Multiple Myeloma and Plasma Cell Neoplasm
Conditions
Keywords
refractory multiple myeloma
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.
Interventions
DRUGdexamethasone
20 mg orally Days 1, 8, 15, 22 of 28 day cycle
DRUGsorafenib 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 progression
DRUGLenalidomide
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
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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: 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) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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) | — |
| 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 |
| 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 | — |
| Plasma Cell Gene Expression Profiles and Correlation With > Clinical Outcomes | Post treatment | — |
| 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%) |
Countries
United States
Participant flow
Recruitment details
Thirteen (13) participants were recruited at Mayo Clinic between August 2008 and March 2010.
Pre-assignment details
This was a phase I/II trial. A total of 13 participants were accrued, all to the phase I portion. This trial was terminated due to study design and toxicity during the phase I; therefore, the phase II portion will never open. No results from the phase II portion are available.
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib + Lenalidomide + Dexamethasone | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Sorafenib + Lenalidomide + Dexamethasone |
|---|---|
| Age, Continuous | 62 years |
| Prior Lenalidomide No | 11 participants |
| Prior Lenalidomide Yes | 2 participants |
| Prior Transplant No | 1 participants |
| Prior Transplant Yes | 12 participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 13 |
| serious Total, serious adverse events | 3 / 13 |
Outcome results
Primary
Number of Participants Who Achieve a Confirmed Response (Partial Response [PR], Very Good PR [VGPR], Complete Response [CR], or Stringent CR [sCR]) (Phase II)
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
Time frame: Duration on Treatment (up to 3 years)
Population: No participants proceeded to Phase II for evaluation.
Primary
Number of Participants With a Grade 3 and 4 Adverse Event (Phase I)
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
Time frame: up to 3 years
Population: One participant refused further treatment prior to being assessed for adverse events.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib + Lenalidomide + Dexamethasone | Number of Participants With a Grade 3 and 4 Adverse Event (Phase I) | 11 participants |
Secondary
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)
Secondary
Change in VEGF Expression Levels and Correlation With Clinical Outcomes (Phase II)
Time frame: Post treatment
Secondary
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)
Secondary
Overall Survival (Phase II)
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 frame: From registration to death (up to 3 years)
Population: No participants proceeded to Phase II for evaluation.
Secondary
Percentage of Stained Circulating Endothelial Cells and Endothelial Progenitor Cells and Correlation With Clinical Outcomes (Phase II
Time frame: Post treatment
Secondary
Plasma Cell Gene Expression Profiles and Correlation With > Clinical Outcomes
Time frame: Post treatment
Secondary
Time to Disease Progression (Phase II)
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%)
Time frame: From registration to progression (up to 3 years)
Population: No participants proceeded to Phase II for evaluation.