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Lenalidomide and Temsirolimus in Treating Patients With Previously Treated Multiple Myeloma

Primary Purpose

Refractory Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
lenalidomide
temsirolimus
pharmacological study
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:

  • Diagnosis of multiple myeloma (MM)

    • Salmon-Durie stage IIA or IIIA
    • No stage B disease
  • Meets ≥ 1 major AND 1 minor criterion OR ≥ 3 minor criteria

    • The following are considered major criteria:

      • Plasmacytoma on tissue biopsy
      • Bone marrow plasmacytosis with ≥ 30% plasma cells
      • Monoclonal paraprotein ≥ 3,500 mg/dL (IgG) or ≥ 2,000 mg/dL (IgA) OR monoclonal protein (Bence-Jones protein) ≥ 1,000 mg by 24-hour urine collection
    • The following are considered minor criteria:

      • Bone marrow plasmacytosis 10-29% of marrow cellularity
      • Monoclonal globulin spike < 3,500 mg/dL (IgG) or < 2,000 mg/dL (IgA)
      • Lytic bone lesions
      • Decrease in normal IgM (< 50 mg/dL), IgA (< 100 mg/dL), or IgG (< 600 mg/dL)
  • Disease progression after ≥ 1 prior systemic treatment regimen* for MM (e.g., chemotherapy, high-dose corticosteroids, thalidomide, or bortezomib), defined as > 25% increase in serum or urine M-protein
  • No solitary plasmacytoma
  • No non-secretory MM (absent serum or urinary M-protein)
  • ECOG performance status 0-2
  • Life expectancy > 6 months
  • Bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • AST and ALT ≤ 3 times ULN
  • Creatinine ≤ 2.0 mg/dL
  • Absolute neutrophil count ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Fasting cholesterol ≤ 350 mg/dL
  • Fasting triglycerides ≤ 400 mg/dL
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective double-method contraception
  • Must agree not to donate blood, sperm, or ova during and for 4 weeks after completion of study treatment
  • No other prior or concurrent malignancy or myelodysplasia except for the following:

    • Basal cell or squamous cell skin cancer
    • Carcinoma in situ of the cervix
    • Localized cancer treated with surgery only with no evidence of disease for > 5 years
  • No history of recurrent deep vein thrombosis (DVT)/pulmonary embolism (PE) or DVT/PE occurring while on therapeutic levels of anticoagulation

    • Patients with DVT/PE within the past 6 months are eligible provided they receive full anticoagulation during study treatment
  • No active infection requiring oral or intravenous antibiotics
  • No uncontrolled illness including, but not limited to, any of the following:

    • Ongoing or active infection
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Psychiatric illness or social situations that would preclude study compliance
  • No known hepatitis B or C
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to lenalidomide or CCI-779
  • See Disease Characteristics
  • Prior lenalidomide allowed
  • Prior high-dose chemotherapy with stem cell transplantation allowed
  • More than 4 weeks since prior chemotherapy or other antimyeloma systemic therapy (e.g., thalidomide, bortezomib, or high-dose corticosteroids) and recovered
  • No prior exposure to both lenalidomide and mTOR inhibitors (given together)

    • Treatment with single-agent lenalidomide or single-agent mTOR inhibitor allowed
  • No other concurrent investigational agents
  • No concurrent corticosteroids unless for physiologic maintenance
  • No concurrent antiretroviral therapy for HIV-positive patients
  • No concurrent myeloid growth factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF])
  • No concurrent grapefruit or grapefruit juice

Sites / Locations

  • Ohio State University Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (antiangiogenesis, chemotherapy, enzyme inhibitor)

Arm Description

Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Maximum tolerated dose (MTD) of temsirolimus when given together with lenalidomide
The MTD is the dose level at which less than 2 out of 6 patients experience dose limiting toxicities (DLT). The National Cancer Institute Common Terminology Criteria for Adverse events (CTCAE) version 3.0 will used to characterize toxicities.

