Clinical trial NCT01073163: 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)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Non-Hodgkin's Lymphoma
Mantle Cell Lymphoma
Lead sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Sponsor class: INDUSTRY
First posted: 2010-02-23
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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:

    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

Primary outcomes:
measure: Mean Change From Baseline in QT Interval as Corrected by the Fridericia Method (QTcF) at End of Infusion
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.
Secondary outcomes:
measure: Mean Change From Baseline in QTcF at 1 Hour Postinfusion
timeFrame: Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): 1 hour postinfusion.
measure: Number of Participants With QTcF New Outlier Events at End of Infusion and 1 Hour Postinfusion
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.
measure: Number of Participants With New Onset ECG Waveform Morphological Changes
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.
measure: Number of Participants With Treatment-Emergent Cardiac Disorders
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.
measure: Change From Baseline in QTcF at Maximum Concentration (Cmax) of Bendamustine and Its Metabolites (M3 and M4)
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.
measure: Model-predicted Bayesian Bendamustine Clearance in the Presence of Rituximab
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.
measure: Rituximab Concentrations at 0.5 Hours, 24 Hours, and 7 Days Postinfusion
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.
measure: Percentage of Participants With Complete Response (CR)
timeFrame: The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.
measure: Percentage of Participants With Overall Response
timeFrame: The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.
measure: Overview of Adverse Events
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.
measure: Eastern Cooperative Oncology Group (ECOG) Performance Status at Endpoint
timeFrame: End of study. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.
measure: Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall
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.
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Hematology Oncology Physicans Extenders Group
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Fullerton
country: United States
facility: St. Jude Heritage Medical Group
state: California
city: Palm Springs
country: United States
facility: Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Denver
country: United States
facility: Rocky Mountain Cancer Center
state: Colorado
city: New Britain
country: United States
facility: The Hospital of Central Connecticut
state: Connecticut
city: Southington
country: United States
facility: Cancer Center of Central Connecticut
state: Connecticut
city: Hollywood
country: United States
facility: Memorial Cancer Institute
state: Florida
city: Orlando
country: United States
facility: Cancer Centers of Florida
state: Florida
city: Orlando
country: United States
facility: MD Anderson Cancer Cnt Orlando
state: Florida
city: Columbus
country: United States
facility: John B Amos Cancer Center
state: Georgia
city: Beech Grove
country: United States
facility: St Francis Cancer Research Foundation
state: Indiana
city: Waterloo
country: United States
facility: Cedar Valley Medical Specialists
state: Iowa
city: Wichita
country: United States
facility: Cancer Center of Kansas
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Shreveport
country: United States
facility: LSU Health Sciences Center - Shreveport
state: Louisiana
city: Augusta
country: United States
facility: MaineGeneral Medical Center
state: Maine
city: Columbia
country: United States
facility: Missouri Cancer Associates
state: Missouri
city: Kansas City
country: United States
facility: Kansas City Cancer Center
state: Missouri
city: Albuquerque
country: United States
facility: UNM Cancer Center/New Mexico Cancer Care Alliance
state: New Mexico
city: Rochester
country: United States
facility: Interlakes Foundation, Inc
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate / Upstate Medical University
state: New York
city: Springfield
country: United States
facility: Willamette Valley Cancer Center
state: Oregon
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Pennsylvania Oncology Hematology Associates, Inc.
state: Pennsylvania
city: Charleston
country: United States
facility: Charleston Hematology Oncology, PA
state: South Carolina
city: Nashville
country: United States
facility: Sarah Cannon Cancer Center
state: Tennessee
city: Fort Worth
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Center of South Texas
state: Texas
city: Tyler
country: United States
facility: Texas Oncology
state: Texas
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Richlands
country: United States
facility: Cancer Outreach Asscociates, PC
state: Virginia
city: Spokane
country: United States
facility: Cancer Care Northwest-South
state: Washington
city: Vancouver
country: United States
facility: Northwest Cancer Specialists, PC
state: Washington
city: Morgantown
country: United States
facility: West Virginia University School of Medicine
state: West Virginia
city: Garran
country: Australia
facility: The Canberra Hospital
state: Australian Capital Territory
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Woodville
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Ottawa
country: Canada
facility: Ottawa Hospital - General Campus
state: Ontario
Study officials:
affiliation: Cephalon
name: Sponsor's Medical Expert
role: STUDY_DIRECTOR
References: