A Study of the Safety and Efficacy of CNTO 328 and Bortezomib to Bortezomib Alone in Patients With Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of Part 1 of the study is to determine the safety of the combination of Siltuximab (CNTO 328) and bortezomib (Velcade). The purpose of Part 2 of the study is to compare the length of progression free survival for those patients given CNTO 328 and bortezomib to those patients given bortezomib alone.

Detailed Description
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The purpose of this study is to see what effects CNTO 328 has on relapsed or refractory multiple myeloma. The study drug, CNTO 328, is a chimeric (part mouse) antibody (small protein that is important for fighting infection).CNTO 328 blocks a small protein called Interleukin 6 (IL-6). IL-6 is made naturally by your body, and at normal levels is important for inflammatory response. High levels of IL-6 can help cancer cells grow and interfere with chemotherapy drugs killing cancer cells. Cancer-related sickness such as cachexia (weight loss), bone resorption (weakening of your bones), and depression have been linked to high levels of IL-6. CNTO 328 has been shown to slow down tumor growth or shrink tumors when tested in animals. In other clinical trials, over 100 patients have received CNTO 328. There are studies ongoing in participants with kidney cancer, hematologic malignancies (blood cancers such as multiple myeloma), and prostate cancer, to see if CNTO 328 is safe and to see what effects it has on these types of cancer. At this time, it is unknown what effect CNTO 328 has had on the participants' cancer. Bortezomib is a type of drug known as a proteasome inhibitor. A proteasome is a substance that is found in every cell and it is there to help to break down other substances ('proteins') and has a role in the way cells divide. If the proteasome is inhibited, it cannot perform its function in the cell, and if a cell cannot divide it dies. Over 8000 patients with multiple myeloma and other types of cancer have been treated with bortezomib. Bortezomib has been extensively studied in patients with previously treated multiple myeloma. Based on its established activity in pretreated multiple myeloma, bortezomib is registered in the United States and in Europe for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. Bortezomib is currently also being studied in several other cancer types.This study consists of two parts. The purpose of Part 1 is to determine the safety of CNTO 328 and bortezomib when given together as a treatment. The purpose of Part 2 is to compare the safety and effects (good and bad) of the combination of CNTO 328 and bortezomib to the safety and effects of bortezomib alone. About 20 patients will take part in the first part of the study. About 270 patients will take part in the second part of the study at approximately 70 sites in the US, Canada, and Europe. Patients will be in the study for about 12 months, with a follow-up period of around 9 months. The study is divided into four different phases: Screening phase-which lasts up to 4 weeks. During this phase the study doctor will perform tests to see if the patient can participate in the study.Treatment phase-which may last up to 4 cycles of 42 days each during which the patient will be treated with CNTO 328 and bortezomib. Maintenance phase-If the patient benefits from the therapy in the treatment phase, the patient will continue to receive CNTO 328 and bortezomib, but now in cycles of 35 days each. Follow up phase, this includes an end of treatment visit 4 weeks after the patient's last infusion and follow up visits every three months until the patient starts a new anti-cancer treatment. CNTO 328 6mg/kg ( 6 milligrams per kilogram of body weight) will be given intravenously (into the vein) over 2 hours once every 2 weeks. Patients who respond with stable disease or better may receive additional doses. Bortezomib will be given IV (into the vein) at 1.3 mg/m2 over 3-5 seconds twice a week for 2 weeks followed by 1 week of rest.

