Obatoclax Mesylate, Rituximab, and Bendamustine Hydrochloride in Treating Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects and the best dose of obatoclax mesylate when given together with rituximab and bendamustine hydrochloride to see how well it works compared with rituximab and bendamustine hydrochloride alone in treating patients with relapsed or refractory non-Hodgkin lymphoma. Obatoclax mesylate may stop the growth of cancer cells by blocking some of the proteins needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as bendamustine hydrochloride, also work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving obatoclax mesylate together with rituximab and bendamustine hydrochloride may kill more cancer cells

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of the combination of obatoclax mesylate, rituximab, and bendamustine hydrochloride in patients with relapsed or refractory, indolent, B-cell non-Hodgkin lymphoma (phase I). II. To define the qualitative and quantitative toxicities of the combination of obatoclax mesylate, rituximab, and bendamustine (phase I). III. To detect an improvement in median progression-free survival (PFS) from 6 to 12 months with the addition of obatoclax mesylate to rituximab and bendamustine hydrochloride in patients with indolent B-cell non-Hodgkin lymphoma (phase II). SECONDARY OBJECTIVES: I. To determine the overall objective response rate to the combination of obatoclax mesylate, rituximab, and bendamustine versus rituximab and bendamustine hydrochloride in patients with relapsed or refractory, indolent, B-cell non-Hodgkin lymphoma. II. To characterize two-year PFS of patients with indolent B-cell non-Hodgkin lymphoma receiving obatoclax mesylate, rituximab, and bendamustine hydrochloride versus rituximab and bendamustine hydrochloride. III. To assess the pharmacokinetics of obatoclax mesylate in patients with relapsed or refractory, indolent, B-cell non-Hodgkin lymphoma. IV. To assess the pharmacokinetics of the combination of bendamustine hydrochloride and obatoclax mesylate in patients with relapsed or refractory, indolent, B-cell non-Hodgkin lymphoma. V. To determine the effects of the combination of rituximab, bendamustine hydrochloride, and obatoclax mesylate on histone-oligodeoxynucleotide (ODNA) and levels of activated Bax and Bak pro-apoptotic proteins in peripheral blood mononuclear cells and bone marrow aspirate specimens. VI. To identify associations of genetic polymorphisms in drug-metabolizing enzymes, transporters, or target genes with pharmacokinetics, pharmacodynamics, or clinical outcomes. OUTLINE: This is a phase I, dose-escalation study of obatoclax mesylate followed by a randomized phase II study. PHASE I: Patients receive obatoclax mesylate IV over 3 hours on days 1-3, rituximab IV over 4-8 hours on day 1 (day 3 of course 1), and bendamustine hydrochloride IV over 30 minutes on day 1-2 (day 2-3 of course 1). Treatment repeats every 28 days for a maximum of 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are stratified according to prior bendamustine hydrochloride (yes vs no). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive obatoclax mesylate IV over 3 hours on days 1-3, rituximab IV over 4-8 hours on day 1, and bendamustine hydrochloride IV over 30 minutes on days 1-2. ARM II: Patients receive rituximab and bendamustine hydrochloride as in arm I. In both arms, treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood and bone marrow sample collection at baseline and periodically during study for pharmacokinetics, pharmacodynamic, and pharmacogenetic studies. After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Official Title
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A Phase I/II Trial of Rituximab, Bendamustine, and Obatoclax in Patients With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma

Conditions
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Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Splenic Marginal Zone Lymphoma

Intervention / Treatment
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* Drug: bendamustine hydrochloride
* Drug: obatoclax mesylate
* Biological: rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed indolent B-cell non-Hodgkin lymphoma (NHL), including any of the following subtypes recognized by WHO classification: Marginal zone lymphoma Lymphoplasmacytic lymphoma Follicular lymphoma Mantle cell lymphoma Transformed lymphoma from a low-grade, indolent NHL allowed provided patient has received ≥ 1 prior therapy for indolent disease Must have received ≥ 1 prior therapy Relapsed disease after autologous or allogeneic stem cell transplantation (SCT) allowed (phase I) No relapse after allogeneic SCT (phase II) No known CNS lymphoma ECOG performance status 0-2 ANC ≥ 1,000/µL Platelet count ≥ 50,000/µL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 50 mL/min Not pregnant or nursing Fertile patients must use effective contraception prior to and for the duration of study participation No active hepatitis B infection Patients with a history of hepatitis B (surface antigen or core antibody positive) must take lamivudine or equivalent during study therapy No history of documented human anti-globulin antibodies, or a history of allergic reactions attributed to compounds of similar chemical or biologic composition to rituximab, bendamustine hydrochloride, or obatoclax mesylate No uncontrolled intercurrent illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness and/or social situations that would limit compliance with study requirements HIV infection allowed provided patient meets the following criteria: No evidence of co-infection with hepatitis B or C CD4 cell count ≥ 400/mm³ No evidence of resistant strains of HIV HIV viral load ≤ 10,000 copies HIV RNA/mL for patients not on anti-HIV combination antiretroviral therapy OR HIV viral load ≤ 50,000 copies HIV RNA/mL for patients on anti-HIV therapy No history of AIDS-defining conditions No active secondary malignancy except for non-melanomatous skin cancer No other concurrent investigational agents Prior bendamustine hydrochloride allowed provided patient has completed a bendamustine-containing regimen within the past 6 months and achieved a partial response or better More than 4 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive obatoclax mesylate IV over 3 hours on days 1-3, rituximab IV over 4-8 hours on day 1, and bendamustine hydrochloride IV over 30 minutes on days 1-2. | Drug: bendamustine hydrochloride<br>* Given IV<br>* Other names: Treanda;Drug: obatoclax mesylate<br>* Given IV<br>* Other names: GX15-070MS;Biological: rituximab<br>* Given IV<br>* Other names: Rituxan;|
| Experimental: Arm II<br>Patients receive rituximab and bendamustine hydrochloride as in arm I. | Drug: bendamustine hydrochloride<br>* Given IV<br>* Other names: Treanda;Biological: rituximab<br>* Given IV<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerable dose, defined as the dose level beneath which 2 or more of 6 patients experience DLT (phase I) | Graded using CTCAE version 4 criteria. DLTs are defined as grade 3-4 neutropenia or thrombocytopenia that persists beyond day 42; grade 4 febrile neutropenia or infection; grade 3 febrile neutropenia or infection that fails to resolve within 7days, grade 3-4 somnolence, ataxia, or confusion that requires inpatient admission on day 1 for observation and prevents patient discharge from outpatient clinic, or other grade 3-4 non-hematologic toxicity excluding infection. | 28 days | 
| Change in median progression-free survival (PFS) (phase II) | Estimated using the method of Kaplan-Meier. | From 6 to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall objective response rate (phase II) | 95% confidence intervals will be provided. | Up to 3 years | 
| PFS (phase II) | Estimated using the method of Kaplan-Meier. | From the date of start of therapy to disease progression or death, whichever occurs first, assessed at 2 years |