A Phase 3 Randomized Study Comparing Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed by Ciltacabtagene Autoleucel, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against BCMA Versus Bortezomib, Lenalidomide, and Dexamethasone (VRd) Followed by Lenalidomide and Dexamethasone (Rd) Therapy in Participants With Newly Diagnosed Multiple Myeloma for Whom Hematopoietic Stem Cell Transplant is Not Planned as Initial Therapy
概览
- 阶段
- 3 期
- 干预措施
- Dexamethasone
- 疾病 / 适应症
- Multiple Myeloma
- 发起方
- Janssen Research & Development, LLC
- 入组人数
- 743
- 试验地点
- 186
- 主要终点
- Progression Free Survival (PFS)
- 状态
- 进行中（未招募）
- 最后更新
- 19天前
概览
简要总结
The purpose of this study is to compare the efficacy of Bortezomib, Lenalidomide and Dexamethasone (VRd) induction followed by a single administration of ciltacabtagene autoleucel (cilta-cel) versus VRd induction followed by Lenalidomide and Dexamethasone (Rd) maintenance in newly diagnosed multiple myeloma participants for whom ASCT is not planned as initial therapy in terms of Progression Free Survival (PFS).
详细描述
Multiple myeloma (MM) is a malignant plasma cell disorder characterized by the production of monoclonal immunoglobulin (Ig) proteins or protein fragments (M proteins) that have lost their function. JNJ-68284528 (ciltacabtagene autoleucel \[cilta-cel\]) is an autologous chimeric antigen receptor T cell (CAR-T) therapy that targets B-cell maturation antigen (BCMA), a molecule expressed on the surface of mature B lymphocytes and malignant plasma cells. The primary hypothesis of this study is that in participants with newly diagnosed MM, treatment with VRd induction followed by a single administration of cilta-cel will significantly improve progression free survival compared to Bortezomib, Lenalidomide and Dexamethasone (VRd) induction followed by Rd maintenance. The study will screen participants with newly diagnosed MM who are not planned to receive autologous stem cell transplant (ASCT) as initial therapy. This study will be conducted in 4 phases: Screening (up to 28 days), Pre-randomization Treatment, Treatment, and Follow-up. Assessments like patient-reported outcome(s) (PROs), electrocardiogram (ECG), vital signs and pharmacokinetics will be performed during the study. Safety evaluations will include review of adverse events, laboratory test results, vital sign measurements, physical examination findings, assessment of cardiac function, Immune-Effector Cell-Associated Encephalopathy (ICE) and handwriting assessments (only for Arm B) and Eastern Cooperative Oncology Group (ECOG) performance status. Safety data will be periodically reviewed by an Independent Data Monitoring Committee (IDMC). The duration of the study is approximately 12 years 5 months.
研究者
入排标准
入选标准
- •Documented diagnosis of multiple myeloma (MM) according to International Myeloma Working Group (IMWG) diagnostic criteria
- •Measurable disease at screening as defined by any of the following: Serum monoclonal paraprotein (M-protein) level greater than or equal to (\>=)1.0 gram per deciliter (g/dL) or urine M-protein level \>=200 milligram (mg)/24 hours; or Light chain MM in whom only measurable disease is by serum free light chain (FLC) levels: Serum immunoglobin (Ig) free light chain \>=10 milligrams per deciliter (mg/dL) and abnormal serum Ig kappa/lambda FLC ratio
- •Eastern Cooperative Oncology Group Performance Status grade of 0 or 1
- •Not considered for high-dose chemotherapy with Autologous Stem Cell Transplant (ASCT) due to: Ineligible due to advanced age; or Ineligible due to presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with ASCT; or Deferral of high-dose chemotherapy with ASCT as initial treatment
- •A woman of childbearing potential (WOCBP) must have 2 negative highly sensitive serum or urine pregnancy tests (beta-human chorionic gonadotropin) prior to starting Bortezomib, Lenalidomide and Dexamethasone (VRd) and must agree to further testing during the study.
