Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as CNTO 328
Siltuximab · 6 trials · 5 indications
One-year PFS rate is defined as the percentage (%) of participants surviving 1 year after randomization without progression to multiple myeloma or death estimated by the Kaplan-Meier method and based on the International Myeloma Working Group (IMWG) calcium, renal, anemia, and bone lesions (CRAB) criteria. Progressive disease (PD) is defined as presence of an M- component in serum plus clonal plasma cells in the bone marrow plus 1 or more of the following: Calcium elevation (greater than \[\>\] 11.5 milligram per deciliter \[mg/dL\] \[\> 2.88 millimoles per liter {mmol/L}\]); Renal insufficiency (creatinine \> 2 mg/dL \[177 micromoles per liter or more\]; Anemia (hemoglobin less than \[\<\] 10 gram per deciliter \[g/dL\] or 2 g/dL lower than lower limit of normal \[LLN\] \[hemoglobin \< 6.5 mmol/L or 1.25 mmol/L lower than LLN\]); Bone disease (lytic lesions or osteopenia).
An adverse event (AE) is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Durable tumor and symptomatic response is complete response (CR) + partial response (PR). CR: complete disappearance of all measurable and evaluable disease (eg, pleural effusion) and resolution of baseline symptoms attributed to multicentric Castleman's disease, sustained for at least 18 weeks. PR: \>=50 percent decrease in sum of the product of the diameters of indicator lesion(s), with at least stable disease in all other evaluable disease in the absence of treatment failure sustained for at least 18 weeks. The statistical analysis shows difference in symptomatic response rate (siltuximab+best supportive care \[BSC\] minus Placebo+BSC).
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.
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.
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.
| Arm | Type | Description |
|---|---|---|
| Siltuximab | EXPERIMENTAL | Type=exact, unit=mg/kg, number=15, form=intravenous infusion, route=intravenous use, every 4 weeks until progression to symptomatic multiple myeloma, unacceptable toxicity, withdrawal of consent, or the end of the study. |
| Placebo | PLACEBO_COMPARATOR | Form=intravenous infusion, route=intravenous use route=intravenous, use every 4 weeks until progression to symptomatic multiple myeloma, unacceptable toxicity, withdrawal of consent, or the end of the study. |
| Siltuximab+best supportive care (BSC) | EXPERIMENTAL | Siltuximab 11 mg/kg will be administered as a 1-hour intravenous infusion every 3 weeks + BSC. |
| Placebo+BSC | PLACEBO_COMPARATOR | Placebo will be administered as a 1-hour intravenous infusion every 3 weeks + BSC. Participants who do not respond to placebo during the blinded treatment period will have option to crossover and receive siltuximab 11 mg/kg which will be administered by 1-hour intravenous infusion every 3 weeks + BSC during the unblinded treatment period. |
| Part 1: VMP+Siltuximab 11 mg/kg | EXPERIMENTAL | 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). |
| Part 2, Arm A: VMP+Siltuximab 8.3 mg/kg or 11 mg/kg | EXPERIMENTAL | 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 |
| Part 2, Arm B: VMP | ACTIVE_COMPARATOR | 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 |
| Part 1: Siltuximab Plus Bortezomib | EXPERIMENTAL | 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. |
| Part 2: Bortezomib + Placebo | EXPERIMENTAL | 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. |
| Part 2: Bortezomib + Siltuximab | EXPERIMENTAL | 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. |
| 001 | EXPERIMENTAL | Siltuximab 15mg/kg IV infusion every 3 weeks for 4 cycles. If applicable extended dosing of 15 mg/kg IV infusion every 4 weeks for up to 2 years. |
| Name | Type | Description |
|---|---|---|
| Siltuximab | DRUG | Type=exact, unit=mg/kg, number=15, form=intravenous infusion, route=intravenous use, every 4 weeks until progression to symptomatic multiple myeloma, unacceptable toxicity, withdrawal of consent, or the end of the study. |
| Placebo | DRUG | Form=intravenous infusion, route=intravenous use route=intravenous, use every 4 weeks until progression to symptomatic multiple myeloma, unacceptable toxicity, withdrawal of consent, or the end of the study. |
| Best Supportive Care (BSC) | DRUG | BSC included treatment for effusions, antipyretics, antipuretics, antihistamines, pain medication, treatment for infections, transfusions, management of infusion-related reactions, and corticosteroids. |
| Siltuximab11 mg/kg | DRUG | Participants will receive siltuximab 11 mg/kg as a 1-hour intravenous infusion every 3 weeks in Part 1. |
| Siltuximab 8.3 mg/kg or 11 mg/kg | DRUG | 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. |
| Velcade (bortezomib) | DRUG | Participants will receive Velcade 1.3 mg/m2 as an intravenous bolus injection according to the current approved package insert in Part 1. |
| Melphalan | DRUG | 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. |
| Prednisone | DRUG | 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. |
| Bortezomib | DRUG | 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. |
| Dexamethasone | DRUG | 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. |
Inclusion Criteria: * Diagnosis of smoldering multiple myeloma (SMM) for \<4 years * Diagnosis of high-risk SMM (defined as bone marrow plasma cells \>=10% and either serum monoclonal protein \>=3 g/dL, or abnormal free light chain ratio \<0.126 or \>8 and serum M-protein \<3 g/dL but \>=1 g/dL) * ...
Siltuximab is being studied in oncology for high-risk smoldering multiple myeloma, monoclonal gammopathy of undetermined significance, multicentric Castleman's disease, and multiple myeloma. It is an investigational monoclonal antibody developed by Johnson & Johnson (JNJ).
Siltuximab targets interleukin-6 (IL6). It acts as an antagonist, binding to IL6 and blocking its activity. This mechanism is being evaluated in conditions where IL6 signaling is thought to play a role, such as multicentric Castleman's disease and plasma cell disorders.
Siltuximab is being developed by Johnson & Johnson, which trades under the ticker JNJ. The company is responsible for the clinical development program across the studied indications.
Siltuximab is in Phase 2 clinical development. It is investigational and has not been approved by the FDA for the indications studied. The Phase 2 trials have been completed, and no active trials are currently listed.
Siltuximab has been evaluated in completed trials including NCT01484275 in high-risk smoldering multiple myeloma, NCT01400503 and NCT01024036 in multicentric Castleman's disease, and NCT01219010 in monoclonal gammopathy of undetermined significance and multiple myeloma. These trials enrolled a total of 425 participants.