Sorafenib, Lenalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma

• Sponsor: Mayo Clinic (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00687674
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 13
• Location: 1
• Arm: 1
• Duration (Months): 39
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Drug: dexamethasone; Drug: sorafenib tosylate; Drug: Lenalidomide	Phase 1

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 Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of Sorafenib, Lenalidomide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Sorafenib + Lenalidomide + Dexamethasone

Drug: dexamethasone; 20 mg orally Days 1, 8, 15, 22 of 28 day cycle; Drug: 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 progression; Drug: 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

Outcome Measures

Primary Outcome Measures

1. 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

2. 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 Outcome Measures

1. 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

2. 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%)

3. Changes in Microvessel Density From Baseline to Post-treatment and Correlation With > Clinical Outcomes (Phase II) [Pre and Post treatment (up to 3 years)]

4. Change in Apoptosis Rate From Baseline to Post-treatment and Correlation With > Clinical Outcomes (Phase II) [Pre and Post treatment (up to 3 years)]

5. Plasma Cell Gene Expression Profiles and Correlation With > Clinical Outcomes [Post treatment]

6. Percentage of Stained Circulating Endothelial Cells and Endothelial Progenitor Cells and Correlation With Clinical Outcomes (Phase II [Post treatment]

7. Change in VEGF Expression Levels and Correlation With Clinical Outcomes (Phase II) [Post treatment]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Shaji K. Kumar, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00687674
• Other Study ID Numbers: CDR0000597065; P30CA015083; MC078A; 07-006234; NCI-2009-01284; RV-MM-PI-0142; SR06-933
• First Posted: Jun 2, 2008
• Last Update Posted: Aug 20, 2019
• Last Verified: May 1, 2018

• Keywords provided by Mayo Clinic: refractory multiple myeloma
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Dexamethasone; Lenalidomide; Sorafenib

Study Results

Participant Flow

Recruitment Details	Thirteen (13) participants were recruited at Mayo Clinic between August 2008 and March 2010.
Pre-assignment Detail	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.

Arm/Group Title	Sorafenib + Lenalidomide + Dexamethasone
Arm/Group Description
Period Title: Overall Study
STARTED	13
COMPLETED	11
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Sorafenib + Lenalidomide + Dexamethasone
Arm/Group Description
Overall Participants	13
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	6 46.2%
Male	7 53.8%
Region of Enrollment (participants) [Number]
United States	13 100%
Prior Lenalidomide (participants) [Number]
Yes	2 15.4%
No	11 84.6%
Prior Transplant (participants) [Number]
Yes	12 92.3%
No	1 7.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With a Grade 3 and 4 Adverse Event (Phase I)
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
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

One participant refused further treatment prior to being assessed for adverse events.

Arm/Group Title	Sorafenib + Lenalidomide + Dexamethasone
Arm/Group Description
Measure Participants	12
Number [participants]	11 84.6%

2. Primary Outcome

Title	Number of Participants Who Achieve a Confirmed Response (Partial Response [PR], Very Good PR [VGPR], Complete Response [CR], or Stringent CR [sCR]) (Phase II)
Description	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)

Outcome Measure Data

Analysis Population Description

No participants proceeded to Phase II for evaluation.

Arm/Group Title	Sorafenib + Lenalidomide + Dexamethasone
Arm/Group Description
Measure Participants	0

3. Secondary Outcome

Title	Overall Survival (Phase II)
Description	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)

Outcome Measure Data

Analysis Population Description

No participants proceeded to Phase II for evaluation.

Arm/Group Title	Sorafenib + Lenalidomide + Dexamethasone
Arm/Group Description
Measure Participants	0

4. Secondary Outcome

Title	Time to Disease Progression (Phase II)
Description	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)

Outcome Measure Data

Analysis Population Description

No participants proceeded to Phase II for evaluation.

Arm/Group Title	Sorafenib + Lenalidomide + Dexamethasone
Arm/Group Description
Measure Participants	0

5. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Plasma Cell Gene Expression Profiles and Correlation With > Clinical Outcomes
Time Frame	Post treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Percentage of Stained Circulating Endothelial Cells and Endothelial Progenitor Cells and Correlation With Clinical Outcomes (Phase II
Time Frame	Post treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Change in VEGF Expression Levels and Correlation With Clinical Outcomes (Phase II)
Time Frame	Post treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Sorafenib + Lenalidomide + Dexamethasone
Arm/Group Description
All Cause Mortality
	Sorafenib + Lenalidomide + Dexamethasone
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Sorafenib + Lenalidomide + Dexamethasone
	Affected / at Risk (%)	# Events
Total	3/13 (23.1%)
Infections and infestations
Pneumonia	1/13 (7.7%)	1
Investigations
Leukopenia	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Rash	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	Sorafenib + Lenalidomide + Dexamethasone
	Affected / at Risk (%)	# Events
Total	12/13 (92.3%)
Blood and lymphatic system disorders
Anemia	11/13 (84.6%)	53
Gastrointestinal disorders
Diarrhea	4/13 (30.8%)	9
Nausea	2/13 (15.4%)	2
Oral cavity Mucositis/stomatitis (clinical exam)	2/13 (15.4%)	3
General disorders
Fatigue	9/13 (69.2%)	63
Fever	1/13 (7.7%)	1
Pain	1/13 (7.7%)	6
Infections and infestations
Infection without neutropenia	1/13 (7.7%)	1
Pneumonia	1/13 (7.7%)	2
Urinary tract infection	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Bruising	1/13 (7.7%)	5
Investigations
Bilirubin	1/13 (7.7%)	1
Leukopenia	10/13 (76.9%)	64
Lymphocyte count decreased	1/13 (7.7%)	5
Neutrophil count decreased	10/13 (76.9%)	62
Platelet count decreased	10/13 (76.9%)	74
Metabolism and nutrition disorders
Hyperglycemia	1/13 (7.7%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/13 (7.7%)	1
Myalgia	1/13 (7.7%)	4
Respiratory, thoracic and mediastinal disorders
Nasal congestion	1/13 (7.7%)	7
Pulmonary	1/13 (7.7%)	9
Skin and subcutaneous tissue disorders
Alopecia	1/13 (7.7%)	3
Hand-foot skin reaction	2/13 (15.4%)	2
Rash	7/13 (53.8%)	8
Vascular disorders
Hypertension	4/13 (30.8%)	13

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.