A Study to Evaluate Two Different Regimens of VELCADE in Combination With Dexamethasone, Thalidomide and Cyclophosphamide (VDT vs VDTC) in Newly Diagnosed Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this Phase 2 randomized study is to evaluate the efficacy and safety of treatment with a regimen of VELCADE, dexamethasone, and thalidomide (VDT) or VELCADE, dexamethasone, thalidomide, and cyclophosphamide (VDTC) in subjects with newly diagnosed symptomatic multiple myeloma who have received no prior treatment and are candidates to receive high-dose therapy and autologous bone marrow/stem cell transplantation.

Official Title
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A Phase 2, Randomized Study of VELCADE® (Bortezomib), Dexamethasone, and Thalidomide Versus VELCADE® (Bortezomib), Dexamethasone, Thalidomide, and Cyclophosphamide in Subjects With Previously Untreated Multiple Myeloma Who Are Candidates for Autologous Transplantation

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: bortezomib, dexamethasone, and thalidomide
* Drug: bortezomib, dexamethasone, thalidomide, and cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between ≥18 and ≤70 years Patient is a candidate for HDT combined with an autologous SCT Karnofsky Performance Status score of ≥60% Multiple myeloma diagnosed according to the following standard criteria AND requiring systemic therapy: Presence of M-component in serum and/or urine, plus clonal plasma cells in the bone marrow and/or a documented clonal plasmacytoma PLUS 1 or more of the following: Calcium elevation (>11.5 mg/dL or >2.65 mmol/L) Renal insufficiency (creatinine >2 mg/dL or >177 umol/L) Anemia (hemoglobin <10 g/dL [<12.5 mmol/L] or at least 2 mg/dL [1.25 mmol/L] below normal) Bone disease (lytic lesions or osteopenia) AND fulfill criteria for measurable disease, as defined by at least 1 of the following 3 measurements: Serum M-protein ≥1 g/dL (≥10 g/L) Urine M-protein ≥200 mg/24 h Serum free light chain (FLC) assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal Women of childbearing potential must agree to use 2 methods of contraception. Males must agree to use barrier contraception. Subjects (or their legally acceptable representatives) must have signed an informed consent document. To participate in the optional pharmacogenomic component of this study, subjects (or their legally acceptable representative) must have signed the informed consent form. Refusal to consent for this component does not exclude a subject from participation in the clinical study. Exclusion Criteria: Diagnosis of smoldering OR non-secretory multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS). Diagnosis of Waldenström's disease or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions. Prior or current systemic therapy for multiple myeloma including steroids. Radiation therapy and/or plasmapheresis within 15 days before randomization. History of allergic reaction attributable to compounds being given (VELCADE, thalidomide, dexamethasone, and/or cyclophosphamide) or compounds containing boron or mannitol. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. Uncontrolled or severe cardiovascular disease Concurrent medical condition or disease (e.g., active systemic infection, uncontrolled diabetes) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study. Use of any investigational drugs within 30 days before randomization Pregnant or lactating women: A serum β-hCG pregnancy test must be performed at the Screening visit for female subjects of childbearing potential. Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: 1<br>bortezomib, dexamethasone, and thalidomide | Drug: bortezomib, dexamethasone, and thalidomide<br>* VELCADE (bortezomib) twice weekly for 4 cycles (4 doses per cycle), prior to high-dose chemotherapy (HDT) and stem cell transplantation(SCT). Subjects will receive VELCADE 1.3 mg/m2 as an intravenous (i.v.) bolus injection on Days 1,4,8, and 11, followed by a 10 day rest period (Days 12 to 21) Dexamethasone 40 mg/day will be given by mouth (p.o.) on Days 1-4 and Days 9-12 in each of 4 cycles. Thalidomide will be given by mouth (p.o.)every day, starting on Day 1 of Cycle 1 (e.g. the same day of the first dose of VELCADE) and continuing until Day 21 of Cycle 4 at a dose of 100 mg/day (bedtime).<br>|
| Experimental: 2<br>bortezomib, dexamethasone, thalidomide, and cyclophosphamide | Drug: bortezomib, dexamethasone, thalidomide, and cyclophosphamide<br>* VELCADE (bortezomib) twice weekly for 4 cycles (4 doses per cycle), prior to high-dose chemotherapy(HDT)and stem cell transplantation(SCT). Subjects will receive VELCADE 1.3 mg/m2 as an intravenous (i.v.) bolus injection on Days 1,4,8, and 11, followed by a 10 day rest period (Days 12 to 21). Dexamethasone 40 mg/day will be given by mouth (p.o.) on Days 1-4 and Days 9-12 in each of 4 cycles. Thalidomide will be given by mouth (p.o.) every day, starting on Day 1 of Cycle 1 (e.g., the same day of the first dose of VELCADE) and continuing until Day 21 of Cycle 4 at a dose of 100 mg/day (bedtime). Cyclophosphamide will be given as an intravenous (i.v.) dose of 400 mg/m2 on Day 1 and Day 8 of each 3-week cycle, for a total of 4 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Particpants Achieving Overall Combined Complete Response (CR) Following Induction | Percent of Particpants Achieving Overall combined complete response (CR w/normalized serum κ:λ ratio + CR + near complete response (nCR)) following induction therapy. CR criteria: negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. κ:λ ratio: normal free light chain (FLC) ratio nCR criteria: positive immunofixation analysis of serum or urine as the only evidence of disease; disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. | all data included in clinical database as of 10 April 2009 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants Achieving Overall Combined Complete Response (CR) Following High-dose Chemotherapy (HDT)/Stem Cell Transplantation (SCT) | Percent of Participants Achieving Overall Combined Complete Response (CR) (CR w/normalized serum κ:λ ratio + CR + Near Complete Response (nCR)) following stem cell transplantation. CR criteria: negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. κ:λ ratio: normal free light chain (FLC) ratio nCR criteria: positive immunofixation analysis of serum or urine as the only evidence of disease; disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. | all data included in clinical database as of 10 April 2009 |