Clinical trial NCT00098475: Lenalidomide and Dexamethasone With or Without Thalidomide in Treating Patients With Multiple Myeloma
Official title: A Randomized Phase III Study of CC-5013 Plus Dexamethasone Versus CC-5013 Plus Low Dose Dexamethasone in Multiple Myeloma With Thalidomide Plus Dexamethasone Salvage Therapy for Non-Responders
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: DS Stage I Multiple Myeloma
DS Stage II Multiple Myeloma
DS Stage III Multiple Myeloma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2004-12-08
Enrollment: 452
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized phase III trial studies lenalidomide and low-dose dexamethasone to see how well it works compared to lenalidomide and standard-dose dexamethasone, given with or without thalidomide, in treating patients with multiple myeloma. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Lenalidomide and thalidomide may also stop the growth of multiple myeloma by blocking blood flow to the cancer. 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. Giving lenalidomide, thalidomide, and dexamethasone together may kill more cancer cells.

Detailed description: PRIMARY OBJECTIVE:

I. To evaluate the response rate and toxicity of lenalidomide (CC-5013) plus dexamethasone (standard dose) versus CC-5013 plus low dose dexamethasone in patients with newly diagnosed myeloma at any time in the first 4 cycles of treatment and to determine if CC-5013 plus low dose dexamethasone will have similar response rate with lower toxicity (First Phase).

SECONDARY OBJECTIVES:

I. To evaluate the response rate of thalidomide plus dexamethasone (Thal/Dex) in patients with newly diagnosed myeloma who do not achieve a complete or partial response at any time in the first 4 cycles with the CC-5013 and dexamethasone combination in either of the two arms (First Phase).

II. To study the effect of CC-5013 on bone marrow microvessel density and angiogenesis grade, on plasma cell labeling index (PCLI), and on the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in the marrow (First Phase).

III. To study the effect of CC-5013 and dexamethasone on bone marrow mesenchymal progenitor cells (MPCs) (First Phase).

IV. To evaluate in a separate expansion phase the efficacy of aspirin (325 mg/day) versus Coumadin (dose adjusted to maintain a target international normalized ratio \[INR\] of 2-3) in preventing deep vein thrombosis (DVT) in patients with newly diagnosed myeloma receiving CC-5013 plus standard dose dexamethasone.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, and standard-dose dexamethasone PO QD on days 1-4, 9-12, and 17-20.

Arm II: Patients receive lenalidomide as in Arm I and low-dose dexamethasone PO QD on days 1, 8, 15, and 22.

In both arms, cycles repeat every 28 days in the absence of unacceptable toxicity or disease progression. Patients not responding at any point during the first 4 cycles of lenalidomide and dexamethasone are assigned to 1 of 2 salvage therapy arms. Patients who progress during treatment on Arms I or II have the option to register on salvage therapy Arms III or IV respectively.

Arm III (patients with no response after treatment on Arm I): Patients receive thalidomide PO QD on days 1-28 and standard-dose dexamethasone PO QD on days 1-4, 9-12, and 17-20.

Arm IV (patients with no response after treatment on Arm II): Patients receive thalidomide as in Arm III and low-dose dexamethasone PO QD on days 1, 8, 15, and 22.

In both salvage therapy arms, cycles repeat every 28 days in the absence of unacceptable toxicity or disease progression. After completion of 4 cycles of therapy, patients may undergo stem cell harvest (using growth factors only) for cryopreservation.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 2 years.

Eligibility criteria: Inclusion Criteria:

* Patients must be diagnosed with symptomatic multiple myeloma within the past 90 days confirmed by the following:

  * Bone marrow plasmacytosis with \>= 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma which must be obtained within 4 weeks prior to randomization
  * Measurable levels of monoclonal protein (M protein): \>= 1.0 g/dL on serum protein electrophoresis or \>= 200 mg of monoclonal light chain on a 24 hour urine protein electrophoresis which must be obtained within 4 weeks prior to randomization; both serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) are required to be performed within 28 days prior to randomization; please note that if both serum and urine m-components are present, both must be followed in order to evaluate response
* Hemoglobin \> 7 g/dL
* Platelet count \> 75,000 cells/mm\^3
* Absolute neutrophil count \> 1000 cells/mm\^3
* Creatinine \< 2.5 mg/dL and creatinine clearance (measured or calculated) \>= 60 mL/min
* Bilirubin =\< 1.5 mg/dL
* Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) =\< 2.5 times the upper limit of normal
* Prior palliative and/or localized radiation therapy is permitted provided at least 4 weeks have passed from date of last radiation therapy to date of registration; patients with prior solitary plasmacytoma treated with radiation therapy with curative intent are eligible if the disease has now progressed to active multiple myeloma meeting all the eligibility criteria for this protocol
* Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
* Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24 hours prior to starting cycle 1 of lenalidomide; further, they must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method (intrauterine device \[IUD\], birth control pills, tubal ligation or partner's vasectomy) and one additional effective method (condom, diaphragm or cervical cap); FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy starting 4 weeks prior to and while taking CC5013 or thalidomide and for four weeks after discontinuing this therapy; a FCBP is a sexually mature woman who: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure
* Patients with a history of prior malignancy are eligible provided there is no active malignancy and a low expectation of recurrence within 6 months