Secondary Outcome Measures

Toxicity of lenalidomide and temsirolimus combination therapy in previously treated mulple myeloma patients
Measured by NCI CTCAE version 3.0.
Pharmacokinetic analysis of lenalidomide
Plasma drug levels will be measured by liquid chromatography and tandem mass spectroscopy.
Pharmacodynamics of temsirolimus in peripheral blood mononuclear cells (PBMC)
PBMC will be used to assess the phosphorylation status of p70S6K to evaluate the pharmacodynamic activity of each dose level. This will assist in determining the biologically active dose in the event that dose limiting toxicity is not observed. The analysis of p70^S6K and phospho (P)-p70^S6K will be assessed by Western blotting using specific antibodies. The expression level will be quantified by densitometry. The inhibition of P- p70S6K will be correlated with clinical endpoints and PK parameters.
Assessment of serum cytokines; IL-2, sIL-2R, TNF-alpha, IFN-gamma, IL-1 beta, IL-1Ra, GM-CSF, IL-8, IL-6, sIL-6R, MIP-1 alpha, VEGF, and b-FGF
Assessed by ELISA.
Assessment of peripheral blood immune cell subsets
We will investigate immune cell subsets by flow-cytometry.

Full Information

First Posted
November 9, 2006
Last Updated
September 27, 2013
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00398515
Brief Title
Lenalidomide and Temsirolimus in Treating Patients With Previously Treated Multiple Myeloma
Official Title
A Phase I Trial of CC-5013 (Lenalidomide) and CCI-779 in Patients With Relapsed or Refractory Multiple Myeloma
Study Type
Interventional

