Sorafenib, Lenalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma
- Conditions
- Multiple Myeloma and Plasma Cell Neoplasm
- Interventions
- Registration Number
- NCT00687674
- Lead Sponsor
- Mayo Clinic
- Brief Summary
RATIONALE: Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. 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. Sorafenib and lenalidomide may also stop the growth of cancer cells by blocking blood flow to the cancer. Giving sorafenib together with lenalidomide and dexamethasone may kill more cancer cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of sorafenib when given together with lenalidomide and dexamethasone and to see how well they work in treating patients with relapsed or refractory multiple myeloma.
- Detailed Description
OBJECTIVES:
Primary
* To determine the maximum tolerated dose of sorafenib tosylate and lenalidomide in combination with dexamethasone in patients with relapsed or refractory multiple myeloma. (phase I)
* To describe the toxicity of this regimen in these patients. (phase I)
* To evaluate the confirmed response in patients treated with this regimen. (phase II)
Secondary
* To correlate clinical effects (adverse events and/or tumor response or activity) with pharmacologic parameters (pharmacokinetics or pharmacodynamics) and/or biologic results (correlative laboratory). (phase II)
* To assess overall survival and time to disease progression in patients treated with this regimen. (phase II)
OUTLINE: This is a phase I, dose-escalation study of sorafenib tosylate in combination with lenalidomide followed by a phase II study.
Patients receive oral sorafenib tosylate once to twice daily on days 1-28, oral lenalidomide once daily on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Patients undergo blood and bone marrow sample collection periodically during study for laboratory correlative studies. Bone marrow plasma samples (i.e., fresh marrow aspirates) are assessed for marrow angiogenesis (microvessel density) by IHC; angiogenic capability (tubular network formation) by in vitro angiogenesis assay; tumor cell proliferation by bromo-2-deoxyuridine uptake; tumor cell apoptosis by three-color flow cytometry (CD38, CD45 or CD138, and 7AAD); and expression of VEGF and soluble VEGF receptors on plasma cells by enzyme-linked immunosorbent assay. Bone marrow biopsies are assessed for various phosphoproteins by IHC; phosphorylation status of ERK1/2 by immunoblotting; and for pharmacodynamic markers (e.g., P70 S6K) by immunoblotting. Blood samples are assessed for surface markers of circulating endothelial cells (CD105, CD34, and CD146) by flow cytometry and for circulating endothelial cell progenitors by late colony formation in mononuclear cells. The endothelial lineage is confirmed by phenotyping of surface markers for endothelial cells.
After completion of study therapy, patients are followed periodically for up to 3 years.
PROJECTED ACCRUAL: A total of 39 patients will be accrued for phase I and 44 for phase II of this study.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 13
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Sorafenib + Lenalidomide + Dexamethasone Lenalidomide - Sorafenib + Lenalidomide + Dexamethasone dexamethasone - Sorafenib + Lenalidomide + Dexamethasone sorafenib tosylate -
- Primary Outcome Measures
Name Time Method Number of Participants With a Grade 3 and 4 Adverse Event (Phase I) up to 3 years Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.
Description of Grades:
Grade 1: Mild Grade 2: Moderate Grade 3: Severe Grade 4: Life-threatening Grade 5: DeathNumber of Participants Who Achieve a Confirmed Response (Partial Response [PR], Very Good PR [VGPR], Complete Response [CR], or Stringent CR [sCR]) (Phase II) Duration on Treatment (up to 3 years) Response that was confirmed on 2 consecutive evaluations during treatment
* CR: Complete disappearance of M-protein from serum \& urine on immunofixation, \<5% plasma cells in bone marrow (BM)
* sCR: CR plus normal FLC ratio \& absence of clonal cells in BM
* VGPR: \>=90% reduction in serum M-component; Urine M-Component \<100 mg per 24 hours; \<=5% plasma cells in BM
* PR: \>= 50% reduction in serum M-Component and/or Urine M-Component \>= 90% reduction or \<200 mg per 24 hours; or \>= 50% decrease in difference between involved and uninvolved FLC levels
- Secondary Outcome Measures
Name Time Method Time to Disease Progression (Phase II) From registration to progression (up to 3 years) Time to disease progression (TTP) was defined as the time from registration to progression. The median TTP with 95%CI was estimated using the Kaplan Meier method.
Progression was defined as any one or more of the following:
An increase of 25% from lowest confirmed response in:
* Serum M-component (absolute increase \>= 0.5g/dl)
* Urine M-component (absolute increase \>= 200mg/24hour
* Difference between involved and uninvolved Free Light Chain levels (absolute increase \>= 10mg/dl
* Bone marrow plasma cell percentage (absolute increase of \>=10%)Changes in Microvessel Density From Baseline to Post-treatment and Correlation With > Clinical Outcomes (Phase II) Pre and Post treatment (up to 3 years) Change in Apoptosis Rate From Baseline to Post-treatment and Correlation With > Clinical Outcomes (Phase II) Pre and Post treatment (up to 3 years) Plasma Cell Gene Expression Profiles and Correlation With > Clinical Outcomes Post treatment Percentage of Stained Circulating Endothelial Cells and Endothelial Progenitor Cells and Correlation With Clinical Outcomes (Phase II Post treatment Change in VEGF Expression Levels and Correlation With Clinical Outcomes (Phase II) Post treatment Overall Survival (Phase II) From registration to death (up to 3 years) Overall Survival (OS) was defined as the time from registration to death of any cause. Participants were followed for a maximum of 2 years from registration. The median OS with 95%CI was estimated using the Kaplan Meier method
Trial Locations
- Locations (1)
Mayo Clinic
🇺🇸Rochester, Minnesota, United States