Exclusion Criteria:

* No prior systemic therapy with the exception of bisphosphonates for multiple myeloma
* Prior glucocorticosteroid therapy for the treatment of multiple myeloma is not permitted; prior systemic glucocorticosteroid use for the treatment of non-malignant disorders is permitted; concurrent use after registration on the study should be restricted to the equivalent of prednisone 10 mg per day; prior or concurrent topical or localized glucocorticosteroid therapy to treat non-malignant comorbid disorders is permitted
* Patients must not have active, uncontrolled seizure disorder; patients must have had no seizures in the last 6 months
* Patients must not have uncontrolled intercurrent illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance with the study, or a prior history of Stevens Johnson syndrome
* Patients with smoldering myeloma or monoclonal gammopathy of undetermined significance are not eligible
* Patients must not have grade 2 or higher peripheral neuropathy due to other medical conditions at the time of randomization
* Patients must not have active, uncontrolled infection
* Patients must not have a history of current or previous deep vein thrombosis or pulmonary embolism regardless of whether or not the patient is receiving anticoagulation therapy

  * For patients registered prior to activation of Addendum # 6; patients must be willing and able to take prophylaxis with either aspirin at 325 mg/day or alternative prophylaxis with either low molecular weight heparin or Coumadin
  * For patients registered after activation of Addendum # 6; patients entering the expansion phase of the protocol, which tests anticoagulant prophylaxis, must be able and willing to be randomized between aspirin at 325 mg/day and Coumadin
* Female patients MUST NOT be pregnant or breastfeeding; due to the potential teratogenic properties of CC 5013, and the known teratogenicity associated with thalidomide, the use of these drugs in this patient population is ABSOLUTELY CONTRAINDICATED

