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

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVES: I. To establish the maximum tolerated dose of obatoclax mesylate when administered with bortezomib in patients with aggressive relapsed or recurrent non-Hodgkin lymphoma. II. To describe the toxicities of this regimen at each dose studied in these patients. III. To characterize the pharmacokinetic behavior of this regimen in these patients. IV. To obtain preliminary information regarding the effect of obatoclax mesylate on several apoptotic regulatory pathways. V. 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.

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

Conditions
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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

Intervention / Treatment
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* Drug: obatoclax mesylate
* Drug: bortezomib
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (obatoclax mesylate, bortezomib)<br>Patients will receive a 3-hour infusion of obatoclax and an infusion of bortezomib once a week for 4 weeks | Drug: obatoclax mesylate<br>* Given IV<br>* Other names: GX15-070MS;Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Other: laboratory biomarker analysis<br>* correlative study<br>Other: pharmacological study<br>* correlative study<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of obatoclax mesylate when administered with bortezomib | 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. | 35 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity as assessed by NCI CTCAE version 3.0 | 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. | Up to 26 weeks after completion of study treatment | 
| 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 |