- •Clinical laboratory values meeting the following criteria during the screening phase: hemoglobin greater than or equal to (\>=) 8.0 g/dL (\>=5 millimoles per liter \[mmol/L\]), recombinant human erythropoietin use is permitted; platelets \>=75 \*10\^9/L; absolute lymphocyte count \>=0.3 \*10\^9/L; absolute neutrophil count (ANC) \>=1.0 ×10\^9/L (prior growth factor support is permitted but must be without support in the 7 days prior to the laboratory test); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to (\<=) 3.0 \* upper limit of normal (ULN); estimated glomerular filtration rate \>=40 milliliter per minute/1.73 meter square (mL/min/1.73 m\^2) based upon modified diet in renal disease formula (MDRD-4) calculation or a 24-hour urine collection; total bilirubin \<=2.0 \* ULN; except in participants with congenital hyperbilirubinemia, such as Gilbert syndrome (in which case direct bilirubin \<=2.0 \* ULN is required)
排除标准
- •Frailty index of \>=2 according to Myeloma Geriatric Assessment score
- •Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5
- •Known active, or prior history of central nervous system (CNS) involvement or clinical signs of meningeal involvement of MM
- •Stroke or seizure within 6 months of signing Informed Consent Form (ICF)
- •Seropositive for human immunodeficiency virus (HIV)
- •Vaccinated with live, attenuated vaccine within 4 weeks prior to first dose of VRd
- •Participant must not require continuous supplemental oxygen
- •Hepatitis B infection
- •Hepatitis C infection
- •Prior treatment with chimeric antigen receptor T (CAR-T) therapy directed at any target
研究组 & 干预措施
Arm A: VRd+Rd (Standard Therapy)
Participants will receive bortezomib, lenalidomide, and dexamethasone (VRd) regimen for 6 cycles before randomization. Following randomization, participants in Arm A will receive 2 more cycles of VRd. In VRd treatment, participants will receive bortezomib 1.3 milligram per meter square (mg/m\^2) subcutaneously (SC) on Days 1, 4, 8 and 11 of each cycle (Cycles 1 to 8), oral lenalidomide 25 mg on Days 1 to 14 of each cycle (Cycles 1 to 8) and oral dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle (Cycles 1 to 8). Each cycle will consist of 21 days. After 8 cycles of VRd, treatment will continue with lenalidomide and dexamethasone (Rd) maintenance therapy. In Rd treatment, participants will receive oral lenalidomide 25 mg on Days 1 to 21 of each cycle and oral dexamethasone 40 mg on Days 1, 8, 15, and 22 of each cycle. Each cycle will consist of 28 days. Participants will continue to receive Rd until confirmed progressive disease or unacceptable toxicity.
干预措施: Dexamethasone
Arm B: VRd+Ciltacabtagene Autoleucel (Cilta-cel)
Participants will receive VRd regimen for 6 cycles before randomization. Following randomization, participants in Arm B will undergo apheresis and receive two more cycles of VRd as bridging therapy. In VRd treatment, participants will receive bortezomib 1.3 mg/m\^2 SC on Days 1, 4, 8 and 11 of each cycle for Cycles 1 to 8; oral lenalidomide 25 mg on days 1 to 14 of each cycle for Cycles 1 to 8 and oral dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of each cycle for Cycles 1 to 8. Each cycle will consist of 21 days. After 8 cycles of VRd, participants will receive a conditioning regimen (cyclophosphamide 300 mg/m\^2 intravenous \[IV\] and fludarabine 30 mg/m\^2 IV daily for 3 days) and Cilta-cel infusion 0.75\*10\^6 chimeric antigen receptor (CAR)-positive viable T cells/kilogram (kg).
干预措施: Cilta-cel
Arm A: VRd+Rd (Standard Therapy)
Participants will receive bortezomib, lenalidomide, and dexamethasone (VRd) regimen for 6 cycles before randomization. Following randomization, participants in Arm A will receive 2 more cycles of VRd. In VRd treatment, participants will receive bortezomib 1.3 milligram per meter square (mg/m\^2) subcutaneously (SC) on Days 1, 4, 8 and 11 of each cycle (Cycles 1 to 8), oral lenalidomide 25 mg on Days 1 to 14 of each cycle (Cycles 1 to 8) and oral dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle (Cycles 1 to 8). Each cycle will consist of 21 days. After 8 cycles of VRd, treatment will continue with lenalidomide and dexamethasone (Rd) maintenance therapy. In Rd treatment, participants will receive oral lenalidomide 25 mg on Days 1 to 21 of each cycle and oral dexamethasone 40 mg on Days 1, 8, 15, and 22 of each cycle. Each cycle will consist of 28 days. Participants will continue to receive Rd until confirmed progressive disease or unacceptable toxicity.
