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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00719901
• Collaborator: (none)
• Enrollment: 11
• Location: 1
• Arm: 1
• Duration (Months): 47
• Patients Per Site Per Month: 0.2

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Refractory Multiple Myeloma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma	Drug: obatoclax mesylate; Drug: bortezomib; Other: laboratory biomarker analysis	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. To determine the duration of progression-free and overall survival of these patients.

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of Obatoclax Mesylate (GX15-070MS) in Combination With Bortezomib for the Treatment of Relapsed Multiple Myeloma
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (enzyme inhibitor therapy) 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; Given IV; Other Names: GX15-070MS ; Drug: bortezomib; Given IV; Other Names: LDP 341 MLN341 VELCADE ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Alexander Stewart, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00719901
• Other Study ID Numbers: NCI-2009-00255; NCI-2009-00255; CDR0000597950; MAYO-MC068A; MC068A; 7952; N01CM62205; P01CA136447; N01CM62208; N01CM62203; NCT01647048
• First Posted: Jul 22, 2008
• Last Update Posted: Jan 12, 2015
• Last Verified: Oct 1, 2013

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Bortezomib; Obatoclax

Study Results

Participant Flow

Recruitment Details	Participants were recruited from 5 medical clinics in the United States between February 2008 and January 2011.
Pre-assignment Detail	This was a phase I/II trial. A total of 11 participants were accrued, all to the phase I portion. 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. No results from the phase II portion are available.

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive obatoclax mesylate IV over 3 hours and bortezomib (1.3 mg/m^2) IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	11
COMPLETED	0
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive obatoclax mesylate IV over 3 hours and bortezomib (1.3 mg/m^2) IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Overall Participants	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.1 (10.4)
Sex: Female, Male (Count of Participants)
Female	4 40%
Male	6 60%
Region of Enrollment (participants) [Number]
United States	10 100%
Performance Status (participants) [Number]
0=Fully active	1 10%
1=Restricted in physically strenuous activity	9 90%
Dose Level (participants) [Number]
Obatoclax mesylate IV 14 mg/m^2	3 30%
Obatoclax mesylate IV 30 mg/m^2	4 40%
Obatoclax mesylate IV 40 mg/m^2	3 30%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive obatoclax mesylate IV over 3 hours and bortezomib (1.3 mg/m^2) IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	10
Number [Toxicity Incidents]	4

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

No participants proceeded to Phase II for evaluation.

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive obatoclax mesylate IV over 3 hours and bortezomib (1.3 mg/m^2) IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive obatoclax mesylate IV over 3 hours and bortezomib (1.3 mg/m^2) IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	10
Number [participants]	4 40%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

No participants proceeded to Phase II for evaluation.

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive obatoclax mesylate IV over 3 hours and bortezomib (1.3 mg/m^2) IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

No participants proceeded to Phase II for evaluation.

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive obatoclax mesylate IV over 3 hours and bortezomib (1.3 mg/m^2) IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

No participants proceeded to Phase II for evaluation.

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive obatoclax mesylate IV over 3 hours and bortezomib (1.3 mg/m^2) IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

No participants proceeded to Phase II for evaluation.

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive obatoclax mesylate IV over 3 hours and bortezomib (1.3 mg/m^2) IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

Adverse Events

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive obatoclax mesylate IV over 3 hours and bortezomib (1.3 mg/m^2) IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Treatment (Enzyme Inhibitor Therapy)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Enzyme Inhibitor Therapy)
	Affected / at Risk (%)	# Events
Total	3/10 (30%)
Investigations
Neutrophil count decreased	2/10 (20%)	2
Nervous system disorders
Depressed level of consciousness	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Enzyme Inhibitor Therapy)
	Affected / at Risk (%)	# Events
Total	10/10 (100%)
Blood and lymphatic system disorders
Hemoglobin decreased	10/10 (100%)	36
Cardiac disorders
Cardiac disorder	1/10 (10%)	1
Eye disorders
Diplopia	1/10 (10%)	1
Gastrointestinal disorders
Constipation	2/10 (20%)	2
Diarrhea	7/10 (70%)	12
Nausea	4/10 (40%)	7
Vomiting	2/10 (20%)	3
General disorders
Fatigue	5/10 (50%)	6
Immune system disorders
Hypersensitivity	1/10 (10%)	1
Investigations
Leukocyte count decreased	9/10 (90%)	27
Lymphocyte count decreased	4/10 (40%)	4
Neutrophil count decreased	8/10 (80%)	26
Platelet count decreased	8/10 (80%)	23
Metabolism and nutrition disorders
Anorexia	2/10 (20%)	2
Musculoskeletal and connective tissue disorders
Myalgia	4/10 (40%)	10
Nervous system disorders
Ataxia	1/10 (10%)	1
Depressed level of consciousness	1/10 (10%)	1
Dizziness	1/10 (10%)	1
Extrapyramidal disorder	1/10 (10%)	1
Headache	6/10 (60%)	9
Peripheral motor neuropathy	2/10 (20%)	6
Peripheral sensory neuropathy	7/10 (70%)	27
Speech disorder	1/10 (10%)	1
Psychiatric disorders
Anxiety	2/10 (20%)	4
Depression	1/10 (10%)	2
Euphoria	4/10 (40%)	6
Psychosis	3/10 (30%)	3
Respiratory, thoracic and mediastinal disorders
Dyspnea	8/10 (80%)	15
Hypoxia	1/10 (10%)	1
Pulmonary fibrosis	1/10 (10%)	1
Skin and subcutaneous tissue disorders
Rash desquamating	2/10 (20%)	2

Limitations/Caveats

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. No results from the phase II portion are available.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.