Clinical trial NCT00693433: Temsirolimus and Dexamethasone in Treating Patients With Recurrent or Refractory Multiple Myeloma
Official title: A Phase 1 Study of CCI-779 in Combination With Dexamethasone in Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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: 2008-06-09
Enrollment: 15
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 trial is studying the side effects and best dose of temsirolimus when given together with dexamethasone in treating patients with recurrent or refractory multiple myeloma. Temsirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving temsirolimus together with dexamethasone may kill more cancer cells.

Detailed description: PRIMARY OBJECTIVES:

I. To assess the toxicity and safety of temsirolimus in combination with dexamethasone in patients with recurrent or refractory multiple myeloma.

II. To assess a dose of temsirolimus that is capable of inhibiting the mammalian target of rapamycin (mTOR) in myeloma tumor cells.

SECONDARY OBJECTIVES:

I. To assess the efficacy of temsirolimus in combination with dexamethasone in these patients.

II. To correlate the efficacy of this regimen with molecular characteristics of the individual tumor clones.

OUTLINE: This is a multicenter, dose-escalation study of temsirolimus.

Patients receive temsirolimus intravenously (IV) over 30 minutes once weekly on days 1, 8, 15, and 22 and oral dexamethasone once on days 1, 2, 8, 9, 15, 16, 22, and 23. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo bone marrow aspiration and blood sample collection periodically for correlative studies. Correlative studies include analysis of p70S6 kinase activity in peripheral blood mononuclear cells and in multiple myeloma cells; analysis of the degree of AKT phosphorylation and degree of PTEN expression in multiple myeloma cells by immunohistochemistry; Ras mutational analysis; and Myc 5'UTR mutational analysis.

After completion of study treatment, patients are followed for 4 weeks.

Eligibility criteria: Inclusion Criteria:

* Pathologically confirmed multiple myeloma

  * Measurable levels of M protein in serum and/or urine
* Recurrent or refractory disease

  * Progressive disease after treatment with ≥ 2 separate chemotherapeutic regimens

    * At least 1 of the regimens must have included high-dose dexamethasone (40 mg on days 1-4, 9-12, and 17-20) or medium-dose dexamethasone (40 mg on days 1, 8, 15, and 22) of a 28-day course
* ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
* Life expectancy ≥ 8 weeks
* Absolute neutrophil count \> 1,000/mm\^3
* Platelet count \> 100,000/mm \^3
* Total bilirubin \< 2 mg/dL
* AST and ALT \< 3 times upper limit of normal
* Creatinine \< 2 mg/dL
* Fasting cholesterol \< 350 mg/dL
* Fasting triglycerides \< 400 mg/dL
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No history of allergic reactions attributed to compounds of similar chemical or biological composition to temsirolimus or dexamethasone
* No concurrent uncontrolled illness including, but not limited to, any of the following:

  * Ongoing or active infection
  * Poorly controlled hypertension
  * Diabetes mellitus
  * Symptomatic congestive heart failure
  * Unstable angina pectoris
  * Cardiac arrhythmia
  * Psychiatric illness or social situation that would limit compliance with study requirements
* See Disease Characteristics
* At least 4 weeks since prior cytotoxic therapy
* More than 4 weeks since prior chemotherapy and recovered
* No concurrent anticonvulsive or antiarrhythmic medications
* No concurrent enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital) or other CYP3A4 inhibitors or inducers (e.g., rifampin or Hypericum perforatum \[St. John wort\])
* No concurrent prophylactic hematopoietic colony-stimulating factors
* No other concurrent investigational therapy
* No other concurrent anticancer therapy

Primary outcomes:
measure: Maximum tolerated dose of temsirolimus
timeFrame: Course 1 (first 28 days)
measure: Toxicity and safety
timeFrame: Continuously from start of treatment study
Secondary outcomes:
measure: Correlation between response to treatment with temsirolimus and the degree of p70 inhibition in peripheral blood mononuclear cells and in multiple myeloma (MM) cells
timeFrame: Every 4 weeks
measure: Correlation between response to treatment with temsirolimus and the degree of pre-treatment AKT activation in MM cells
timeFrame: Every 4 weeks
measure: Correlation between response to treatment with temsirolimus and the degree of PTEN expression in MM cells
timeFrame: Every 4 weeks
measure: Correlation between response to treatment with temsirolimus and the presence of RAS mutations
timeFrame: Every 4 weeks
measure: Correlation between response to treatment with temsirolimus and the presence of myc mutations
timeFrame: Every 4 weeks
Other outcomes:
Locations:
city: Las Angeles
country: United States
facility: Veteran's Administration Medical Center
state: California
Study officials:
affiliation: Veterans Administration Los Angeles Healthcare System
name: Alan Lichtenstein
role: PRINCIPAL_INVESTIGATOR
References: