- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00687674
Sorafenib, Lenalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma
Phase I/II Study of Sorafenib, Lenalidomide, and Dexamethasone in Relapsed/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.
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Minnesota
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Rochester, Minnesota, United States, 55905
- Mayo Clinic
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
DISEASE CHARACTERISTICS:
Diagnosis of multiple myeloma
- Relapsed or refractory disease requiring treatment
Measurable disease, as defined by at least 1 of the following:
- Serum monoclonal protein ≥ 1.0 g
- More than 200 mg of monoclonal protein in the urine on 24-hour electrophoresis
- Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
- Monoclonal bone marrow plasmacytosis ≥ 30% (i.e., evaluable disease)
- No known standard therapy that is potentially curative for the patient's disease
PATIENT CHARACTERISTICS:
- ECOG performance status 0-2
- Life expectancy ≥ 12 weeks
- ANC ≥ 1,000/μL
- Platelet count ≥ 75,000/μL
- Hemoglobin ≥ 9 g/dL
- Direct bilirubin ≤ 1.5 times upper limit of normal (ULN)
- AST ≤ 3 times ULN (≤ 5 times ULN if the liver is involved)
- Creatinine ≤ 2.5 times ULN
- Patients with treated or untreated POEMS (Patient-Oriented Evidence That Matters) allowed, provided they satisfy the criteria for measurable disease
- No other prior malignancy within the past year except currently treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or breast, or prostate cancer not requiring therapy
- No other active malignancy requiring treatment that would interfere with the assessments of response of the myeloma to protocol treatment
INR < 1.5 OR PT/PTT ≤ 1.5 times ULN
- Patients receiving anticoagulation treatment with an agent such as warfarin or heparin are allowed
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use 2 methods of effective contraception for 28 days prior, during, and for 28 days after discontinuation of lenalidomide
- Willing to provide research samples according to the test schedule
- No uncontrolled infection
- No NYHA classification III or IV heart disease
- No unstable angina (i.e., anginal symptoms at rest), new-onset angina (i.e., began within the past 3 months), or myocardial infarction within the past 6 months
- No uncontrolled hypertension, defined as systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mm Hg, despite optimal medical management
- No thrombotic or embolic events within the past 6 months, including cerebrovascular accidents and transient ischemic attacks
- More than 4 weeks since prior pulmonary hemorrhage or other bleeding event > grade 2
- No serious nonhealing wound or ulcer
- More than 4 weeks since prior significant traumatic injury
- No known positivity for HIV infection or infectious hepatitis, type A, B, or C
- No known hypersensitivity to thalidomide or lenalidomide
- No prior development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs
- Able to take aspirin (325 mg) daily as prophylactic anticoagulation
PRIOR CONCURRENT THERAPY:
- Recovered from prior chemotherapy, regardless of interval since last treatment
- Prior lenalidomide therapy allowed
- More than 4 weeks since prior experimental therapy
- More than 4 weeks since prior major surgery or open biopsy
- No concurrent enrollment in any other study involving a pharmacologic agent or investigative therapy (i.e., drug, biologic, immunotherapy approaches, gene therapy) whether for symptom control or therapeutic intent
- No other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational
- No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (i.e., phenytoin, carbamazepine, and phenobarbital), rifampin, or Hypericum perforatum (St. John wort)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Sorafenib + Lenalidomide + Dexamethasone
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20 mg orally Days 1, 8, 15, 22 of 28 day cycle
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 progression
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
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With a Grade 3 and 4 Adverse Event (Phase I)
Time Frame: 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: Death |
up to 3 years
|
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)
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Response that was confirmed on 2 consecutive evaluations during treatment
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Duration on Treatment (up to 3 years)
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Overall Survival (Phase II)
Time Frame: From registration to death (up to 3 years)
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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
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From registration to death (up to 3 years)
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Time to Disease Progression (Phase II)
Time Frame: From registration to progression (up to 3 years)
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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:
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From registration to progression (up to 3 years)
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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)
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Pre and Post treatment (up to 3 years)
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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)
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Pre and Post treatment (up to 3 years)
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Plasma Cell Gene Expression Profiles and Correlation With > Clinical Outcomes
Time Frame: Post treatment
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Post treatment
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Percentage of Stained Circulating Endothelial Cells and Endothelial Progenitor Cells and Correlation With Clinical Outcomes (Phase II
Time Frame: Post treatment
|
Post treatment
|
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Change in VEGF Expression Levels and Correlation With Clinical Outcomes (Phase II)
Time Frame: Post treatment
|
Post treatment
|
Collaborators and Investigators
Sponsor
Collaborators
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
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
- Plasmacytoma
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Autonomic Agents
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Anti-Inflammatory Agents
- Antineoplastic Agents
- Immunologic Factors
- Antiemetics
- Gastrointestinal Agents
- Glucocorticoids
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Angiogenesis Inhibitors
- Angiogenesis Modulating Agents
- Growth Substances
- Growth Inhibitors
- Protein Kinase Inhibitors
- Dexamethasone
- Sorafenib
- Lenalidomide
Other Study ID Numbers
- CDR0000597065
- P30CA015083 (U.S. NIH Grant/Contract)
- MC078A (Other Identifier: Mayo Clinic)
- 07-006234 (Other Identifier: Mayo Clinic IRB)
- NCI-2009-01284 (Registry Identifier: NCI-CTRP)
- RV-MM-PI-0142 (Other Identifier: Celgene Protocol)
- SR06-933 (Other Identifier: Bayer Protocol)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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