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

Primary Purpose

Multiple Myeloma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
VELCADE (bortezomib)
dexamethasone
cyclophosphamide
Revlimid (lenalidomide)
Sponsored by
Millennium Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Myeloma focused on measuring Treatment for patients with multiple myeloma, who have received no prior treatment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Rocky Mountain Cancer Center
  • Mayo Clinic

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

VDR

VDCR

VDC

VDC-mod

Arm Description

VELCADE (bortezomib), dexamethasone, and Revlimid (lenalidomide)

VELCADE (bortezomib), dexamethasone, cyclophosphamide, Revlimid (lenalidomide)

VELCADE (bortezomib), dexamethasone, cyclophosphamide

Modified dosing of VELCADE (bortezomib), dexamethasone, cyclophosphamide

Outcomes

Primary Outcome Measures

Number of Patients With Combined Complete Response and Very Good 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. 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

Number of Patients With Adverse Events (AEs)
Evaluate the safety and tolerability of the combination therapy
Number of Patients With Overall Response
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.
Number of Patients With Stringent Complete Response Rate
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.
Number of Patients With Complete Response Rate + Near Complete Response Rate
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.
Duration of Response
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.
Time to 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.
Time to 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.
Progression-free Survival
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.
Probability of 1-year Survival
Overall Survival
Overall survival is defined as time from the date of randomization to the date of death

Full Information

First Posted
July 25, 2007
Last Updated
July 18, 2013
Sponsor
Millennium Pharmaceuticals, Inc.
Collaborators
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
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1. Study Identification

Unique Protocol Identification Number
NCT00507442
Brief Title
Phase 1/2 Study of VELCADE® in Combination With Other Drugs to Treat Previously Untreated Multiple Myeloma Patients
Acronym
EVOLUTION
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 Type
Interventional

2. Study Status

Record Verification Date
April 2012
Overall Recruitment Status
Completed
Study Start Date
August 2007 (undefined)
Primary Completion Date
October 2010 (Actual)
Study Completion Date
November 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Millennium Pharmaceuticals, Inc.
Collaborators
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma
Keywords
Treatment for patients with multiple myeloma, who have received no prior treatment

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
158 (Actual)

8. Arms, Groups, and Interventions

Arm Title
VDR
Arm Type
Experimental
Arm Description
VELCADE (bortezomib), dexamethasone, and Revlimid (lenalidomide)
Arm Title
VDCR
Arm Type
Experimental
Arm Description
VELCADE (bortezomib), dexamethasone, cyclophosphamide, Revlimid (lenalidomide)
Arm Title
VDC
Arm Type
Experimental
Arm Description
VELCADE (bortezomib), dexamethasone, cyclophosphamide
Arm Title
VDC-mod
Arm Type
Experimental
Arm Description
Modified dosing of VELCADE (bortezomib), dexamethasone, cyclophosphamide
Intervention Type
Drug
Intervention Name(s)
VELCADE (bortezomib)
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
dexamethasone
Intervention Description
dexamethasone 40 mg orally on days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Intervention Description
cyclophosphamide 500 mg/m^2 orally on days 1 and 8 of a 3-week cycle for 8 cycles, then stop
Intervention Type
Drug
Intervention Name(s)
Revlimid (lenalidomide)
Intervention Description
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)
Primary Outcome Measure Information:
Title
Number of Patients With Combined Complete Response and Very Good Partial Response
Description
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
Time Frame
Up to 48 weeks or until disease progression
Secondary Outcome Measure Information:
Title
Number of Patients With Adverse Events (AEs)
Description
Evaluate the safety and tolerability of the combination therapy
Time Frame
From first dose of study drug through the 30 day post-treatment AE assessment visit
Title
Number of Patients With Overall Response
Description
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.
Time Frame
Up to 48 weeks or until disease progression
Title
Number of Patients With Stringent Complete Response Rate
Description
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.
Time Frame
Up to 48 weeks or until disease progression
Title
Number of Patients With Complete Response Rate + Near Complete Response Rate
Description
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.
Time Frame
Up to 48 weeks or until disease progression
Title
Duration of Response
Description
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.
Time Frame
Up to 48 weeks or until disease progression
Title
Time to Disease Progression
Description
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.
Time Frame
Up to 48 weeks or until disease progression
Title
Time to Response
Description
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.
Time Frame
Up to 48 weeks or until disease response
Title
Progression-free Survival
Description
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.
Time Frame
Up to 48 weeks or until disease progression/death
Title
Probability of 1-year Survival
Time Frame
survival probability at 1 year after randomization
Title
Overall Survival
Description
Overall survival is defined as time from the date of randomization to the date of death
Time Frame
Up to 48 weeks or until death

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Millennium Pharmaceuticals, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Rocky Mountain Cancer Center
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55904-0001
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22422823
Citation
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.
Results Reference
derived
PubMed Identifier
20508619
Citation
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.
Results Reference
derived

Learn more about this trial

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

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