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)
Condition: Non-Hodgkin's Lymphoma; Mantle Cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell
Intervention: Bendamustine; Rituximab
Intervention description: Bendamustine at 90 mg/m^2 IV on Days 1 and 2 of a 28-day cycle.; Rituximab at 375 mg/m^2 IV on Day 1 of a 28-day cycle.
Intervention MeSH terms: Rituximab; Bendamustine Hydrochloride
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 54.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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).
    

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