A Phase I/II Trial of Rituximab, Bendamustine, and Obatoclax in Patients With Relapsed or Refractory Indolent Non-Hodgkin's 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.
Interventional
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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
Yes
Elizabeth Christian
Principal Investigator
Ohio State University Comprehensive Cancer Center
United States: Food and Drug Administration
NCI-2011-02536
NCT01238146
October 2010
Name | Location |
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Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center | Columbus, Ohio 43210-1240 |