干预措施: Bortezomib
Arm B: VRd+Ciltacabtagene Autoleucel (Cilta-cel)
Participants will receive VRd regimen for 6 cycles before randomization. Following randomization, participants in Arm B will undergo apheresis and receive two more cycles of VRd as bridging therapy. In VRd treatment, participants will receive bortezomib 1.3 mg/m\^2 SC on Days 1, 4, 8 and 11 of each cycle for Cycles 1 to 8; oral lenalidomide 25 mg on days 1 to 14 of each cycle for Cycles 1 to 8 and oral dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of each cycle for Cycles 1 to 8. Each cycle will consist of 21 days. After 8 cycles of VRd, participants will receive a conditioning regimen (cyclophosphamide 300 mg/m\^2 intravenous \[IV\] and fludarabine 30 mg/m\^2 IV daily for 3 days) and Cilta-cel infusion 0.75\*10\^6 chimeric antigen receptor (CAR)-positive viable T cells/kilogram (kg).
干预措施: Bortezomib
Arm B: VRd+Ciltacabtagene Autoleucel (Cilta-cel)
Participants will receive VRd regimen for 6 cycles before randomization. Following randomization, participants in Arm B will undergo apheresis and receive two more cycles of VRd as bridging therapy. In VRd treatment, participants will receive bortezomib 1.3 mg/m\^2 SC on Days 1, 4, 8 and 11 of each cycle for Cycles 1 to 8; oral lenalidomide 25 mg on days 1 to 14 of each cycle for Cycles 1 to 8 and oral dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of each cycle for Cycles 1 to 8. Each cycle will consist of 21 days. After 8 cycles of VRd, participants will receive a conditioning regimen (cyclophosphamide 300 mg/m\^2 intravenous \[IV\] and fludarabine 30 mg/m\^2 IV daily for 3 days) and Cilta-cel infusion 0.75\*10\^6 chimeric antigen receptor (CAR)-positive viable T cells/kilogram (kg).
干预措施: Lenalidomide
Arm B: VRd+Ciltacabtagene Autoleucel (Cilta-cel)
Participants will receive VRd regimen for 6 cycles before randomization. Following randomization, participants in Arm B will undergo apheresis and receive two more cycles of VRd as bridging therapy. In VRd treatment, participants will receive bortezomib 1.3 mg/m\^2 SC on Days 1, 4, 8 and 11 of each cycle for Cycles 1 to 8; oral lenalidomide 25 mg on days 1 to 14 of each cycle for Cycles 1 to 8 and oral dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of each cycle for Cycles 1 to 8. Each cycle will consist of 21 days. After 8 cycles of VRd, participants will receive a conditioning regimen (cyclophosphamide 300 mg/m\^2 intravenous \[IV\] and fludarabine 30 mg/m\^2 IV daily for 3 days) and Cilta-cel infusion 0.75\*10\^6 chimeric antigen receptor (CAR)-positive viable T cells/kilogram (kg).
干预措施: Dexamethasone
Arm A: VRd+Rd (Standard Therapy)
Participants will receive bortezomib, lenalidomide, and dexamethasone (VRd) regimen for 6 cycles before randomization. Following randomization, participants in Arm A will receive 2 more cycles of VRd. In VRd treatment, participants will receive bortezomib 1.3 milligram per meter square (mg/m\^2) subcutaneously (SC) on Days 1, 4, 8 and 11 of each cycle (Cycles 1 to 8), oral lenalidomide 25 mg on Days 1 to 14 of each cycle (Cycles 1 to 8) and oral dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle (Cycles 1 to 8). Each cycle will consist of 21 days. After 8 cycles of VRd, treatment will continue with lenalidomide and dexamethasone (Rd) maintenance therapy. In Rd treatment, participants will receive oral lenalidomide 25 mg on Days 1 to 21 of each cycle and oral dexamethasone 40 mg on Days 1, 8, 15, and 22 of each cycle. Each cycle will consist of 28 days. Participants will continue to receive Rd until confirmed progressive disease or unacceptable toxicity.
