Phase 1/2 Study of VELCADE® in Combination With Other Drugs to Treat Previously Untreated Multiple Myeloma Patients (EVOLUTION)

Study Description

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

The purpose of this Phase 1/2 study is to evaluate the efficacy and safety of treatment with VELCADE, dexamethasone, and Revlimid® (VDR) as well as VELCADE, dexamethasone, cyclophosphamide, and Revlimid (VDCR) in patients with multiple myeloma who have received no prior treatment. This study will evaluate whether the addition of Revlimid to VELCADE and Dexamethasone will increase the complete response (CR)/ very good partial response (VGPR) rate.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma	Drug: VELCADE (bortezomib); Drug: dexamethasone; Drug: cyclophosphamide; Drug: Revlimid (lenalidomide)	Phase 1; Phase 2

Study Design

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	158 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase 1/2 Study of VELCADE® (Bortezomib), Dexamethasone, and Revlimid® (Lenalidomide) Versus VELCADE, Dexamethasone, Cyclophosphamide, and Revlimid Versus VELCADE, Dexamethasone and Cyclophosphamide in Subjects With Previously Untreated Multiple Myeloma
Study Start Date :	August 2007
Actual Primary Completion Date :	October 2010
Actual Study Completion Date :	November 2010

Arms and Interventions

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Experimental: VDR; VELCADE (bortezomib), dexamethasone, and Revlimid (lenalidomide)	Drug: VELCADE (bortezomib); bortezomib 1.3 mg/m^2 given via IV on days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles, then on days 1, 8, 15 and 22 of a 6-week cycle for 4 cycles (maintenance). Drug: dexamethasone; dexamethasone 40 mg orally on days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop Drug: Revlimid (lenalidomide); lenalidomide 25 mg orally on days 1 to 14 of a 3-week cycle for 8 cycles then stop (VDR arm) lenalidomide 15 mg orally on days 1 to 14 of a 3-week cycle for 8 cycles then stop (VDCR arm)
Experimental: VDCR; VELCADE (bortezomib), dexamethasone, cyclophosphamide, Revlimid (lenalidomide)	Drug: VELCADE (bortezomib); bortezomib 1.3 mg/m^2 given via IV on days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles, then on days 1, 8, 15 and 22 of a 6-week cycle for 4 cycles (maintenance). Drug: dexamethasone; dexamethasone 40 mg orally on days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop Drug: cyclophosphamide; cyclophosphamide 500 mg/m^2 orally on days 1 and 8 of a 3-week cycle for 8 cycles, then stop Drug: Revlimid (lenalidomide); lenalidomide 25 mg orally on days 1 to 14 of a 3-week cycle for 8 cycles then stop (VDR arm) lenalidomide 15 mg orally on days 1 to 14 of a 3-week cycle for 8 cycles then stop (VDCR arm)
Experimental: VDC; VELCADE (bortezomib), dexamethasone, cyclophosphamide	Drug: VELCADE (bortezomib); bortezomib 1.3 mg/m^2 given via IV on days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles, then on days 1, 8, 15 and 22 of a 6-week cycle for 4 cycles (maintenance). Drug: dexamethasone; dexamethasone 40 mg orally on days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop Drug: cyclophosphamide; cyclophosphamide 500 mg/m^2 orally on days 1 and 8 of a 3-week cycle for 8 cycles, then stop
Experimental: VDC-mod; Modified dosing of VELCADE (bortezomib), dexamethasone, cyclophosphamide	Drug: VELCADE (bortezomib); bortezomib 1.3 mg/m^2 given via IV on days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles, then on days 1, 8, 15 and 22 of a 6-week cycle for 4 cycles (maintenance). Drug: dexamethasone; dexamethasone 40 mg orally on days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop Drug: cyclophosphamide; cyclophosphamide 500 mg/m^2 orally on days 1 and 8 of a 3-week cycle for 8 cycles, then stop

Outcome Measures

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. Number of Patients With Combined Complete Response and Very Good Partial Response [ Time Frame: Up to 48 weeks or until disease progression ]

   Complete response requires negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow.

   Very good partial response requires serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 h

Secondary Outcome Measures :

1. Number of Patients With Adverse Events (AEs) [ Time Frame: From first dose of study drug through the 30 day post-treatment AE assessment visit ]
   Evaluate the safety and tolerability of the combination therapy
2. Number of Patients With Overall Response [ Time Frame: Up to 48 weeks or until disease progression ]

   Overall Response includes complete response and partial response.

   Complete response requires negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow.

   Partial response requires at least 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by at least 90% or to < 200 mg per 24 hour.

3. Number of Patients With Stringent Complete Response Rate [ Time Frame: Up to 48 weeks or until disease progression ]
   Stringent Complete Response is defined as complete response plus normal free light chain (kappa/lambda) ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.
4. Number of Patients With Complete Response Rate + Near Complete Response Rate [ Time Frame: Up to 48 weeks or until disease progression ]

   Complete response requires negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow.

   Near Complete response requires positive immunofixation on the serum and/or urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow.

5. Duration of Response [ Time Frame: Up to 48 weeks or until disease progression ]

   Duration of response is the time from date of first documented confirmed response to date of first documented progressive disease. A confirmed response is a response that has been observed on at least two consecutive assessments.

