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Phase I/II Study of Sorafenib, Lenalidomide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Phase 1/Phase 2
18 Years
Not Enrolling
Multiple Myeloma and Plasma Cell Neoplasm

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Trial Information

Phase I/II Study of Sorafenib, Lenalidomide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma



- 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.

Inclusion Criteria


- 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


- 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


- 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)

Type of Study:


Study Design:

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Participants With a Grade 3 and 4 Adverse Event (Phase I)

Outcome Description:

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

Outcome Time Frame:

up to 3 years

Safety Issue:


Principal Investigator

Shaji K. Kumar, M.D.

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

August 2008

Completion Date:

November 2011

Related Keywords:

  • Multiple Myeloma and Plasma Cell Neoplasm
  • refractory multiple myeloma
  • Neoplasms
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma



Mayo Clinic Rochester, Minnesota  55905