2. Study Status

Record Verification Date
September 2013
Overall Recruitment Status
Completed
Study Start Date
March 2007 (undefined)
Primary Completion Date
February 2012 (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 lenalidomide in treating patients with previously treated multiple myeloma. Lenalidomide may stop the growth of multiple myeloma by blocking blood flow to the cancer. Drugs used in chemotherapy, such as temsirolimus, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Temsirolimus may also stop the growth of cancer cells by blocking some of the enzymes needed for their growth. Giving lenalidomide together with temsirolimus may kill more cancer cells.
Detailed Description
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of CCI-779 (temsirolimus) when given together with lenalidomide in patients with previously treated multiple myeloma. SECONDARY OBJECTIVES: I. Determine the toxicity of this regimen in these patients. II. Determine the clinical response of patients treated with this regimen. III. Determine the pharmacokinetics of this regimen. IV. Determine the pharmacodynamic effects of this regimen in these patients. V. Determine the effect of this regimen on immunological cellular and serological parameters and hematopoietic precursor cells. OUTLINE: This is a dose-escalation study of CCI-779. Patients receive temsirolimus intravenously (IV) over 30 minutes on days 1, 8, 15, and 22 and oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients achieving at least a partial response after 12 courses may continue to receive CCI-779 and lenalidomide as above in the absence of disease progression. Cohorts of 3 patients receive escalating doses of CCI-779 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Ten patients are treated at the MTD. Patients undergo blood sample and bone marrow collection periodically during study treatment for pharmacokinetic and pharmacodynamic studies, and to determine the immunomodulatory effects of CCI-779 and lenalidomide.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Refractory 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
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (antiangiogenesis, chemotherapy, enzyme inhibitor)
Arm Type
Experimental
Arm Description
Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
lenalidomide
Other Intervention Name(s)
CC-5013, IMiD-1, Revlimid
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)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Maximum tolerated dose (MTD) of temsirolimus when given together with lenalidomide
Description
The MTD is the dose level at which less than 2 out of 6 patients experience dose limiting toxicities (DLT). The National Cancer Institute Common Terminology Criteria for Adverse events (CTCAE) version 3.0 will used to characterize toxicities.
Time Frame
Course 1 (first 28 days)
Secondary Outcome Measure Information:
Title
Toxicity of lenalidomide and temsirolimus combination therapy in previously treated mulple myeloma patients
Description
Measured by NCI CTCAE version 3.0.
Time Frame
From the time of their first treatment with lenalidomide and temsirolimus
Title
Pharmacokinetic analysis of lenalidomide
Description
Plasma drug levels will be measured by liquid chromatography and tandem mass spectroscopy.
Time Frame
Baseline and days 1 and 22 (lenalidomide only) of course 1
Title
Pharmacodynamics of temsirolimus in peripheral blood mononuclear cells (PBMC)
Description
PBMC will be used to assess the phosphorylation status of p70S6K to evaluate the pharmacodynamic activity of each dose level. This will assist in determining the biologically active dose in the event that dose limiting toxicity is not observed. The analysis of p70^S6K and phospho (P)-p70^S6K will be assessed by Western blotting using specific antibodies. The expression level will be quantified by densitometry. The inhibition of P- p70S6K will be correlated with clinical endpoints and PK parameters.
Time Frame
Days 1 and 8 of course 1
Title
Assessment of serum cytokines; IL-2, sIL-2R, TNF-alpha, IFN-gamma, IL-1 beta, IL-1Ra, GM-CSF, IL-8, IL-6, sIL-6R, MIP-1 alpha, VEGF, and b-FGF
Description
Assessed by ELISA.
Time Frame
Baseline and then every 4 weeks
Title
Assessment of peripheral blood immune cell subsets
Description
We will investigate immune cell subsets by flow-cytometry.
Time Frame
Baseline and then every 4 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of multiple myeloma (MM) Salmon-Durie stage IIA or IIIA No stage B disease Meets ≥ 1 major AND 1 minor criterion OR ≥ 3 minor criteria The following are considered major criteria: Plasmacytoma on tissue biopsy Bone marrow plasmacytosis with ≥ 30% plasma cells Monoclonal paraprotein ≥ 3,500 mg/dL (IgG) or ≥ 2,000 mg/dL (IgA) OR monoclonal protein (Bence-Jones protein) ≥ 1,000 mg by 24-hour urine collection The following are considered minor criteria: Bone marrow plasmacytosis 10-29% of marrow cellularity Monoclonal globulin spike < 3,500 mg/dL (IgG) or < 2,000 mg/dL (IgA) Lytic bone lesions Decrease in normal IgM (< 50 mg/dL), IgA (< 100 mg/dL), or IgG (< 600 mg/dL) Disease progression after ≥ 1 prior systemic treatment regimen* for MM (e.g., chemotherapy, high-dose corticosteroids, thalidomide, or bortezomib), defined as > 25% increase in serum or urine M-protein No solitary plasmacytoma No non-secretory MM (absent serum or urinary M-protein) ECOG performance status 0-2 Life expectancy > 6 months Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 3 times ULN Creatinine ≤ 2.0 mg/dL Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Fasting cholesterol ≤ 350 mg/dL Fasting triglycerides ≤ 400 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective double-method contraception Must agree not to donate blood, sperm, or ova during and for 4 weeks after completion of study treatment No other prior or concurrent malignancy or myelodysplasia except for the following: Basal cell or squamous cell skin cancer Carcinoma in situ of the cervix Localized cancer treated with surgery only with no evidence of disease for > 5 years No history of recurrent deep vein thrombosis (DVT)/pulmonary embolism (PE) or DVT/PE occurring while on therapeutic levels of anticoagulation Patients with DVT/PE within the past 6 months are eligible provided they receive full anticoagulation during study treatment No active infection requiring oral or intravenous antibiotics No uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness or social situations that would preclude study compliance No known hepatitis B or C No history of allergic reactions attributed to compounds of similar chemical or biologic composition to lenalidomide or CCI-779 See Disease Characteristics Prior lenalidomide allowed Prior high-dose chemotherapy with stem cell transplantation allowed More than 4 weeks since prior chemotherapy or other antimyeloma systemic therapy (e.g., thalidomide, bortezomib, or high-dose corticosteroids) and recovered No prior exposure to both lenalidomide and mTOR inhibitors (given together) Treatment with single-agent lenalidomide or single-agent mTOR inhibitor allowed No other concurrent investigational agents No concurrent corticosteroids unless for physiologic maintenance No concurrent antiretroviral therapy for HIV-positive patients No concurrent myeloid growth factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF]) No concurrent grapefruit or grapefruit juice
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Craig Hofmeister
Organizational Affiliation
Ohio State University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Lenalidomide and Temsirolimus in Treating Patients With Previously Treated Multiple Myeloma

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