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

Primary Purpose

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

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
dexamethasone
temsirolimus
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:

  • 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

Sites / Locations

  • Veteran's Administration Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (enzyme inhibitor, chemotherapy)

Arm Description

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.

Outcomes

Primary Outcome Measures

Maximum tolerated dose of temsirolimus
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
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.

Secondary Outcome Measures

Correlation between response to treatment with temsirolimus and the degree of p70 inhibition in peripheral blood mononuclear cells and in multiple myeloma (MM) cells
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
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
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
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
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.

Full Information

First Posted
June 6, 2008
Last Updated
December 3, 2015
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00693433
Brief Title
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

2. Study Status

Record Verification Date
June 2013
Overall Recruitment Status
Completed
Study Start Date
December 2008 (undefined)
Primary Completion Date
August 2010 (Actual)
Study Completion Date
undefined (undefined)

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 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.

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
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (enzyme inhibitor, chemotherapy)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
dexamethasone
Other Intervention Name(s)
Aeroseb-Dex, Decaderm, Decadron, DM, DXM
Intervention Description
Given orally
Intervention Type
Drug
Intervention Name(s)
temsirolimus
Other Intervention Name(s)
CCI-779, cell cycle inhibitor 779, Torisel
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Maximum tolerated dose of temsirolimus
Description
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).
Time Frame
Course 1 (first 28 days)
Title
Toxicity and safety
Description
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.
Time Frame
Continuously from start of treatment study
Secondary Outcome Measure Information:
Title
Correlation between response to treatment with temsirolimus and the degree of p70 inhibition in peripheral blood mononuclear cells and in multiple myeloma (MM) cells
Description
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.
Time Frame
Every 4 weeks
Title
Correlation between response to treatment with temsirolimus and the degree of pre-treatment AKT activation in MM cells
Description
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.
Time Frame
Every 4 weeks
Title
Correlation between response to treatment with temsirolimus and the degree of PTEN expression in MM cells
Description
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.
Time Frame
Every 4 weeks
Title
Correlation between response to treatment with temsirolimus and the presence of RAS mutations
Description
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.
Time Frame
Every 4 weeks
Title
Correlation between response to treatment with temsirolimus and the presence of myc mutations
Description
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.
Time Frame
Every 4 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alan Lichtenstein
Organizational Affiliation
Veterans Administration Los Angeles Healthcare System
Official's Role
Principal Investigator
Facility Information:
Facility Name
Veteran's Administration Medical Center
City
Las Angeles
State/Province
California
ZIP/Postal Code
90073
Country
United States

12. IPD Sharing Statement

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

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