Obatoclax and Bortezomib in Treating Patients With Aggressive Relapsed or Recurrent Non-Hodgkin Lymphoma

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Terminated

CT.gov ID

NCT00538187

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

Obatoclax may stop the growth of non-Hodgkin lymphoma by blocking blood flow to the cancer. Bortezomib and obatoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving obatoclax together with bortezomib may kill more cancer cells. This phase I/II trial is studying the side effects and best dose of obatoclax when given together with bortezomib and to see how well they work in treating patients with aggressive relapsed or recurrent non-Hodgkin lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Adult Non-Hodgkin Lymphoma Recurrent Adult Diffuse Large Cell Lymphoma Recurrent Grade 1 Follicular Lymphoma Recurrent Grade 2 Follicular Lymphoma Recurrent Grade 3 Follicular Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Marginal Zone Lymphoma Recurrent Small Lymphocytic Lymphoma	Drug: obatoclax mesylate Drug: bortezomib Other: laboratory biomarker analysis Other: pharmacological study	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

To establish the maximum tolerated dose of obatoclax mesylate when administered with bortezomib in patients with aggressive relapsed or recurrent non-Hodgkin lymphoma.
To describe the toxicities of this regimen at each dose studied in these patients.
To characterize the pharmacokinetic behavior of this regimen in these patients.
To obtain preliminary information regarding the effect of obatoclax mesylate on several apoptotic regulatory pathways.
To document all clinical responses in these patients to this regimen.

OUTLINE: This is a multicenter study.

PHASE I: Patients receive obatoclax mesylate IV over 3 hours followed by bortezomib IV on days 1, 8, 15, and 22.

Treatment repeats every 35 days in the absence of disease progression or unacceptable toxicity. Pharmacokinetic evaluations of obatoclax mesylate are conducted in all patients during the first course.

PHASE II: Patients receive obatoclax mesylate IV over 3 hours followed by bortezomib IV on days 1, 8, 15, and 22 at the maximum tolerated dose determined in phase I.

Treatment repeats every 35 days for up to 1 year in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 26 weeks.

Study Design

Study Type:

Interventional

Actual Enrollment :

18 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study of GX15-070 (NSC # 729280) and Bortezomib in Aggressive Relapsed/Recurrent Non-Hodgkin's Lymphoma

Study Start Date :

Dec 1, 2007

Actual Primary Completion Date :

Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (obatoclax mesylate, bortezomib) Patients will receive a 3-hour infusion of obatoclax and an infusion of bortezomib once a week for 4 weeks	Drug: obatoclax mesylate Given IV Other Names: GX15-070MS Drug: bortezomib Given IV Other Names: LDP 341 MLN341 VELCADE Other: laboratory biomarker analysis correlative study Other: pharmacological study correlative study Other Names: pharmacological studies

Arm

Intervention/Treatment

Experimental: Treatment (obatoclax mesylate, bortezomib)

Patients will receive a 3-hour infusion of obatoclax and an infusion of bortezomib once a week for 4 weeks

Drug: obatoclax mesylate

Given IV

Other Names:

GX15-070MS

Drug: bortezomib

Given IV

Other Names:

LDP 341

MLN341

VELCADE

Other: laboratory biomarker analysis

correlative study

Other: pharmacological study

correlative study

Other Names:

pharmacological studies

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of obatoclax mesylate when administered with bortezomib [35 days]
Defined as the highest dose tested in which fewer than 33% of patients experienced DLT attributable to the study drug(s), when at least six patients were treated at that dose and are evaluable for toxicity. Graded according to the NCI CTCAE, Version 3.0.

Secondary Outcome Measures

Toxicity as assessed by NCI CTCAE version 3.0 [Up to 26 weeks after completion of study treatment]
Summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity and nadir or maximum values for the laboratory measures, time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course.
Pharmacokinetics of obatoclax mesylate when administered with bortezomib [Dose 1 of course 1, pre-infusion, 1 and 2 hours into the infusion, immediately prior to the end of the infusion, then at 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, and 168 hours]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed relapsed or refractory non-Hodgkin lymphoma for which standard curative or palliative measures do not exist or are no longer effective, including any of the following subtypes:
Follicular grade I, II, or III lymphoma
Marginal zone lymphoma
Mantle cell lymphoma
Diffuse large B cell lymphoma
Small lymphocytic lymphoma
Must have had at least one prior chemotherapeutic regimen:
Steroids or rituximab alone or local radiotherapy do not count as regimens
Tositumomab or ibritumomab tiuxetan allowed as regimens
Clear evidence of disease progression or lack of response after the most recent therapy, including rituximab or local radiotherapy, is required
At least 3 months since prior autologous stem cell transplantation and relapsed (>= 1 year since prior allogeneic transplantation and relapsed) and no active related infections (i.e., fungal or viral)
In the case of allogeneic transplantation relapse, there should be no active acute graft-versus-host disease (GVHD) of any grade and no chronic GVHD other than mild skin, oral, or ocular GVHD not requiring systemic immunosuppression
No known active brain metastases, other neurological disorders/dysfunction or history of seizure disorder, or other neurological dysfunction
Karnofsky performance status 60-100%
Life expectancy > 3 months
Total bilirubin normal
AST and ALT =< 2.5 times upper limit of normal
Creatinine normal or creatinine clearance >= 60 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective double-barrier contraception during and for 3 months after the last dose of obatoclax mesylate
At least 4 weeks since prior radiotherapy
More than 2 days since prior steroids
More than 2 weeks since prior low-dose chlorambucil
WBC >= 3,000/mm^3
ANC >= 1,500/mm^3
Platelet count >= 100,000/mm^3
At least 2 weeks since prior valproic acid

Exclusion Criteria:

Uncontrolled concurrent medical condition or illness including, but not limited to, any of the following:
Ongoing or active infection
Symptomatic congestive heart failure
Unstable angina pectoris
Cardiac arrhythmia including QTc > 450 msec
Patients who are intolerant or refractory to prior treatment with bortezomib (refractory is defined as no response to prior treatment with bortezomib)
Chemotherapy within the past 4 weeks (6 weeks for nitrosoureas or mitomycin C)
Rituximab within the past 3 months (unless there is evidence of progression)
Patients who have not recovered from adverse events due to agents administered more than 4 weeks earlier
Other concurrent investigational agents
Combination antiretroviral therapy for HIV-positive patients
No history of allergic reactions attributed to bortezomib, polyethylene glycol (PEG 300), or polysorbate 20
No psychiatric illness or social situation that would limit compliance with study requirements