   Disease progression requires any one or more of the following: serum m-protein increase >= 25% from nadir(absolute increase >= 0.5 g/dL); Urine m-protein increase >= 25% from nadir(absolute increase >= 200 mg/24 hr), bone marrow plasma cell percentage increase >= 25% from nadir(absolute increase >= 10%), new bone lesion or soft tissue plasmacytomas.

6. Time to Disease Progression [ Time Frame: Up to 48 weeks or until disease progression ]

   Time to disease progression is defined as time from the date of randomization to the date of first documented progressive disease.

   Disease progression requires any one or more of the following: serum m-protein increase >= 25% from nadir(absolute increase >= 0.5 g/dL); Urine m-protein increase >= 25% from nadir(absolute increase >= 200 mg/24 hr), bone marrow plasma cell percentage increase >= 25% from nadir(absolute increase >= 10%), new bone lesion or soft tissue plasmacytomas.

7. Time to Response [ Time Frame: Up to 48 weeks or until disease response ]
   Time to response is defined as time from date of randomization to the date of the first documentation of a confirmed response. confirmed response is a response that has been observed on at least two consecutive assessments.
8. Progression-free Survival [ Time Frame: Up to 48 weeks or until disease progression/death ]

   Progression-free survival is defined as time from the date of randomization to the date of the first documented progressive disease or death.

   Disease progression requires any one or more of the following: serum m-protein increase >= 25% from nadir(absolute increase >= 0.5 g/dL); Urine m-protein increase >= 25% from nadir(absolute increase >= 200 mg/24 hr), bone marrow plasma cell percentage increase >= 25% from nadir(absolute increase >= 10%), new bone lesion or soft tissue plasmacytomas.

9. Probability of 1-year Survival [ Time Frame: survival probability at 1 year after randomization ]
10. Overall Survival [ Time Frame: Up to 48 weeks or until death ]
    Overall survival is defined as time from the date of randomization to the date of death

Eligibility Criteria

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Voluntary written informed consent
• Male or female subject 18 years of age or older
• A Karnofsky Performance Status score of ≥50% (Eastern Cooperative Oncology Group Performance Status score ≤2)
• Subjects must have symptomatic myeloma or asymptomatic myeloma with myeloma-related organ damage
• Diagnosed Multiple myeloma
• Subjects must have measurable disease requiring systemic therapy
• Subjects must not have been treated previously with any systemic therapy for multiple myeloma
• Two weeks must have elapsed since the date of the last radiotherapy treatment
• Women of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 to 14 days prior to therapy and repeated within 24 hours before starting study drug. They must commit to continued abstinence from heterosexual intercourse or begin 2 acceptable methods of birth control (1 highly effective method and 1 additional effective method) used at the same time, beginning at least 4 weeks before initiation of Revlimid treatment. Women must also agree to ongoing pregnancy testing
• Men must agree to not father a child and agree to use a latex condom during therapy and for 4 weeks after the last dose of study drug, even if they have had a successful vasectomy, if their partner is of childbearing potential
• All subjects must agree to comply with the requirements of the RevAssistSM program

Exclusion Criteria:

• History of allergy to any of the study medications, their analogues, or excipients in the various formulations
• ≥Grade 2 peripheral neuropathy on clinical examination
• Myocardial infarction within 6 months prior to enrollment or New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or clinically significant conduction system abnormalities.
• Female subject who is pregnant or breast-feeding
• Clinically relevant active infection or serious comorbid medical conditions
• Any condition, including laboratory abnormalities, that in the opinion of the Investigator places the subject at unacceptable risk if he/she were to participate in the study. This includes but is not limited to serious medical or psychiatric illness likely to interfere with participation in this clinical study
• Active prior malignancy diagnosed or treated within the last 3 years

Contacts and Locations

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Colorado
Rocky Mountain Cancer Center
Denver, Colorado, United States, 80218
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55904-0001

Sponsors and Collaborators

Millennium Pharmaceuticals, Inc.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Investigators

Study Director:	Medical Monitor	Millennium Pharmaceuticals, Inc.

More Information

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. doi: 10.1182/blood-2011-11-395749. Epub 2012 Mar 15.

Kumar SK, Flinn I, Noga SJ, Hari P, Rifkin R, Callander N, Bhandari M, Wolf JL, Gasparetto C, Krishnan A, Grosman D, Glass J, Sahovic EA, Shi H, Webb IJ, Richardson PG, Rajkumar SV. Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study. Leukemia. 2010 Jul;24(7):1350-6. doi: 10.1038/leu.2010.116. Epub 2010 May 27.

Responsible Party:	Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT00507442 History of Changes
Other Study ID Numbers:	C05008
First Posted:	July 26, 2007
Results First Posted:	December 29, 2011
Last Update Posted:	July 26, 2013
Last Verified:	April 2012

Keywords provided by Millennium Pharmaceuticals, Inc.:

Treatment for patients with multiple myeloma; who have received no prior treatment

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Dexamethasone acetate	Dexamethasone; Lenalidomide; Cyclophosphamide; Thalidomide; Bortezomib; BB 1101; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists