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

• Number of dose-limiting toxicity (DLT) incidents (Phase I) [ Time Frame: Up to 21 days of every first course ] [ Designated as safety issue: Yes ]
  DLT will be 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 will be 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.
• Proportion of patients who achieve a partial response or better. (Phase II) [ Time Frame: From baseline to up to 3 years ] [ Designated as safety issue: No ]
  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. Clinical outcomes on these patients will also be evaluated in a descriptive manner. Clinical outcomes will be summarized by simple descriptive summary statistics.

• Number of dose-limiting toxicity incidents (Phase I) [ Designated as safety issue: Yes ]
• Response (Phase II) [ Designated as safety issue: No ]

• Time to progression [ Time Frame: Time from registration to the time of progression ] [ Designated as safety issue: No ]
  The distribution of time to progression will be estimated using the method of Kaplan-Meier.
• Overall survival [ Time Frame: Time from registration to death due to any cause ] [ Designated as safety issue: No ]
  The distribution of overall survival will be estimated using the method of Kaplan-Meier.
• Time to treatment failure [ Time Frame: Time from study entry to the date patients end treatment ] [ Designated as safety issue: No ]
  Time to treatment failure will be evaluated using the method of Kaplan-Meier.
• Toxicity as assessed by the National Cancer Institute (NCI) CTCAE v 3.0 [ Time Frame: From baseline to up to 3 years ] [ Designated as safety issue: Yes ]
  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.

• Time to progression [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]
• Time to treatment failure [ Designated as safety issue: No ]
• Toxicity as assessed by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]

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

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.

• Refractory Multiple Myeloma
• Stage I Multiple Myeloma
• Stage II Multiple Myeloma
• Stage III Multiple Myeloma

• Drug: obatoclax mesylate
  Given IV
  Other Name: GX15-070MS
• Other: laboratory biomarker analysis
  Correlative studies
• Genetic: gene expression analysis
  Correlative studies
• Genetic: microarray analysis
  Correlative studies
  Other Name: gene expression profiling
• Drug: bortezomib
  Given IV
  Other Names:

  • LDP 341
  • MLN341
  • VELCADE

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