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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


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
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

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Trial Information

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.


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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerable dose, defined as the dose level beneath which 2 or more of 6 patients experience DLT (phase I)

Outcome Description:

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.

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Elizabeth Christian

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02536

NCT ID:

NCT01238146

Start Date:

October 2010

Completion Date:

Related Keywords:

  • 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
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Non-Hodgkin
  • Lymphoma, B-Cell
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Mantle-Cell

Name

Location

Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical CenterColumbus, Ohio  43210-1240