Clinical trial NCT00719901: 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
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Refractory Multiple Myeloma
Stage I Multiple Myeloma
Stage II Multiple Myeloma
Stage III Multiple Myeloma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-07-22
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Dose-limiting Toxicity (DLT) Incidents (Phase I)
timeFrame: Up to 21 days of every first course
measure: Proportion of Patients Who Achieve a Partial Response or Better. (Phase II)
timeFrame: From baseline to up to 3 years
Secondary outcomes:
measure: Number of Patients Who Have at Least a Partial Response (Phase I)
timeFrame: From baseline to up to 3 years
measure: Time to Progression (Phase II)
timeFrame: Time from registration to the time of progression
measure: Overall Survival (Phase II)
timeFrame: Time from registration to death due to any cause
measure: Time to Treatment Failure (Phase II)
timeFrame: Time from study entry to the date patients end treatment
measure: Toxicity as Assessed by the National Cancer Institute (NCI) CTCAE v 3.0 (Phase II)
timeFrame: From baseline to up to 3 years
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Alexander Stewart
role: PRINCIPAL_INVESTIGATOR
References: