Multiple Myeloma
Conditions
Keywords
multiple myeloma, Monoclonal Antibody, Intravenous, refractory or relapsed multiple myeloma, velcade, bortezomib
Brief summary
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
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.
Interventions
BIOLOGICALSiltuximab
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.
DRUGBortezomib
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.
DRUGPlacebo
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.
DRUGDexamethasone
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.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Randomization until disease progression or death, which ever occured first (maximum up to 5 years) | 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. |
| Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | up to 5 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Best Confirmed Response of Complete Response (CR) or Partial Response (PR) (Overall Response Rate) | Randomization until disease progression (maximum up to 5 years) | 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. |
| Percentage of Participants With Confirmed Complete Response (CR Rate) | Randomization until disease progression (maximum up to 5 years) | 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. |
| Overall Survival | up to 5 years | 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. |
Countries
Belgium, Brazil, Bulgaria, Canada, Czechia, France, Germany, Greece, Hungary, Netherlands, Poland, Portugal, Romania, Russia, Slovakia, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
144 participants were randomized to bortezomib plus placebo group; of which, 3 participants received incorrect treatment (bortezomib plus siltuximab).
Participants by arm
| Arm | Count |
|---|---|
| Part 1 - Bortezomib + Siltuximab 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. | 21 |
| Part 2 - Bortezomib + Placebo 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. | 144 |
| Part 2 - Bortezomib + Siltuximab 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. | 142 |
| Total | 307 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Achieved Complete Response | 1 | 5 | 11 |
| Overall Study | Adverse Event | 7 | 26 | 27 |
| Overall Study | Death | 0 | 8 | 10 |
| Overall Study | Disease progression | 10 | 60 | 49 |
| Overall Study | End of Study | 1 | 1 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 2 |
| Overall Study | Other Unspecified | 0 | 3 | 5 |
| Overall Study | Physician Decision | 0 | 16 | 10 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Randomized but not Treated | 0 | 2 | 3 |
| Overall Study | Received incorrect treatment | 0 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 5 | 5 |
| Overall Study | Withdrawal of consent to study agent | 1 | 15 | 17 |
Baseline characteristics
| Characteristic | Part 1 - Bortezomib + Siltuximab | Total | Part 2 - Bortezomib + Siltuximab | Part 2 - Bortezomib + Placebo |
|---|---|---|---|---|
| Age, Continuous | 66 years STANDARD_DEVIATION 10.76 | 63.1 years STANDARD_DEVIATION 9.6 | 63.5 years STANDARD_DEVIATION 9.32 | 62.3 years STANDARD_DEVIATION 9.65 |
| Region of Enrollment Belgium | 0 participants | 3 participants | 1 participants | 2 participants |
| Region of Enrollment Brazil | 0 participants | 10 participants | 4 participants | 6 participants |
| Region of Enrollment Bulgaria | 0 participants | 26 participants | 10 participants | 16 participants |
| Region of Enrollment Canada | 3 participants | 12 participants | 5 participants | 4 participants |
| Region of Enrollment Czech Republic | 0 participants | 24 participants | 11 participants | 13 participants |
| Region of Enrollment France | 7 participants | 19 participants | 7 participants | 5 participants |
| Region of Enrollment Germany | 0 participants | 2 participants | 1 participants | 1 participants |
| Region of Enrollment Greece | 0 participants | 10 participants | 5 participants | 5 participants |
| Region of Enrollment Hungary | 0 participants | 20 participants | 10 participants | 10 participants |
| Region of Enrollment Netherlands | 2 participants | 11 participants | 5 participants | 4 participants |
| Region of Enrollment Poland | 0 participants | 30 participants | 11 participants | 19 participants |
| Region of Enrollment Portugal | 0 participants | 9 participants | 4 participants | 5 participants |
| Region of Enrollment Romania | 0 participants | 13 participants | 5 participants | 8 participants |
| Region of Enrollment Russian Federation | 0 participants | 48 participants | 27 participants | 21 participants |
| Region of Enrollment Spain | 2 participants | 17 participants | 10 participants | 5 participants |
| Region of Enrollment United Kingdom | 0 participants | 27 participants | 15 participants | 12 participants |
| Region of Enrollment United States | 7 participants | 26 participants | 11 participants | 8 participants |
| Sex: Female, Male Female | 13 Participants | 142 Participants | 70 Participants | 59 Participants |
| Sex: Female, Male Male | 8 Participants | 165 Participants | 72 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 21 | 135 / 139 | 140 / 142 |
| serious Total, serious adverse events | 10 / 21 | 44 / 139 | 47 / 142 |
Outcome results
Primary
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.
Time frame: up to 5 years
Population: The safety population included all participants who received at least 1 dose of study treatment in Part 1 or Part 2. Participants were analyzed as per actual treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 2 - Bortezomib + Placebo | Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | Serious Adverse Events (SAEs) | 10 participants |
| Part 2 - Bortezomib + Placebo | Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | Adverse Events (AEs) | 21 participants |
| Part 2 - Bortezomib + Siltuximab | Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | Serious Adverse Events (SAEs) | 44 participants |
| Part 2 - Bortezomib + Siltuximab | Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | Adverse Events (AEs) | 138 participants |
| Part 2 - Bortezomib + Siltuximab | Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | Serious Adverse Events (SAEs) | 47 participants |
| Part 2 - Bortezomib + Siltuximab | Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | Adverse Events (AEs) | 140 participants |
Primary
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.
Time frame: Randomization until disease progression or death, which ever occured first (maximum up to 5 years)
Population: Intent-to-treat (ITT) population included all participants randomized in Part 2. Participants were analyzed as per initial randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2 - Bortezomib + Placebo | Progression-free Survival | 232 days |
| Part 2 - Bortezomib + Siltuximab | Progression-free Survival | 245 days |
Secondary
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.
Time frame: up to 5 years
Population: ITT population included all participants randomized in Part 2. Participants were analyzed as per initial randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2 - Bortezomib + Placebo | Overall Survival | 1121 days |
| Part 2 - Bortezomib + Siltuximab | Overall Survival | 937 days |
Secondary
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.
Time frame: Randomization until disease progression (maximum up to 5 years)
Population: Response-evaluable population:all participants in Part 2 with confirmed diagnosis of multiple myeloma and measurable,secretory disease:either serum M-protein 1 \>= gram per deciliter(g/dL)/urine M-protein \>200 mg per 24 hours,at study entry;had at least 1 study agent administration;at least 1 post-baseline disease assessment before dexamethasone.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 - Bortezomib + Placebo | Percentage of Participants With Best Confirmed Response of Complete Response (CR) or Partial Response (PR) (Overall Response Rate) | 46.7 percentage of participants |
| Part 2 - Bortezomib + Siltuximab | Percentage of Participants With Best Confirmed Response of Complete Response (CR) or Partial Response (PR) (Overall Response Rate) | 55.0 percentage of participants |
Secondary
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.
Time frame: Randomization until disease progression (maximum up to 5 years)
Population: Response-evaluable population:all participants in Part 2 with confirmed diagnosis of multiple myeloma and measurable,secretory disease:either serum M-protein 1 \>= gram per deciliter(g/dL)/urine M-protein \>200 mg per 24 hours,at study entry;had at least 1 study agent administration;at least 1 post-baseline disease assessment before dexamethasone.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 - Bortezomib + Placebo | Percentage of Participants With Confirmed Complete Response (CR Rate) | 7.3 percentage of participants |
| Part 2 - Bortezomib + Siltuximab | Percentage of Participants With Confirmed Complete Response (CR Rate) | 10.7 percentage of participants |