A Study to Compare CNTO 328 (Anti-IL-6 Monoclonal Antibody) and VELCADE-Melphalan-Prednisone (VMP) With VMP Alone in Previously Untreated Multiple Myeloma Patients

Study Overview
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Brief Summary
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The purpose of this study is to evaluate safety and effectiveness of CNTO 328 (siltuximab) when it is administered together with velcade-melphalan-prednisone (VMP) in comparison with VMP alone in participants with multiple myeloma (a type of cancer that affects the blood and bone marrow).

Detailed Description
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The study will be conducted in 2 parts (Part 1 and Part 2) and will consist of screening period up to 2 weeks; treatment period; maintenance period (CNTO 328 hereafter referred to as siltuximab) for a maximum of 18 months and follow up period until the study ends. Part 1 is an open-label (all people know the identity of the intervention), single group safety lead-in part to evaluate the safety of siltuximab. Approximately 12 patients will be treated with siltuximab in combination with VMP. If the safety profile of the combination is acceptable, the study will proceed to Part 2. Part 2 is a randomized (the study medication is assigned by chance), open-label, 2-arm (Arm A: siltuximab + VMP; Arm B: VMP alone) study. Approximately 104 patients will be equally randomized, followed by a maintenance period with siltuximab in particiants in Arm A who achieve a partial response (PR) or better. Particiants in both parts of the study will be treated up to a maximum of nine 6-week cycles provided there is no evidence of disease progression, unacceptable toxicity, or withdrawal from treatment. Study medication will be continued for at least 2 additional cycles after confirmation of complete response, and preferably for the full 9 cycles of the treatment period. Participants who will be receiving maintenance treatment after the 12-month effectiveness analysis may continue to receive treatment with siltuximab only after careful consideration by the treating physician and on evidence of clinical benefit and in the absence of unwarranted toxicities. Safety assessments will include evaluation of adverse events, clinical laboratory tests, eastern cooperative oncology group performance status, electrocardiogram, vital signs, and physical examination which will be monitored throughout the study.

Official Title
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A Randomized, Open-Label, Phase 2 Study of CNTO 328 (Anti-IL-6 Monoclonal Antibody) and VELCADE-Melphalan-Prednisone Compared With VELCADE-Melphalan-Prednisone for the Treatment of Previously Untreated Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Siltuximab11 mg/kg
* Drug: Siltuximab 8.3 mg/kg or 11 mg/kg
* Drug: Velcade (bortezomib)
* Drug: Velcade (bortezomib)
* Drug: Melphalan
* Drug: Melphalan
* Drug: Prednisone
* Drug: Prednisone
* Drug: Velcade (bortezomib)
* Drug: Melphalan
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of previously untreated multiple myeloma and not a candidate for high dose chemotherapy with stem cell transplantation Eastern cooperative oncology group performance status score of less than or equal to 2 Measurable secretory disease, defined as either serum monoclonal paraprotein greater than or equal to 1 g/dL or urine monoclonal protein greater than 200 mg/24 hours Adequate laboratory results that will be confirmed by a study physician Agrees to protocol-defined use of effective contraception Exclusion Criteria: Diagnosed with primary amyloidosis, asymptomatic or smoldering multiple myeloma or monoclonal gammopathy of undetermined significance Diagnosed with Waldenstrom'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 Received prior or current systemic therapy or stem cell transplantation for multiple myeloma Peripheral neuropathy or neuropathic pain (Grade 2 or higher) Received radiation therapy, plasmapheresis or surgery within 14 days Transplanted solid organ, with the exception of a corneal transplant Serious concurrent illness or history of uncontrolled heart disease

