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

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.