Sorafenib, Lenalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma
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.
Multiple Myeloma and Plasma Cell Neoplasm
Drug: sorafenib tosylate
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Study of Sorafenib, Lenalidomide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma|
- Number of Participants With a Grade 3 and 4 Adverse Event (Phase I) [ Time Frame: up to 3 years ] [ Designated as safety issue: Yes ]
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: Death
- Number of Participants Who Achieve a Confirmed Response (Partial Response [PR], Very Good PR [VGPR], Complete Response [CR], or Stringent CR [sCR]) (Phase II) [ Time Frame: Duration on Treatment (up to 3 years) ] [ Designated as safety issue: No ]
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
- Overall Survival (Phase II) [ Time Frame: From registration to death (up to 3 years) ] [ Designated as safety issue: No ]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
- Time to Disease Progression (Phase II) [ Time Frame: From registration to progression (up to 3 years) ] [ Designated as safety issue: No ]
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) [ Time Frame: Pre and Post treatment (up to 3 years) ] [ Designated as safety issue: No ]
- Change in Apoptosis Rate From Baseline to Post-treatment and Correlation With > Clinical Outcomes (Phase II) [ Time Frame: Pre and Post treatment (up to 3 years) ] [ Designated as safety issue: No ]
- Plasma Cell Gene Expression Profiles and Correlation With > Clinical Outcomes [ Time Frame: Post treatment ] [ Designated as safety issue: No ]
- Percentage of Stained Circulating Endothelial Cells and Endothelial Progenitor Cells and Correlation With Clinical Outcomes (Phase II [ Time Frame: Post treatment ] [ Designated as safety issue: No ]
- Change in VEGF Expression Levels and Correlation With Clinical Outcomes (Phase II) [ Time Frame: Post treatment ] [ Designated as safety issue: No ]
|Study Start Date:||August 2008|
|Study Completion Date:||November 2011|
|Primary Completion Date:||November 2011 (Final data collection date for primary outcome measure)|
|Experimental: Sorafenib + Lenalidomide + Dexamethasone||
20 mg orally Days 1, 8, 15, 22 of 28 day cycleDrug: sorafenib tosylate
Phase I - dose escalating: 200mg once daily dose level -2, 200mg once daily dose level -1, 200mg once daily dose level 0, 200mg twice daily dose level 1, 200mg twice daily dose level 2, 400mg AM & 200mg PM daily dose level 2a, 400mg twice daily dose level 3 orally days 1-28 every 28 days until progressionDrug: Lenalidomide
Phase I - dose escalating: 5mg level -2, 10mg level -1, 15mg level 0, 15mg level 1, 25mg level 2, 25mg level 2a, 25mg level 3 orally days 1-21 every 28 days until progression
- 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)
- 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.
|United States, Minnesota|
|Rochester, Minnesota, United States, 55905|
|Study Chair:||Shaji K. Kumar, M.D.||Mayo Clinic|