Primary outcomes:
measure: Proportion of Patients With Objective Response (First Phase, Step 1)
timeFrame: Assessed every 4 weeks for 16 weeks during Step 1
Secondary outcomes:
measure: Proportion of Patients With Objective Response (First Phase, Step 2)
timeFrame: Assessed every 4 weeks for 16 weeks during Step 2
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Huntsville
country: United States
facility: Huntsville Hospital
state: Alabama
city: Anchorage
country: United States
facility: Providence Alaska Medical Center
state: Alaska
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Burbank
country: United States
facility: Providence Saint Joseph Medical Center/Disney Family Cancer Center
state: California
city: Fullerton
country: United States
facility: Saint Jude Medical Center
state: California
city: Mountain View
country: United States
facility: El Camino Hospital
state: California
city: San Diego
country: United States
facility: Kaiser Permanente-San Diego Mission
state: California
city: Aurora
country: United States
facility: The Medical Center of Aurora
state: Colorado
city: Colorado Springs
country: United States
facility: Penrose-Saint Francis Healthcare
state: Colorado
city: Denver
country: United States
facility: Saint Joseph Hospital - Cancer Centers of Colorado
state: Colorado
city: Englewood
country: United States
facility: Swedish Medical Center
state: Colorado
city: Fort Collins
country: United States
facility: Poudre Valley Hospital
state: Colorado
city: Loveland
country: United States
facility: Banner McKee Medical Center
state: Colorado
city: Danbury
country: United States
facility: Danbury Hospital
state: Connecticut
city: Norwich
country: United States
facility: Eastern Connecticut Hematology and Oncology Associates
state: Connecticut
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital
state: Florida
city: Gainesville
country: United States
facility: University of Florida Health Science Center - Gainesville
state: Florida
city: Jacksonville
country: United States
facility: Baptist MD Anderson Cancer Center
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic in Florida
state: Florida
city: Stuart
country: United States
facility: Martin Hospital South
state: Florida
city: Albany
country: United States
facility: Phoebe Putney Memorial Hospital
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Atlanta Regional CCOP
state: Georgia
city: Augusta
country: United States
facility: Augusta Oncology Associates PC-D'Antignac
state: Georgia
city: Decatur
country: United States
facility: Emory Decatur Hospital
state: Georgia
city: Macon
country: United States
facility: Atrium Health Navicent
state: Georgia
city: Savannah
country: United States
facility: Lewis Cancer and Research Pavilion at Saint Joseph's/Candler
state: Georgia
city: Honolulu
country: United States
facility: University of Hawaii Cancer Center
state: Hawaii
city: Boise
country: United States
facility: Saint Luke's Cancer Institute - Boise
state: Idaho
city: Alton
country: United States
facility: OSF Saint Anthony's Health Center
state: Illinois
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: John H Stroger Jr Hospital of Cook County
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Elk Grove Village
country: United States
facility: Ascension Alexian Brothers - Elk Grove Village
state: Illinois
city: Hines
country: United States
facility: Edward Hines Jr VA Hospital
state: Illinois
city: Joliet
country: United States
facility: Midwest Center for Hematology Oncology
state: Illinois
city: Joliet
country: United States
facility: Duly Health and Care Joliet
state: Illinois
city: Rockford
country: United States
facility: Swedish American Hospital
state: Illinois
city: Rockford
country: United States
facility: UW Health Carbone Cancer Center Rockford
state: Illinois
city: Skokie
country: United States
facility: Edward H Kaplan MD and Associates
state: Illinois
city: Elkhart
country: United States
facility: Elkhart General Hospital
state: Indiana
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology Inc-Parkview
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University/Melvin and Bren Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: Franciscan Health Indianapolis
state: Indiana
city: Lafayette
country: United States
facility: IU Health Arnett Cancer Care
state: Indiana
city: Mishawaka
country: United States
facility: Saint Joseph Regional Medical Center-Mishawaka
state: Indiana
city: South Bend
country: United States
facility: Memorial Hospital of South Bend
state: Indiana
city: Ames
country: United States
facility: McFarland Clinic - Ames
state: Iowa
city: Bettendorf
country: United States
facility: University of Iowa Healthcare Cancer Services Quad Cities
state: Iowa
city: Des Moines
country: United States
facility: Iowa Methodist Medical Center
state: Iowa
city: Sioux City
country: United States
facility: Siouxland Regional Cancer Center
state: Iowa
city: Waterloo
country: United States
facility: MercyOne Waterloo Cancer Center
state: Iowa
city: Prairie Village
country: United States
facility: Kansas City NCI Community Oncology Research Program
state: Kansas
city: Augusta
country: United States
facility: Harold Alfond Center for Cancer Care
state: Maine
city: Baltimore
country: United States
facility: Greater Baltimore Medical Center
state: Maryland
city: Leominster
country: United States
facility: HealthAlliance Hospital - Leominster
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health Saint John Hospital
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Coon Rapids
country: United States
facility: Mercy Hospital
state: Minnesota
city: Edina
country: United States
facility: Fairview Southdale Hospital
state: Minnesota
city: Fridley
country: United States
facility: Unity Hospital
state: Minnesota
city: Maplewood
country: United States
facility: Saint John's Hospital - Healtheast
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Saint Louis
country: United States
facility: Mercy Hospital Saint Louis
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis-Cape Girardeau CCOP
state: Missouri
city: Billings
country: United States
facility: Montana Cancer Consortium NCORP
state: Montana
city: Great Falls
country: United States
facility: Great Falls Clinic
state: Montana
city: Lincoln
country: United States
facility: Nebraska Cancer Research Center
