a substudy in a subset of patients enrolled in the phase 3 study C18083/3064/NL/MN (NCT00877006) who were randomly assigned to treatment with bendamustine in combination with rituximab (BR) and who satisfied additional eligibility criteria related to cardiac function. The objective of the substudy was to obtain results to assess the effect of bendamustine treatment on cardiac polarization and any potential changes in the QT interval (corrected by the Fridericia method [QTcF]). After a period of time, the substudy was amended to be a separate stand-alone study to ensure that an adequate number of patients were included. Patients were treated for 6, and up to 8, cycles in the stand-alone study, and efficacy and safety were also assessed. In addition, a requirement to assess the pharmacokinetics of bendamustine and rituximab when used as combination therapy was added to the objectives, to determine the potential for drug interaction between bendamustine and rituximab.

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 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)
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Bendamustine; Bendamustine at 90 mg/m^2 IV on Days 1 and 2 of a 28-day cycle.; Other Names: Treakisym Ribomustin Levact Treanda SDX-105 ; Drug: Rituximab; Rituximab at 375 mg/m^2 IV on Day 1 of a 28-day cycle.; Other Names: Rituxan MabThera IDEC-C2B8

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in QT Interval as Corrected by the Fridericia Method (QTcF) at End of Infusion [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.]

   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.

Secondary Outcome Measures

1. Mean Change From Baseline in QTcF at 1 Hour Postinfusion [Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): 1 hour postinfusion.]

   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.

2. Number of Participants With QTcF New Outlier Events at End of Infusion and 1 Hour Postinfusion [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.

3. Number of Participants With New Onset ECG Waveform Morphological Changes [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.]

   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.

4. Number of Participants With Treatment-Emergent Cardiac Disorders [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.]

   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.

5. Change From Baseline in QTcF at Maximum Concentration (Cmax) of Bendamustine and Its Metabolites (M3 and M4) [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.]

   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.

6. Model-predicted Bayesian Bendamustine Clearance in the Presence of Rituximab [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.]

   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.

7. Rituximab Concentrations at 0.5 Hours, 24 Hours, and 7 Days Postinfusion [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.]

8. Percentage of Participants With Complete Response (CR) [The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.]

   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.

9. Percentage of Participants With Overall Response [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.

10. Overview of Adverse Events [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.]

    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.

11. Eastern Cooperative Oncology Group (ECOG) Performance Status at Endpoint [End of study. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.]

    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.

12. Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall [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.]

    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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Histopathologic confirmation of one of the following CD20+ B-cell non-Hodgkin's lymphomas. Tissue diagnostic procedures must be performed within 6 months of study entry and with biopsy material available for review:

• follicular lymphoma (grade 1 or 2)

• immunoplasmacytoma/immunocytoma (Waldenstrom's macroglobulinemia)

• splenic marginal zone B-cell lymphoma

• extra-nodal marginal zone lymphoma of mucosa associated lymphoid tumor (MALT) type

• nodal marginal zone B-cell lymphoma

• mantle cell lymphoma

• Meets one of the following need-for-treatment criteria (with the exception of mantle cell lymphoma for which treatment is indicated):

• presence of at least one of the following B-symptoms:

1. fever (>38ºC) of unclear etiology

2. night sweats

3. weight loss of greater than 10% within the prior 6 months

• large tumor mass (bulky disease)

• presence of lymphoma-related complications, including narrowing of ureters or bile ducts, tumor-related compression of a vital organ, lymphoma induced pain, cytopenias related to lymphoma/leukemia, splenomegaly, pleural effusions, or ascites

• hyperviscosity syndrome due to monoclonal gammopathy

• CD20-positive B cells in lymph node biopsy or other lymphoma pathology specimen

• No prior treatment. Patients on "watch and wait" may enter the study if a recent biopsy (obtained within the last 6 months) is available.

• Adequate hematologic function (unless abnormalities related to lymphoma infiltration of the bone marrow or hypersplenism due to lymphoma) as follows:

• hemoglobin of >= 10.0 g/dL

• absolute neutrophil count (ANC) >=1.5*10^9/L

• platelet count >=100*10^9/L

• Bidimensionally measurable disease (field not previously radiated)

• Able to provide written informed consent

• Eastern Cooperative Oncology Group (ECOG) performance status <=2

• Estimated life expectancy >=6 months

• Serum creatinine of <=2.0 mg/dL or creatinine clearance >=50 mL/min

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5* upper limit of normal (ULN), and alkaline phosphatase and total bilirubin within normal limits

• Left ventricular ejection fraction (LVEF) >=50% by multiple gated acquisition scan (MUGA) or cardiac echocardiogram (ECHO), prior for any patient to be treated with rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP)

• A medically accepted method of contraception to be used by women of childbearing potential (not surgically sterile or at least 12 months naturally postmenopausal)

• Men capable of producing offspring and not surgically sterile must practice abstinence or use a barrier method of birth control

Key Exclusion Criteria:

• Chronic lymphocytic leukemia, small lymphocytic lymphoma (SLL), or grade 3 follicular lymphoma

• Transformed disease. Bone marrow blasts are permitted, however, transformed disease indicating leukemic involvement is not permitted

• Central nervous system (CNS) lymphomatous involvement or leptomeningeal lymphoma

• Prior radiation for non-Hodgkin's lymphoma (NHL), except for a single course of locally delimited radiation therapy with a radiation field not exceeding 2 adjacent lymph node regions

• Active malignancy, other than NHL, within the past 3 years except for localized prostate cancer treated with hormone therapy, cervical carcinoma in situ, breast cancer in situ, or non-melanoma skin cancer following definitive treatment

• New York Heart Association (NYHA) Class III or IV heart failure, arrhythmias or unstable angina, electrocardiographic evidence of active ischemia or active conduction system abnormalities, or myocardial infarction within the last 6 months. (Prior to study entry, ECG abnormalities at screening must be documented by the investigator as not medically relevant)

• Known human immunodeficiency virus (HIV) positivity

• Active hepatitis B or hepatitis C infection (Hepatitis B surface antigen testing required)

• Women who are pregnant or lactating

• Corticosteroids for treatment of lymphoma within 28 days of study entry. Chronically administered low-dose corticosteroids (e.g., prednisone ≤20 mg/day) for indications other than lymphoma or lymphoma-related complications are permitted

• Any serious uncontrolled, medical or psychological disorder that would impair the ability of the patient to receive therapy

• Any condition which places the patient at unacceptable risk or confounds the ability of the investigators to interpret study data

• Any other investigational agent within 28 days of study entry

• Known hypersensitivity to bendamustine, mannitol, or other study-related drugs

• The patient has Ann Arbor stage I disease

• The patient has a history of congenital long QT syndrome

• The patient has a history of cardiac disease with significant potential for QT prolongation

• The patient has screening electrocardiography (ECG) on Day 1 of Cycle 1 with QTcF interval >450 ms that is confirmed by a second ECG. If the QTcF interval is >450 ms on both ECGs, the ECGs will be sent to eResearch Technology, Inc. (ERT), the Central ECG Reader vendor, for an overread (with 24-hour turn around time) and ERT will make a final decision on enrollment

• The patient has serum potassium or magnesium less than the lower limit of normal

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hematology Oncology Physicans Extenders Group	Tucson	Arizona	United States
2	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States
3	St. Jude Heritage Medical Group	Fullerton	California	United States
4	Comprehensive Cancer Center	Palm Springs	California	United States
5	University of Colorado Cancer Center	Aurora	Colorado	United States
6	Rocky Mountain Cancer Center	Denver	Colorado	United States
7	The Hospital of Central Connecticut	New Britain	Connecticut	United States
8	Cancer Center of Central Connecticut	Southington	Connecticut	United States
9	Memorial Cancer Institute	Hollywood	Florida	United States
10	Cancer Centers of Florida	Orlando	Florida	United States
11	MD Anderson Cancer Cnt Orlando	Orlando	Florida	United States
12	John B Amos Cancer Center	Columbus	Georgia	United States
13	St Francis Cancer Research Foundation	Beech Grove	Indiana	United States
14	Cedar Valley Medical Specialists	Waterloo	Iowa	United States
15	Cancer Center of Kansas	Wichita	Kansas	United States
16	University of Kentucky	Lexington	Kentucky	United States
17	LSU Health Sciences Center - Shreveport	Shreveport	Louisiana	United States
18	MaineGeneral Medical Center	Augusta	Maine	United States
19	Missouri Cancer Associates	Columbia	Missouri	United States
20	Kansas City Cancer Center	Kansas City	Missouri	United States
21	UNM Cancer Center/New Mexico Cancer Care Alliance	Albuquerque	New Mexico	United States
22	Interlakes Foundation, Inc	Rochester	New York	United States
23	SUNY Upstate / Upstate Medical University	Syracuse	New York	United States
24	Willamette Valley Cancer Center	Springfield	Oregon	United States
25	Geisinger Medical Center	Danville	Pennsylvania	United States
26	Pennsylvania Oncology Hematology Associates, Inc.	Philadelphia	Pennsylvania	United States
27	Charleston Hematology Oncology, PA	Charleston	South Carolina	United States
28	Sarah Cannon Cancer Center	Nashville	Tennessee	United States
29	Texas Oncology, P.A.	Fort Worth	Texas	United States
30	Cancer Care Center of South Texas	San Antonio	Texas	United States
31	Texas Oncology	Tyler	Texas	United States
32	Virginia Oncology Associates	Norfolk	Virginia	United States
33	Cancer Outreach Asscociates, PC	Richlands	Virginia	United States
34	Cancer Care Northwest-South	Spokane	Washington	United States
35	Northwest Cancer Specialists, PC	Vancouver	Washington	United States
36	West Virginia University School of Medicine	Morgantown	West Virginia	United States
37	The Canberra Hospital	Garran	Australian Capital Territory	Australia
38	Royal Adelaide Hospital	Adelaide	South Australia	Australia
39	The Queen Elizabeth Hospital	Woodville	South Australia	Australia
40	Royal Hobart Hospital	Hobart	Tasmania	Australia
41	The Alfred Hospital	Melbourne	Victoria	Australia
42	Queen Elizabeth II Health Sciences Centre	Halifax	Nova Scotia	Canada
43	Ottawa Hospital - General Campus	Ottawa	Ontario	Canada

Sponsors and Collaborators

• Cephalon

Investigators

• Study Director: Sponsor's Medical Expert, Cephalon

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cephalon
• ClinicalTrials.gov Identifier: NCT01073163
• Other Study ID Numbers: C18083/3070
• First Posted: Feb 23, 2010
• Last Update Posted: Apr 24, 2014
• Last Verified: Apr 1, 2014

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Rituximab; Bendamustine Hydrochloride

Study Results

Participant Flow

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

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
Period Title: Overall Study
STARTED	54
Enrolled But Not Treated	1
Treated With <6 Cycles	4
Treated With >=6 Cycles	49
COMPLETED	51
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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 Participants	54
Age (years) [Mean (Standard Deviation) ]
AgeContinuous	62.9 (10.50)
Sex: Female, Male (Count of Participants)
Female	21 38.9%
Male	33 61.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 3.7%
Not Hispanic or Latino	50 92.6%
Unknown or Not Reported	2 3.7%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	0 0%
Asian	1 1.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	49 90.7%
Other	4 7.4%
Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
Score=0	29 53.7%
Score=1	20 37%
Score=2	5 9.3%
Score=3	0 0%
Score=4	0 0%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in QT Interval as Corrected by the Fridericia Method (QTcF) at End of Infusion
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
Measure Participants	53
Baseline, n=53	410.4 (23.6)
End of Infusion, n=52	6.7 (10.3)

2. Secondary Outcome

Title	Mean Change From Baseline in QTcF at 1 Hour Postinfusion
Description	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.
Time Frame	Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): 1 hour postinfusion.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
Measure Participants	53
Baseline	410.4 (23.6)
1 Hour Postinfusion	4.1 (9.8)

3. Secondary Outcome

Title	Number of Participants With QTcF New Outlier Events at End of Infusion and 1 Hour Postinfusion
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
Measure Participants	53
QTcF New >500 ms at End of Infusion; n=52	0 0%
QTcF New >500 ms 1 Hour Postinfusion; n=53	0 0%
QTcF New >480 ms at End of Infusion; n=52	1 1.9%
QTcF New >480 ms 1 Hour Postinfusion; n=53	0 0%
QTcF New >60 ms at End of Infusion; n=52	0 0%
QTcF New >60 ms 1 Hour Postinfusion; n=53	0 0%
QTcF New 30-60 ms at End of Infusion; n=52	0 0%
QTcF New 30-60 ms 1 Hour Postinfusion; n=53	0 0%

4. Secondary Outcome

Title	Number of Participants With New Onset ECG Waveform Morphological Changes
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
Measure Participants	53
Number [participants]	0 0%

5. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Cardiac Disorders
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
Measure Participants	53
ECG QT prolonged: Overall	3 5.6%
ECG QT prolonged: Grade >/=3	2 3.7%
Blood pressure decreased: Overall	1 1.9%
Blood pressure decreased: Grade >/=3	1 1.9%
Cardiac murmur: Overall	1 1.9%
Cardiac murmur: Grade >/=3	0 0%
ECG ST segment abnormal: Overall	1 1.9%
ECG ST segment abnormal: Grade >/=3	0 0%
Heart rate irregular: Overall	1 1.9%
Heart rate irregular: Grade >/=3	0 0%
Palpitations: Overall	2 3.7%
Palpitations: Grade >/=3	0 0%
Arteriosclerosis coronary artery: Overall	1 1.9%
Arteriosclerosis coronary artery: Grade >/=3	0 0%
Atrial fibrillation: Overall	1 1.9%
Atrial fibrillation: Grade >/=3	0 0%
Cardiac failure congestive: Overall	1 1.9%
Cardiac failure congestive: Grade >/=3	0 0%
Left ventricular dysfunction: Overall	1 1.9%
Left ventricular dysfunction: Grade >/=3	1 1.9%
Sinus tachycardia: Overall	1 1.9%
Sinus tachycardia: Grade >/=3	0 0%
Tachycardia: Overall	1 1.9%
Tachycardia: Grade >/=3	0 0%

6. Secondary Outcome

Title	Change From Baseline in QTcF at Maximum Concentration (Cmax) of Bendamustine and Its Metabolites (M3 and M4)
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
Measure Participants	51
Bendamustine	5.4097
Metabolite M3	5.9995
Metabolite M4	7.1390

7. Secondary Outcome

Title	Model-predicted Bayesian Bendamustine Clearance in the Presence of Rituximab
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
Measure Participants	49
Median (Full Range) [L/h]	32.9 (12.8)

8. Secondary Outcome

Title	Rituximab Concentrations at 0.5 Hours, 24 Hours, and 7 Days Postinfusion
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
Measure Participants	19
0.5 Hours Postinfusion; n=19	173.0
24 Hours Postinfusion; n=19	105.0
7 Days Postinfusion; n=17	30.5

9. Secondary Outcome

Title	Percentage of Participants With Complete Response (CR)
Description	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.
Time Frame	The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Non-Hodgkin Lymphoma	Mantle Cell Lymphoma	Total
Arm/Group Description	Participants with non-Hodgkin 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.	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.	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.
Measure Participants	40	11	51
Number (95% Confidence Interval) [percentage of participants]	40 74.1%	55 NaN	43 NaN

10. Secondary Outcome

Title	Percentage of Participants With Overall Response
Description	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.
Time Frame	The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Non-Hodgkin Lymphoma	Mantle Cell Lymphoma	Total
Arm/Group Description	Participants with non-Hodgkin 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.	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.	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.
Measure Participants	40	11	51
Number (95% Confidence Interval) [percentage of participants]	93 172.2%	100 NaN	94 NaN

11. Secondary Outcome

Title	Overview of Adverse Events
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
Measure Participants	53
Any adverse event	53 98.1%
Severe adverse events (grade 3, 4, 5)	33 61.1%
Treatment-related adverse events	52 96.3%
Deaths	1 1.9%
Other serious adverse events	14 25.9%
Withdrawn from study due to adverse events	1 1.9%

12. Secondary Outcome

Title	Eastern Cooperative Oncology Group (ECOG) Performance Status at Endpoint
Description	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.
Time Frame	End of study. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
Measure Participants	53
Improved	10 18.5%
Stayed the same	35 64.8%
Worsened	8 14.8%

13. Secondary Outcome

Title	Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall
Description	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
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
Measure Participants	53
ANC, Grade 1: <LLN - 1.5*10^9/L	5 9.3%
ANC, Grade 2: <1.5 - 1.0*10^9/L	12 22.2%
ANC, Grade 3: <1.0 - 0.5*10^9/L	11 20.4%
ANC, Grade 4: <0.5*10^9/L	12 22.2%
ANC, Grade 1-4	40 74.1%
Hemoglobin, Grade 1: <LLN - 100 g/L	36 66.7%
Hemoglobin, Grade 2: <100 - 80 g/L	12 22.2%
Hemoglobin, Grade 3: <80 - 65 g/L	1 1.9%
Hemoglobin, Grade 4: <65 g/L	0 0%
Hemoglobin, Grade 1-4	49 90.7%
Lymphocytes ABS, Grade 1: <LLN - 0.8*10^9/L	0 0%
Lymphocytes ABS, Grade 2: <0.8 - 0.5*10^9/L	2 3.7%
Lymphocytes ABS, Grade 3: <0.5 - 0.2*10^9/L	13 24.1%
Lymphocytes ABS, Grade 4: <0.2*10^9/L	22 40.7%
Lymphocytes ABS, Grade 1-4	37 68.5%
Platelets, Grade 1: <LLN - 75.0*10^9/L	19 35.2%
Platelets, Grade 2: <75.0 - 50.0*10^9/L	9 16.7%
Platelets, Grade 3: <50.0 - 25.0*10^9/L	3 5.6%
Platelets, Grade 4: <25.0*10^9 /L	1 1.9%
Platelets, Grade 1-4	32 59.3%
WBC, Grade 1: <LLN - 3.0*10^9/L	9 16.7%
WBC, Grade 2: <3.0 - 2.0*10^9/L	19 35.2%
WBC, Grade 3: <2.0 - 1.0*10^9/L	15 27.8%
WBC, Grade 4: <1.0*10^9/L	5 9.3%
WBC, Grade 1-4	48 88.9%

