- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01238146
Obatoclax Mesylate, Rituximab, and Bendamustine Hydrochloride in Treating Patients With Relapsed or Refractory Non-Hodgkin Lymphoma
A Phase I/II Trial of Rituximab, Bendamustine, and Obatoclax in Patients With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
Ohio
-
Columbus, Ohio, United States, 43210
- Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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.
|
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
|
Experimental: Arm II
Patients receive rituximab and bendamustine hydrochloride as in arm I.
|
Given IV
Other Names:
Given IV
Other Names:
|
What is the study measuring?
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)
Time Frame: 28 days
|
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)
Time Frame: From 6 to 12 months
|
Estimated using the method of Kaplan-Meier.
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From 6 to 12 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Overall objective response rate (phase II)
Time Frame: Up to 3 years
|
95% confidence intervals will be provided.
|
Up to 3 years
|
PFS (phase II)
Time Frame: From the date of start of therapy to disease progression or death, whichever occurs first, assessed at 2 years
|
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
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Elizabeth Christian, Ohio State University Comprehensive Cancer Center
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Immune System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Disease Attributes
- Lymphoma
- Lymphoma, Follicular
- Lymphoma, B-Cell
- Recurrence
- Lymphoma, Non-Hodgkin
- Lymphoma, Mantle-Cell
- Lymphoma, B-Cell, Marginal Zone
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antirheumatic Agents
- Antineoplastic Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Antineoplastic Agents, Immunological
- Bendamustine Hydrochloride
- Rituximab
- Obatoclax
Other Study ID Numbers
- NCI-2011-02536
- U01CA076576 (U.S. NIH Grant/Contract)
- OSU-10040
- CDR0000687197 (Registry Identifier: PDQ (Physician Data Query))
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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