Obatoclax and Bortezomib in Treating Patients With Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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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 relapsed or refractory multiple myeloma. Obatoclax and bortezomib 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.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose and recommended phase II dose of obatoclax mesylate when given in combination with bortezomib in patients with relapsed or refractory multiple myeloma. (Phase I) II. To evaluate the response rate (complete response, partial response, and very good partial response) in patients treated with this regimen. (Phase II) SECONDARY OBJECTIVES: I. To determine the duration of progression-free and overall survival of these patients. II. To evaluate the incidence of toxicities of this regimen in these patients. III. To explore the utility of genetic markers based on initial evidence that they are predictive of drug responsiveness and/or successful target inhibition. OUTLINE: This is a multicenter, phase I, dose-escalation study of obatoclax mesylate followed by a phase II study. Patients receive obatoclax mesylate IV over 3 hours and bortezomib IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months until disease progression and then every 6 months for up to 3 years.

Official Title
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A Phase I/II Trial of Obatoclax Mesylate (GX15-070MS) in Combination With Bortezomib for the Treatment of Relapsed Multiple Myeloma

Conditions
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Refractory Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Symptomatic multiple myeloma, meeting the following criteria at original diagnosis: Bone marrow plasmacytosis with ≥ 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma Symptomatic disease (e.g.,anemia, hypercalcemia, bone disease, or renal dysfunction) that requires the initiation of therapy Measurable diseases assessed by one of the following: Monoclonal plasma cells detectable in the bone marrow Monoclonal serum spike detectable by serum protein electrophoresis or immunofixation Monoclonal protein detectable in the urine by electrophoresis or immunofixation Abnormal levels of the serum free light chains with an abnormal ratio between kappa and lambda Progressive disease after ≥ 1 prior therapy for myeloma Previously treated with ≤ 10 courses (30 weeks) of bortezomib and had no disease progression during therapy OR completed bortezomib therapy within the past 6 weeks No prior discontinuation of bortezomib therapy due to drug intolerance No known brain metastases No intracranial edema, intracranial metastasis, or active epidural disease Patients with lytic lesions of the cranium secondary to myeloma are eligible ECOG performance status 0-2 Life expectancy > 6 months ANC ≥ 1,000/mm³ Platelet count ≥ 50,000/mm³ Bilirubin normal AST and ALT ≤ 2.5 times upper limit of normal (ULN) Creatinine ≤ 2 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No peripheral neuropathy > NCI toxicity grade 2 No history of allergic reactions attributed to compounds of similar chemical or biologic composition to obatoclax mesylate or bortezomib No concurrent uncontrolled illness including, but not limited to the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia, including QTc > 450 msec Psychiatric illness/social situations that would limit compliance with study requirements No history of seizure disorder No other neurological disorder or dysfunction that, in the opinion of the investigator, would confound the evaluation of neurologic and other adverse events associated with obatoclax mesylate At least 14 days since prior chemotherapy and recovered More than 28 days since prior experimental drugs and/or investigational agents No concurrent CYP interactive medications No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent anticancer therapy Growth factors and bisphosphonates are allowed as medically indicated Prednisone (≤ 10 mg per day) allowed provided there has been no dose increase within the past 2 weeks No other concurrent investigational agents

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 (enzyme inhibitor therapy)<br>Patients receive obatoclax mesylate IV over 3 hours and bortezomib IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | 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 studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Dose-limiting Toxicity (DLT) Incidents (Phase I) | DLT was defined as any events that is determined to be possibly, probably, or definitely related to the combination of bortezomib and GX15-070 (as determined by the investigator) and occurring during the first cycle of treatment, irrespective of whether the toxicity resolved. Hematologic DLT measures were assessed using the continuous variables as the outcome measures (primarily nadir and percent change from baseline values) as well as categorization via Common Terminology Criteria for Adverse Events (CTCAE) version 3 standard toxicity grading. | Up to 21 days of every first course | 
| Proportion of Patients Who Achieve a Partial Response or Better. (Phase II) | In order to be classified as a hematologic response, confirmation of serum monoclonal protein, serum immunoglobulin free light chain (when primary determinant of response) and urine monoclonal protein (when primary determinant of response) results must be made by verification on two consecutive determinations. | From baseline to up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Have at Least a Partial Response (Phase I) | In order to be classified as a hematologic response, confirmation of serum monoclonal protein, serum immunoglobulin free light chain (when primary determinant of response) and urine monoclonal protein (when primary determinant of response) results must be made by verification on two consecutive determinations. | From baseline to up to 3 years | 
| Time to Progression (Phase II) | The distribution of time to progression will be estimated using the method of Kaplan-Meier. | Time from registration to the time of progression | 
| Overall Survival (Phase II) | The distribution of overall survival will be estimated using the method of Kaplan-Meier. | Time from registration to death due to any cause | 
| Time to Treatment Failure (Phase II) | Time to treatment failure will be evaluated using the method of Kaplan-Meier. | Time from study entry to the date patients end treatment | 
| Toxicity as Assessed by the National Cancer Institute (NCI) CTCAE v 3.0 (Phase II) | Toxicity is defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. In addition, we will review all toxicities data that is graded as 3, 4, or 5 and classified as either unrelated or unlikely to be related to study treatment in the event of an actual relationship developing. Adverse events and toxicities will be evaluated using all patients who have received any study treatment. | From baseline to up to 3 years |