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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: VELCADE (bortezomib)
* Drug: dexamethasone
* Drug: cyclophosphamide
* Drug: Revlimid (lenalidomide)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VDR<br>VELCADE (bortezomib), dexamethasone, and Revlimid (lenalidomide) | Drug: VELCADE (bortezomib)<br>* 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).<br>Drug: dexamethasone<br>* dexamethasone 40 mg orally on days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop<br>Drug: Revlimid (lenalidomide)<br>* 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)<br>|
| Experimental: VDCR<br>VELCADE (bortezomib), dexamethasone, cyclophosphamide, Revlimid (lenalidomide) | Drug: VELCADE (bortezomib)<br>* 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).<br>Drug: dexamethasone<br>* dexamethasone 40 mg orally on days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop<br>Drug: cyclophosphamide<br>* cyclophosphamide 500 mg/m^2 orally on days 1 and 8 of a 3-week cycle for 8 cycles, then stop<br>Drug: Revlimid (lenalidomide)<br>* 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)<br>|
| Experimental: VDC<br>VELCADE (bortezomib), dexamethasone, cyclophosphamide | Drug: VELCADE (bortezomib)<br>* 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).<br>Drug: dexamethasone<br>* dexamethasone 40 mg orally on days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop<br>Drug: cyclophosphamide<br>* cyclophosphamide 500 mg/m^2 orally on days 1 and 8 of a 3-week cycle for 8 cycles, then stop<br>|
| Experimental: VDC-mod<br>Modified dosing of VELCADE (bortezomib), dexamethasone, cyclophosphamide | Drug: VELCADE (bortezomib)<br>* 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).<br>Drug: dexamethasone<br>* dexamethasone 40 mg orally on days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop<br>Drug: cyclophosphamide<br>* cyclophosphamide 500 mg/m^2 orally on days 1 and 8 of a 3-week cycle for 8 cycles, then stop<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Up to 48 weeks or until disease progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events (AEs) | Evaluate the safety and tolerability of the combination therapy | From first dose of study drug through the 30 day post-treatment AE assessment visit | 
| 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. | Up to 48 weeks or until disease progression | 
| 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. | Up to 48 weeks or until disease progression | 
| 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. | Up to 48 weeks or until disease progression | 
| 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. | Up to 48 weeks or until disease progression | 
| 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. | Up to 48 weeks or until disease progression | 
| 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. | Up to 48 weeks or until disease response | 
| 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. | Up to 48 weeks or until disease progression/death | 
| Probability of 1-year Survival |  | survival probability at 1 year after randomization | 
| Overall Survival | Overall survival is defined as time from the date of randomization to the date of death | Up to 48 weeks or until death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment for patients with multiple myeloma, who have received no prior treatment