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.

Study Overview

• Status: Completed
• Conditions: Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Refractory Multiple Myeloma
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: dexamethasone; Drug: temsirolimus

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Las Angeles, California, United States, 90073
      • Veteran's Administration Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Other: laboratory biomarker analysis; Correlative studies; Drug: dexamethasone; Given orally; Other Names: Aeroseb-Dex; Decaderm; Decadron; DM; DXM; Drug: temsirolimus; Given IV; Other Names: Torisel; CCI-779; cell cycle inhibitor 779

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Course 1 (first 28 days)
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.	Continuously from start of treatment study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Every 4 weeks
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.	Every 4 weeks
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.	Every 4 weeks
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.	Every 4 weeks
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.	Every 4 weeks

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Alan Lichtenstein, Veterans Administration Los Angeles Healthcare System

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): August 1, 2010

Study Registration Dates

• First Submitted: June 6, 2008
• First Submitted That Met QC Criteria: June 6, 2008
• First Posted (Estimate): June 9, 2008

Study Record Updates

• Last Update Posted (Estimate): December 4, 2015
• Last Update Submitted That Met QC Criteria: December 3, 2015
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Dexamethasone; Sirolimus
• Other Study ID Numbers: NCI-2009-00157; VAMC-SC-7353; CDR0000597181