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)

Cephalon54 enrolled

Overview

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).

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 Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Non-Hodgkin's Lymphoma Mantle Cell Lymphoma

Interventions

BendamustineDRUG

Bendamustine at 90 mg/m\^2 IV on Days 1 and 2 of a 28-day cycle.

RituximabDRUG

Rituximab at 375 mg/m\^2 IV on Day 1 of a 28-day cycle.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (43)

Outcomes

Primary Outcomes

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.

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.

Secondary Outcomes

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.

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.

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.

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.

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.

Data from ClinicalTrials.gov

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