Official Title
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A Phase 2, Randomized, Double-blind, Placebo-controlled Study Comparing the Combination of CNTO 328 (Anti-IL-6 Monoclonal Antibody) and Velcade Versus Velcade Alone in Subjects With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: Siltuximab
* Drug: Bortezomib
* Drug: Placebo
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Measurable secretory disease defined as either serum monoclonal paraprotein, (M-protein) greater than or equal to (>=)1 gram per deciliter (g/dL) or urine monoclonal (light chain) protein (> 200 mg/24 hours) Documented disease progression after at least 1 prior line of therapy but no more than 3 or have had no response to previous treatment (primary refractory disease) ECOG performance status score of less than or equal to (<=) 2 Adequate bone marrow, liver, and renal function Exclusion Criteria: No prior treatment with bortezomib Not Refractory to high-dose dexamethasone Not >= Grade 2 peripheral neuropathy Have not received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant No prior or concomitant malignancy (other than multiple myeloma) except adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or other cancer for which the patient has been disease-free for <= 3 years

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Siltuximab Plus Bortezomib<br>Siltuximab 6 milligram per kilogram (mg/kg) will be administered as intravenous infusion once every 2 weeks along with bortezomib 1.3 milligram per square meter (mg/m^2) during cycle 1. | Biological: Siltuximab<br>* Siltuximab 6 mg/kg will be administered as intravenous infusion once every 2 weeks during cycle 1 in Part 1. Siltuximab 6 mg/kg will be administered as intravenous infusion once every 2 weeks during 42-day Treatment Phase and 35-day Maintenance Phase in Part 2.<br>* Other names: CNTO 328;Drug: Bortezomib<br>* Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus once every 2 weeks during cycle 1 in Part 1. Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus on Days 1, 4, 8, 11, followed by a 10-day rest period; and on Days 22, 25, 29, and 32 followed by a 10-day rest period during 42-day treatment phase in Part 2. Bortezomib 1.3 mg/m2 will be administered as intravenous bolus on Days 1, 8, 15, 22 followed by a 13-day rest period (cycle Days 23 to 35) during 35-day Maintenance Phase in Part 2.<br>* Other names: VELCADE;|
| Experimental: Part 2: Bortezomib + Placebo<br>Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus on Days 1, 4, 8, 11, followed by a 10-day rest period; and on Days 22, 25, 29, and 32 followed by a 10-day rest period along with matching placebo administered as intravenous infusion once every 2 weeks during 42-day treatment phase. Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus on Days 1, 8, 15, 22 followed by a 13-day rest period (cycle Days 23 to 35) along with matching placebo once every 2 weeks during 35-day Maintenance Phase. Dexamethasone tablet will be administered at first occurrence of documented disease progression or if bortezomib was discontinued due to intolerable toxicity. Dexamethasone 40 milligram per day (mg/day) will be administered on days 1-4, 9-12, and 17-20 for four 28-day cycles then 40 mg/day for Days 1-4 for all subsequent cycles. | Drug: Bortezomib<br>* Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus once every 2 weeks during cycle 1 in Part 1. Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus on Days 1, 4, 8, 11, followed by a 10-day rest period; and on Days 22, 25, 29, and 32 followed by a 10-day rest period during 42-day treatment phase in Part 2. Bortezomib 1.3 mg/m2 will be administered as intravenous bolus on Days 1, 8, 15, 22 followed by a 13-day rest period (cycle Days 23 to 35) during 35-day Maintenance Phase in Part 2.<br>* Other names: VELCADE;Drug: Placebo<br>* Matching placebo will be administered as intravenous infusion once every 2 weeks during 42-day treatment phase and 35-day maintenance phase in Part 2.<br>Drug: Dexamethasone<br>* Dexamethasone tablet will be administered in this study at the first occurrence of documented disease progression or if bortezomib was discontinued due to intolerable toxicity. Dexamethasone 40 mg/day will be administered on days 1-4, 9-12, and 17-20 for four 28-day cycles then 40 mg/day for Days 1-4 for all subsequent cycles in treatment phase and maintenance phase of Part 2.<br>|
