Temsirolimus and Dexamethasone in Treating Patients With Recurrent or Refractory Multiple Myeloma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00693433
First received: June 6, 2008
Last updated: June 3, 2013
Last verified: June 2013

June 6, 2008
June 3, 2013
December 2008
August 2010   (final data collection date for primary outcome measure)
  • Maximum tolerated dose of temsirolimus [ Time Frame: Course 1 (first 28 days) ] [ Designated as safety issue: Yes ]
    The MTD is the dose level at which less than 2 out of 6 subjects experience DLT. Assessed according to the NCI Common Toxicity Criteria (CTC).
  • Toxicity and safety [ Time Frame: Continuously from start of treatment study ] [ Designated as safety issue: Yes ]
    The description and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be utilized for AE reporting.
  • Maximum tolerated dose of temsirolimus [ Designated as safety issue: Yes ]
  • Toxicity and safety [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00693433 on ClinicalTrials.gov Archive Site
  • Correlation between response to treatment with temsirolimus and the degree of p70 inhibition in peripheral blood mononuclear cells and in multiple myeloma (MM) cells [ Time Frame: Every 4 weeks ] [ Designated as safety issue: No ]
    We will examine a scatter plot of the absolute and Percent change in PBMNC versus the absolute and percent change in BM. Spearman (non-parametric) and Pearson (parametric) correlation coefficients and linear and/or spline smoothing regression on either the original or a transformed scale will be used to assess the relationship. We will compare mean and median levels in those who respond versus those who do not using the Wilcoxon rank sum test and we will report the percent of overlap in P70 between the two groups. Assessed using analysis of variance methods or their non-parametric analog.
  • Correlation between response to treatment with temsirolimus and the degree of pre-treatment AKT activation in MM cells [ Time Frame: Every 4 weeks ] [ Designated as safety issue: No ]
    Assessed by immunohistochemistry (IHC). We will first carry out a bivariate assessment of AKT percent positivity versus the binary outcome of response versus no response to treatment. For AKT score, we will compare mean and median levels in those who respond versus those who do not using the Wilcoxon rank sum test and we will report the percent of overlap in AKT between the two groups.
  • Correlation between response to treatment with temsirolimus and the degree of PTEN expression in MM cells [ Time Frame: Every 4 weeks ] [ Designated as safety issue: No ]
    PTEN expression will be determined by IHC. We will first carry out a bivariate assessment of PTEN score versus the binary outcome of response versus no response to treatment. For PTEN variables, we will report the corresponding contingency table versus response and use Wilcoxon test to assess the association if applicable.
  • Correlation between response to treatment with temsirolimus and the presence of RAS mutations [ Time Frame: Every 4 weeks ] [ Designated as safety issue: No ]
    We will first carry out a bivariate assessment of RAS mutational status versus the binary outcome of response versus no response to treatment. For RAS variables, we will report the corresponding contingency table versus response and use Fishers exact test to assess the association.
  • Correlation between response to treatment with temsirolimus and the presence of myc mutations [ Time Frame: Every 4 weeks ] [ Designated as safety issue: No ]
    We will first carry out a bivariate assessment of MYC mutational status versus the binary outcome of response versus no response to treatment. For MYC variables, we will report the corresponding contingency table versus response and use Fishers exact test to assess the association.
  • Correlation between response to treatment with temsirolimus and the degree of p70 inhibition in peripheral blood mononuclear cells and in multiple myeloma (MM) cells [ Designated as safety issue: No ]
  • Correlation between response to treatment with temsirolimus and the degree of pre-treatment AKT activation in MM cells [ Designated as safety issue: No ]
  • Correlation between response to treatment with temsirolimus and the degree of PTEN expression in MM cells [ Designated as safety issue: No ]
  • Correlation between response to treatment with temsirolimus and the presence of RAS mutations [ Designated as safety issue: No ]
  • Correlation between response to treatment with temsirolimus and the presence of myc mutations [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Temsirolimus and Dexamethasone in Treating Patients With Recurrent or Refractory Multiple Myeloma
A Phase 1 Study of CCI-779 in Combination With Dexamethasone in Multiple Myeloma

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.

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.

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Refractory Multiple Myeloma
  • Stage I Multiple Myeloma
  • Stage II Multiple Myeloma
  • Stage III Multiple Myeloma
  • Drug: dexamethasone
    Given orally
    Other Names:
    • Aeroseb-Dex
    • Decaderm
    • Decadron
    • DM
    • DXM
  • Drug: temsirolimus
    Given IV
    Other Names:
    • CCI-779
    • cell cycle inhibitor 779
    • Torisel
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (enzyme inhibitor, chemotherapy)
Patients receive temsirolimus 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.
Interventions:
  • Drug: dexamethasone
  • Drug: temsirolimus
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
15
Not Provided
August 2010   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00693433
NCI-2009-00157, VAMC-SC-7353, CDR0000597181
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Alan Lichtenstein Veterans Administration Los Angeles Healthcare System
National Cancer Institute (NCI)
June 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP