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 Overview
=================
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).

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.

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)

Conditions
-----------------
Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: Bendamustine
* Drug: Rituximab


Participation Criteria
=================
Eligibility Criteria
-----------------
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: fever (>38ºC) of unclear etiology night sweats 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bendamustine with Rituximab<br>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<br>* Bendamustine at 90 mg/m^2 IV on Days 1 and 2 of a 28-day cycle.<br>* Other names: SDX-105;Drug: Rituximab<br>* Rituximab at 375 mg/m^2 IV on Day 1 of a 28-day cycle.<br>* Other names: IDEC-C2B8;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in QT Interval as Corrected by the Fridericia Method (QTcF) at End of 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in QTcF at 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. | Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): 1 hour postinfusion. | 
| Number of Participants With QTcF New Outlier Events at End of 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. | 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. | 
| Number of Participants With New Onset ECG Waveform Morphological Changes | 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. | 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. | 
| Number of Participants With Treatment-Emergent Cardiac Disorders | 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. | 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. | 
| Change From Baseline in QTcF at Maximum Concentration (Cmax) of Bendamustine and Its Metabolites (M3 and M4) | 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. | 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. | 
| Model-predicted Bayesian Bendamustine Clearance in the Presence of Rituximab | 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. | 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. | 
| 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. | 
| Percentage of Participants With Complete Response (CR) | 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. | The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. | 
| Percentage of Participants With Overall Response | 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. | The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. | 
| Overview of Adverse Events | 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. | 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. | 
| Eastern Cooperative Oncology Group (ECOG) Performance Status at Endpoint | 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. | End of study. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days. | 
| Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall | 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 | 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. |