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

Primary Purpose

Refractory Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
obatoclax mesylate
bortezomib
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Refractory Multiple Myeloma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Mayo Clinic

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (enzyme inhibitor therapy)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
Time to Progression (Phase II)
The distribution of time to progression will be estimated using the method of Kaplan-Meier.
Overall Survival (Phase II)
The distribution of overall survival will be estimated using the method of Kaplan-Meier.
Time to Treatment Failure (Phase II)
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 (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.

Full Information

First Posted
July 19, 2008
Last Updated
January 9, 2015
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00719901
Brief Title
Obatoclax and Bortezomib in Treating Patients With Relapsed or Refractory Multiple Myeloma
Official Title
A Phase I/II Trial of Obatoclax Mesylate (GX15-070MS) in Combination With Bortezomib for the Treatment of Relapsed Multiple Myeloma
Study Type
Interventional

2. Study Status

Record Verification Date
October 2013
Overall Recruitment Status
Terminated
Why Stopped
This trial was terminated due to slow accrual and the drug supply of Obatoclax during the phase I; therefore, the phase II portion will never open.
Study Start Date
July 2008 (undefined)
Primary Completion Date
April 2011 (Actual)
Study Completion Date
June 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Refractory Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
11 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (enzyme inhibitor therapy)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
obatoclax mesylate
Other Intervention Name(s)
GX15-070MS
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
bortezomib
Other Intervention Name(s)
LDP 341, MLN341, VELCADE
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Number of Dose-limiting Toxicity (DLT) Incidents (Phase I)
Description
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.
Time Frame
Up to 21 days of every first course
Title
Proportion of Patients Who Achieve a Partial Response or Better. (Phase II)
Description
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 Frame
From baseline to up to 3 years
Secondary Outcome Measure Information:
Title
Number of Patients Who Have at Least a Partial Response (Phase I)
Description
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 Frame
From baseline to up to 3 years
Title
Time to Progression (Phase II)
Description
The distribution of time to progression will be estimated using the method of Kaplan-Meier.
Time Frame
Time from registration to the time of progression
Title
Overall Survival (Phase II)
Description
The distribution of overall survival will be estimated using the method of Kaplan-Meier.
Time Frame
Time from registration to death due to any cause
Title
Time to Treatment Failure (Phase II)
Description
Time to treatment failure will be evaluated using the method of Kaplan-Meier.
Time Frame
Time from study entry to the date patients end treatment
Title
Toxicity as Assessed by the National Cancer Institute (NCI) CTCAE v 3.0 (Phase II)
Description
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 Frame
From baseline to up to 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alexander Stewart
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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