| Experimental: Part 2: Bortezomib + Siltuximab<br>Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus on Days 1, 4, 8, 11, followed by a 10-day rest period; and on Days 22, 25, 29, and 32 followed by a 10-day rest period along with Siltuximab administered as intravenous infusion once every 2 weeks during 42-day treatment phase. Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus on Days 1, 8, 15, 22 followed by a 13-day rest period (cycle Days 23 to 35) along with Siltuximab administered as intravenous infusion once every 2 weeks for 35-day Maintenance Phase. Dexamethasone tablet will be administered at first occurrence of documented disease progression or if bortezomib was discontinued due to intolerable toxicity. Dexamethasone 40 mg/day will be administered on days 1-4, 9-12, and 17-20 for four 28-day cycles then 40 mg/day for Days 1-4 for all subsequent cycles. | Biological: Siltuximab<br>* Siltuximab 6 mg/kg will be administered as intravenous infusion once every 2 weeks during cycle 1 in Part 1. Siltuximab 6 mg/kg will be administered as intravenous infusion once every 2 weeks during 42-day Treatment Phase and 35-day Maintenance Phase in Part 2.<br>* Other names: CNTO 328;Drug: Bortezomib<br>* Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus once every 2 weeks during cycle 1 in Part 1. Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus on Days 1, 4, 8, 11, followed by a 10-day rest period; and on Days 22, 25, 29, and 32 followed by a 10-day rest period during 42-day treatment phase in Part 2. Bortezomib 1.3 mg/m2 will be administered as intravenous bolus on Days 1, 8, 15, 22 followed by a 13-day rest period (cycle Days 23 to 35) during 35-day Maintenance Phase in Part 2.<br>* Other names: VELCADE;Drug: Dexamethasone<br>* Dexamethasone tablet will be administered in this study at the first occurrence of documented disease progression or if bortezomib was discontinued due to intolerable toxicity. Dexamethasone 40 mg/day will be administered on days 1-4, 9-12, and 17-20 for four 28-day cycles then 40 mg/day for Days 1-4 for all subsequent cycles in treatment phase and maintenance phase of Part 2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival was defined as the time interval between randomization and the first documented sign of disease progression (including relapse from complete response [CR]) by the European Bone Marrow Transplant (EBMT) criteria or death, whichever occurred first. Relapse from CR requires at least 1 of the following: Reappearance of serum or urinary M-protein on immunofixation or routine electrophoresis, confirmed by at least 1 further investigation and excluding oligoclonal immune reconstitution; Greater than or equal to (>=) 5 percent (%) plasma cells either in a bone marrow aspirate or on trephine bone biopsy; Development of new lytic bone lesions or soft tissue plasmacytomas or definite increase in the size of residual bone lesions (development of a compression fracture does not exclude continued response and may not indicate progression); Development of hypercalcemia not attributable to any other cause. | Randomization until disease progression or death, which ever occured first (maximum up to 5 years) | 
| Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Best Confirmed Response of Complete Response (CR) or Partial Response (PR) (Overall Response Rate) | Overall response rate was defined as best response (CR/PR confirmed) for a participant recorded from first administration of study agent or randomization (Part 2) until disease progression/recurrence and before dexamethasone was added. CR: Absence of original M-protein in serum/urine by immunofixation,maintained for minimum of 6 weeks. The presence of oligoclonal bands consistent with oligoclonal immune reconstitution does not exclude CR; Less than 5 percent (%) plasma cells in bone marrow aspirate and also on trephine bone biopsy if biopsy is performed; No increase in size/number of lytic bone lesions; Disappearance of soft tissue plasmacytomas. PR: Greater than or equal to (>=) 50% reduction in level of serum M-protein, maintained for minimum of 6 weeks. Reduction in 24 hour urinary light chain excretion either by >= 90% or to < 200 mg, maintained for minimum of 6 weeks; >= 50% reduction in size of soft tissue plasmacytomas; No increase in size/number of lytic bone lesions. | Randomization until disease progression (maximum up to 5 years) | 
| Percentage of Participants With Confirmed Complete Response (CR Rate) | CR rate was defined as the percentage of participants who achieved a confirmed CR before dexamethasone was added. CR: Absence of original M-protein in serum/urine by immunofixation,maintained for minimum of 6 weeks. The presence of oligoclonal bands consistent with oligoclonal immune reconstitution does not exclude CR; Less than 5 percent (%) plasma cells in bone marrow aspirate and also on trephine bone biopsy if biopsy is performed; No increase in size/number of lytic bone lesions; Disappearance of soft tissue plasmacytomas. | Randomization until disease progression (maximum up to 5 years) | 
| Overall Survival | Overall survival was defined as the interval between the first administration of study agent or randomization (Part 2) and the participant's death from any cause. For participants with unknown survival status as of the data cut-off date, overall survival was censored at the last date known to be alive. | up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple myeloma, Monoclonal Antibody, Intravenous, refractory or relapsed multiple myeloma, velcade, bortezomib