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	Safety Analysis Set: enrolled participants who received 1 or more doses of study drug.
Arm/Group Title	Bendamustine With Rituximab
Arm/Group Description	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.
All Cause Mortality
	Bendamustine With Rituximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bendamustine With Rituximab
	Affected / at Risk (%)	# Events
Total	14/53 (26.4%)
Blood and lymphatic system disorders
Febrile neutropenia	1/53 (1.9%)	1
Neutropenia	1/53 (1.9%)	1
Cardiac disorders
Atrial fibrillation	1/53 (1.9%)	1
Left ventricular dysfunction	1/53 (1.9%)	1
Gastrointestinal disorders
Appendix disorder	1/53 (1.9%)	1
Ascites	1/53 (1.9%)	1
Small intestinal obstruction	1/53 (1.9%)	1
General disorders
Asthenia	1/53 (1.9%)	1
Chills	1/53 (1.9%)	2
Pyrexia	2/53 (3.8%)	3
Infections and infestations
Bacteraemia	1/53 (1.9%)	1
Cellulitis	1/53 (1.9%)	1
Pneumonia	1/53 (1.9%)	1
Urinary tract infection	1/53 (1.9%)	1
Injury, poisoning and procedural complications
Infusion related reaction	3/53 (5.7%)	3
Metabolism and nutrition disorders
Dehydration	1/53 (1.9%)	1
Renal and urinary disorders
Haematuria	1/53 (1.9%)	1
Urinary retention	1/53 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease	1/53 (1.9%)	1
Pleural effusion	1/53 (1.9%)	1
Pneumonitis	1/53 (1.9%)	1
Skin and subcutaneous tissue disorders
Rash	1/53 (1.9%)	1
Transient acantholytic dermatosis	1/53 (1.9%)	1
Other (Not Including Serious) Adverse Events
	Bendamustine With Rituximab
	Affected / at Risk (%)	# Events
Total	53/53 (100%)
Blood and lymphatic system disorders
Anaemia	6/53 (11.3%)	18
Neutropenia	19/53 (35.8%)	50
Thrombocytopenia	11/53 (20.8%)	18
Gastrointestinal disorders
Abdominal discomfort	5/53 (9.4%)	5
Abdominal pain	5/53 (9.4%)	9
Abdominal pain upper	6/53 (11.3%)	6
Constipation	22/53 (41.5%)	28
Diarrhoea	16/53 (30.2%)	21
Dyspepsia	4/53 (7.5%)	4
Gastrooesophageal reflux disease	5/53 (9.4%)	5
Mouth ulceration	3/53 (5.7%)	3
Nausea	38/53 (71.7%)	56
Stomatitis	7/53 (13.2%)	8
Vomiting	16/53 (30.2%)	21
General disorders
Asthenia	3/53 (5.7%)	3
Chills	7/53 (13.2%)	9
Fatigue	27/53 (50.9%)	38
Feeling cold	3/53 (5.7%)	3
Influenza like illness	3/53 (5.7%)	3
Oedema peripheral	4/53 (7.5%)	6
Pain	6/53 (11.3%)	6
Pyrexia	12/53 (22.6%)	20
Immune system disorders
Drug hypersensitivity	8/53 (15.1%)	10
Infections and infestations
Nasopharyngitis	4/53 (7.5%)	4
Oral herpes	3/53 (5.7%)	3
Upper respiratory tract infection	5/53 (9.4%)	5
Urinary tract infection	5/53 (9.4%)	9
Injury, poisoning and procedural complications
Contusion	3/53 (5.7%)	3
Infusion related reaction	19/53 (35.8%)	46
Investigations
Electrocardiogram QT prolonged	3/53 (5.7%)	4
Weight decreased	6/53 (11.3%)	6
Metabolism and nutrition disorders
Decreased appetite	11/53 (20.8%)	12
Dehydration	4/53 (7.5%)	5
Hypokalaemia	5/53 (9.4%)	6
Hypomagnesaemia	3/53 (5.7%)	5
Musculoskeletal and connective tissue disorders
Arthralgia	3/53 (5.7%)	3
Back pain	8/53 (15.1%)	9
Bone pain	6/53 (11.3%)	7
Flank pain	3/53 (5.7%)	3
Myalgia	4/53 (7.5%)	4
Nervous system disorders
Dizziness	5/53 (9.4%)	6
Dysgeusia	9/53 (17%)	10
Headache	9/53 (17%)	10
Psychiatric disorders
Anxiety	5/53 (9.4%)	6
Depression	4/53 (7.5%)	4
Insomnia	12/53 (22.6%)	13
Renal and urinary disorders
Nocturia	3/53 (5.7%)	3
Pollakiuria	4/53 (7.5%)	4
Respiratory, thoracic and mediastinal disorders
Cough	11/53 (20.8%)	12
Dysphonia	4/53 (7.5%)	4
Dyspnoea	7/53 (13.2%)	8
Dyspnoea exertional	4/53 (7.5%)	4
Hiccups	3/53 (5.7%)	4
Oropharyngeal pain	3/53 (5.7%)	3
Pleural effusion	3/53 (5.7%)	3
Productive cough	3/53 (5.7%)	3
Wheezing	3/53 (5.7%)	3
Skin and subcutaneous tissue disorders
Alopecia	4/53 (7.5%)	4
Night sweats	3/53 (5.7%)	3
Pruritus	3/53 (5.7%)	3
Rash	7/53 (13.2%)	9
Vascular disorders
Hot flush	3/53 (5.7%)	3
Hypotension	3/53 (5.7%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.