state: Nebraska
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Omaha
country: United States
facility: Alegent Health Immanuel Medical Center
state: Nebraska
city: Omaha
country: United States
facility: Alegent Health Bergan Mercy Medical Center
state: Nebraska
city: Papillion
country: United States
facility: Midlands Community Hospital
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Hamilton
country: United States
facility: The Cancer Institute of New Jersey Hamilton
state: New Jersey
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: Mount Holly
country: United States
facility: Virtua Memorial
state: New Jersey
city: Neptune
country: United States
facility: Jersey Shore Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Somerville
country: United States
facility: Robert Wood Johnson University Hospital Somerset
state: New Jersey
city: Middletown
country: United States
facility: Garnet Health Medical Center
state: New York
city: Mineola
country: United States
facility: NYU Langone Hospital - Long Island
state: New York
city: New York
country: United States
facility: Mount Sinai Union Square
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Asheville
country: United States
facility: Mission Hospital
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital
state: North Carolina
city: Winston-Salem
country: United States
facility: Southeast Clinical Oncology Research Consortium NCORP
state: North Carolina
city: Bismarck
country: United States
facility: Sanford Bismarck Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Essentia Health Cancer Center-South University Clinic
state: North Dakota
city: Fargo
country: United States
facility: Sanford Broadway Medical Center
state: North Dakota
city: Akron
country: United States
facility: Summa Health System - Akron Campus
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital North
state: Ohio
city: Franklin
country: United States
facility: Atrium Medical Center-Middletown Regional Hospital
state: Ohio
city: Kettering
country: United States
facility: Kettering Medical Center
state: Ohio
city: Oregon
country: United States
facility: Saint Charles Hospital
state: Ohio
city: Sandusky
country: United States
facility: Firelands Regional Medical Center
state: Ohio
city: Sylvania
country: United States
facility: ProMedica Flower Hospital
state: Ohio
city: Tiffin
country: United States
facility: Mercy Hospital of Tiffin
state: Ohio
city: Toledo
country: United States
facility: Toledo Community Hospital Oncology Program CCOP
state: Ohio
city: Toledo
country: United States
facility: Toledo Clinic Cancer Centers-Toledo
state: Ohio
city: Portland
country: United States
facility: Kaiser Permanente Northwest
state: Oregon
city: Abington
country: United States
facility: Jefferson Abington Hospital
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Lancaster
country: United States
facility: Lancaster General Hospital
state: Pennsylvania
city: Langhorne
country: United States
facility: Saint Mary Medical and Regional Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania/Abramson Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Pennsylvania Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple Health - Chestnut Hill Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Einstein Medical Center Philadelphia
state: Pennsylvania
city: Sayre
country: United States
facility: Guthrie Medical Group PC-Robert Packer Hospital
state: Pennsylvania
city: Sellersville
country: United States
facility: Grand View Hospital
state: Pennsylvania
city: State College
country: United States
facility: Mount Nittany Medical Center
state: Pennsylvania
city: West Reading
country: United States
facility: Reading Hospital
state: Pennsylvania
city: Wynnewood
country: United States
facility: Lankenau Medical Center
state: Pennsylvania
city: York
country: United States
facility: WellSpan Health-York Hospital
state: Pennsylvania
city: Florence
country: United States
facility: McLeod Regional Medical Center
state: South Carolina
city: Rapid City
country: United States
facility: Rapid City Regional Hospital
state: South Dakota
city: Sioux Falls
country: United States
facility: Sanford Cancer Center Oncology Clinic
state: South Dakota
city: Charlottesville
country: United States
facility: Sentara Martha Jefferson Hospital
state: Virginia
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Lynchburg
country: United States
facility: Centra Alan B Pearson Regional Cancer Center
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center-First Hill
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Healthcare
state: West Virginia
city: Appleton
country: United States
facility: ThedaCare Regional Cancer Center
state: Wisconsin
city: La Crosse
country: United States
facility: Gundersen Lutheran Medical Center
state: Wisconsin
city: Madison
country: United States
facility: SSM Health Dean Medical Group - South Madison Campus
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - University Hospital
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Medical Center-Marshfield
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Oconomowoc
country: United States
facility: ProHealth Oconomowoc Memorial Hospital
state: Wisconsin
city: Waukesha
country: United States
facility: ProHealth Waukesha Memorial Hospital
state: Wisconsin
Study officials:
affiliation: ECOG-ACRIN Cancer Research Group
name: S. V Rajkumar
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baker A, Braggio E, Jacobus S, Jung S, Larson D, Therneau T, Dispenzieri A, Van Wier SA, Ahmann G, Levy J, Perkins L, Kim S, Henderson K, Vesole D, Rajkumar SV, Jelinek DF, Carpten J, Fonseca R. Uncovering the biology of multiple myeloma among African Americans: a comprehensive genomics approach. Blood. 2013 Apr 18;121(16):3147-52. doi: 10.1182/blood-2012-07-443606. Epub 2013 Feb 19.
citation: Kumar SK, Uno H, Jacobus SJ, Van Wier SA, Ahmann GJ, Henderson KJ, Callander NS, Haug JL, Siegel DS, Greipp PR, Fonseca R, Rajkumar SV. Impact of gene expression profiling-based risk stratification in patients with myeloma receiving initial therapy with lenalidomide and dexamethasone. Blood. 2011 Oct 20;118(16):4359-62. doi: 10.1182/blood-2011-03-342089. Epub 2011 Aug 22.
citation: Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010 Jan;11(1):29-37. doi: 10.1016/S1470-2045(09)70284-0. Epub 2009 Oct 21.