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: Part 1: VMP+Siltuximab 11 mg/kg<br>Siltuximab 11 mg/kg as a 1-hour intravenous infusion every 3 weeks along with VMP (Velcade+Melphalan+Prednisone). Velcade 1.3 mg/m2 will be administered as an intravenous bolus injection according to the current approved package inserts. Melphalan 9 mg/m2 and prednisone 60 mg/m2 will be taken orally (by mouth). | Drug: Siltuximab11 mg/kg<br>* Participants will receive siltuximab 11 mg/kg as a 1-hour intravenous infusion every 3 weeks in Part 1.<br>* Other names: CNTO 328;Drug: Velcade (bortezomib)<br>* Participants will receive Velcade 1.3 mg/m2 as an intravenous bolus injection according to the current approved package insert in Part 1.<br>* Other names: bortezomib;Drug: Melphalan<br>* Participants will take melphalan 9 mg/m2 will be administered orally on Days 1 to 4, followed by a 38-day rest period in Part 1.<br>Drug: Prednisone<br>* Participants will take prednisone 60 mg/m2 will be administered orally on Days 1 to 4, followed by a 38-day rest period in Part 1.<br>|
| Experimental: Part 2, Arm A: VMP+Siltuximab 8.3 mg/kg or 11 mg/kg<br>Siltuximab 8.3 mg/kg or 11 mg/kg as a 1-hour intravenous infusion every 3 weeks along with VMP. Velcade 1.3 mg/m2 will be administered as an intravenous bolus injection according to the current approved package inserts. Melphalan 9 mg/m2 and prednisone 60 mg/m2 will be taken orally | Drug: Siltuximab 8.3 mg/kg or 11 mg/kg<br>* Participants will receive siltuximab 8.3 mg/kg or 11 mg/kg as a 1-hour intravenous infusion every 3 weeks for 9 cycles of treatment in Part 2, Arm A and in maintenance period.<br>* Other names: CNTO 328;Drug: Velcade (bortezomib)<br>* Participants will receive Velcade 1.3 mg/m2 as an intravenous bolus injection for 9 cycles of the treatment period in Part 2. It will be administered twice weekly for first 4 cycles (on Days 1, 4, 8, 11, 22, 25, 29, and 32, followed by a 10-day rest period) and once weekly for next 5 cycles (on Days 1, 8, 22, and 29, followed by a 13-day rest period)<br>* Other names: bortezomib;Drug: Melphalan<br>* Participants will receive melphalan according to currently approved package inserts. Melphalan 9 mg/m2 will be administered orally for 9 cycles of treatment period in Part 2, Arm A.<br>Drug: Prednisone<br>* Participants will take prednisone 60 mg/m2 orally for 9 cycles of treatment period in Part 2, Arm A.<br>|
| Active Comparator: Part 2, Arm B: VMP<br>Velcade 1.3 mg/m2 will be administered as an intravenous bolus injection according to the current approved package inserts. Melphalan 9 mg/m2 and prednisone 60 mg/m2 will be taken orally | Drug: Velcade (bortezomib)<br>* Participants will receive Velcade 1.3 mg/m2 as an intravenous bolus injection according to the current approved package insert.<br>* Other names: bortezomib;Drug: Melphalan<br>* Participants will take melphalan 9 mg/m2 orally according to currently approved package insert.<br>Drug: Prednisone<br>* Participants will take prednisone 60 mg/m2 orally according to the package insert.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Complete Response (CR) - European Group for Blood and Marrow Transplantation (EBMT) Criteria | CR was assessed using EMBT criteria: disappearance of the original monoclonal paraprotein from the blood and urine on at least 2 determinations for a minimum of 6 weeks by immunofixation studies, <5% plasma cells in the bone marrow on at least 1 determination, if skeletal survey is available: no increase in the size or number of lytic bone lesions (development of a compression fracture does not exclude response), disappearance of soft tissue plasmacytomas for at least 6 weeks. | Up to disease progression, approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Overall Response ie, Complete Response (CR) or Partial Response (PR) - European Group for Blood and Marrow Transplantation (EBMT) Criteria | CR or PR was assessed using EBMT criteria. CR: disappearance of the original monoclonal paraprotein from the blood and urine on at least 2 determinations for a minimum of 6 weeks by immunofixation studies, <5% plasma cells in the bone marrow on at least 1 determination, if skeletal survey is available: no increase in the size or number of lytic bone lesions (development of a compression fracture does not exclude response), disappearance of soft tissue plasmacytomas for at least 6 weeks; PR: >=50% reduction in the level of serum monoclonal paraprotein for at least 2 determinations 6 weeks apart, if present, reduction in 24-hour urinary light chain excretion by either >=90% or to <200 mg for at least 2 determinations 6 weeks apart, >=50% reduction in the size of soft tissue plasmacytomas (by clinical or radiographic examination) for at least 6 weeks, if skeletal survey is available: no increase in size or number of lytic bone lesions | Up to disease progression, approximately 3 years | 
| Percentage of Participants Who Achieved Stringent Complete Response (sCR) - International Myeloma Working Group (IMWG) Criteria | sCR was assesses by IMWG Criteria: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, <=5% plasma cells in bone marrow, normal free light chain ratio, absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. sCR is a CR that has been confirmed by immunofixation + free light chain assay + either bone marrow immunohistochemistry or immunofluorescence | Up to disease progression, approximately 3 years | 
| Progression-Free Survival (PFS) | PFS was defined as the time between randomization and either disease progression or death, whichever occurred first. | From the date of randomization until disease progression or death, whichever occurred first, as assessed up to the last efficacy assessment for disease progression (approximately 3 years) | 
| 1-year Progression-Free Survival (PFS) Rate | The 1-year PFS rate was defined as the percentage of participants surviving 1 year after randomization without disease progression or death. | 1 year | 
| Duration of Response (DOR) | DOR was defined as length from the earliest date a participant achieved a complete response (CR) or partial response (PR) to either date for disease progression (including relapse from CR) or the censoring date for progressive disease. Responders without disease progression were censored at the last efficacy assessment for disease progression. | From the date participants achieved CR or PR to either date for disease progression (including relapse from CR) or the censoring date for progressive disease, as assessed Up to 30 days after last dose of study medication | 
| 1-year Survival Rate | Percentage of participants who are alive at the end of year 1 after randomization | 1 year | 
| Overall Survival | Overall survival is defined as the time interval in days between the date of randomization and the participant's death from any cause. | From the date of randomization till the date of death, as assessed up to the end of study (approximately 3 years) | 
| Change From Baseline to Cycle 9 in Global Health Status/Quality of Life Subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30) | Global health status/quality of life is a subscale of the EORTC QOL C30, which comprises two questions related to overall health/quality of life during the past week. The raw score to each question ranged from 1 (very poor) to 7 (excellent). The raw mean score of health status/quality of life subscale is calculated for each participant and a linear transformation applied to standardize the raw score, so that scores range from 0 to 100; a higher score represents a higher (better) health and quality of life. | Baseline (Day 1 predose) and Cycle 9 (Week 54) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, CNTO328, Interleukin-6 (IL-6), Monoclonal antibody, Anti-IL-6 monoclonal antibody, Bortezomib, Velcade, Melphalan, Prednisone