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

Phase 1

Terminated

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

Interventions: Drug: obatoclax mesylate
Drug: bortezomib
Other: laboratory biomarker analysis

Registration Number: NCT00719901

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 11

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (enzyme inhibitor therapy)	obatoclax mesylate	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.
Treatment (enzyme inhibitor therapy)	laboratory biomarker analysis	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.
Treatment (enzyme inhibitor therapy)	bortezomib	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.

Primary Outcome Measures

Name	Time	Method
Number of Dose-limiting Toxicity (DLT) Incidents (Phase I)	Up to 21 days of every first course	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.
Proportion of Patients Who Achieve a Partial Response or Better. (Phase II)	From baseline to up to 3 years	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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (Phase II)	Time from registration to death due to any cause	The distribution of overall survival will be estimated using the method of Kaplan-Meier.
Number of Patients Who Have at Least a Partial Response (Phase I)	From baseline to up to 3 years	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.
Time to Treatment Failure (Phase II)	Time from study entry to the date patients end treatment	Time to treatment failure will be evaluated using the method of Kaplan-Meier.
Time to Progression (Phase II)	Time from registration to the time of progression	The distribution of time to progression will be estimated using the method of Kaplan-Meier.
Toxicity as Assessed by the National Cancer Institute (NCI) CTCAE v 3.0 (Phase II)	From baseline to up to 3 years	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.