干预措施: Lenalidomide
Arm B: VRd+Ciltacabtagene Autoleucel (Cilta-cel)
Participants will receive VRd regimen for 6 cycles before randomization. Following randomization, participants in Arm B will undergo apheresis and receive two more cycles of VRd as bridging therapy. In VRd treatment, participants will receive bortezomib 1.3 mg/m\^2 SC on Days 1, 4, 8 and 11 of each cycle for Cycles 1 to 8; oral lenalidomide 25 mg on days 1 to 14 of each cycle for Cycles 1 to 8 and oral dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of each cycle for Cycles 1 to 8. Each cycle will consist of 21 days. After 8 cycles of VRd, participants will receive a conditioning regimen (cyclophosphamide 300 mg/m\^2 intravenous \[IV\] and fludarabine 30 mg/m\^2 IV daily for 3 days) and Cilta-cel infusion 0.75\*10\^6 chimeric antigen receptor (CAR)-positive viable T cells/kilogram (kg).
干预措施: Fludarabine
Arm B: VRd+Ciltacabtagene Autoleucel (Cilta-cel)
Participants will receive VRd regimen for 6 cycles before randomization. Following randomization, participants in Arm B will undergo apheresis and receive two more cycles of VRd as bridging therapy. In VRd treatment, participants will receive bortezomib 1.3 mg/m\^2 SC on Days 1, 4, 8 and 11 of each cycle for Cycles 1 to 8; oral lenalidomide 25 mg on days 1 to 14 of each cycle for Cycles 1 to 8 and oral dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of each cycle for Cycles 1 to 8. Each cycle will consist of 21 days. After 8 cycles of VRd, participants will receive a conditioning regimen (cyclophosphamide 300 mg/m\^2 intravenous \[IV\] and fludarabine 30 mg/m\^2 IV daily for 3 days) and Cilta-cel infusion 0.75\*10\^6 chimeric antigen receptor (CAR)-positive viable T cells/kilogram (kg).
干预措施: Cyclophosphamide
结局指标
主要结局
Progression Free Survival (PFS)
时间窗: Up to 4 years and 5 months
Progression-free survival is defined as the time from the date of randomization to the date of first documented Progressive Disease (PD), as defined in the International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first.
次要结局
- Overall Survival (OS)(Up to 12 years and 5 months)
- Overall MRD Negative CR(Up to 12 years and 5 months)
- Sustained Minimal Residual Disease (MRD) Negative CR(Up to 12 years and 5 months)
- MRD Negative CR at 9 Months(9 months)
- Complete Response or Better(Up to 12 years and 5 months)
- Change from Baseline in Health-Related Quality of Life (HRQoL) as Assessed by European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC-QLQ-C30) Scale Score(Baseline up to 12 years and 5 months)
- Time to Subsequent Anti-myeloma Therapy(Up to 12 years and 5 months)
- Progression Free Survival on Next-line Therapy (PFS2)(Up to 12 years and 5 months)
- Number of Participants with Adverse Events (AEs), Abnormalities in Laboratory Parameters, 12-Lead Electrocardiogram (ECG), Physical Examination, and Vital Signs(Up to 12 years and 5 months)
- Arm B: Systemic Cytokine Concentrations(Up to Day 112)
- Arm B: Levels of Chimeric Antigen Receptor T cell (CAR-T) Cell Activation Markers(Up to 12 years and 5 months)
- Arm B: Levels of Soluble B-cell Maturation Antigen (BCMA)(Up to 1 year)
- Arm B: Levels of Cilta-cel Expansion (proliferation), and Persistence(Up to 12 years and 5 months)
- Arm B: Number of Participants with Anti-cilta-cel Antibodies(Up to 12 years and 5 months)
- Arm B: Number of Participants with Presence of Replication Competent Lentivirus(Up to 12 years and 5 months)
- Time to Worsening of Symptoms, Functioning and Overall Well-being(Up to 12 year and 5 months)
- Change from Baseline in Health-Related Quality of Life as Assessed by MySIm-Q Scale Score(Baseline up to 12 years and 5 months)
- Change from Baseline in Health-Related Quality of Life as Assessed by European Quality of Life - 5 Dimensions-5 Levels (EQ-5D-5L) Scale Score(Baseline up to 12 years and 5 months)
- Change from Baseline in Health-Related Quality of Life as Assessed by Patient Global Impression of Symptom Severity (PGIS) Scale Score(Baseline up to 12 years and 5 months)
- Patient-reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Items(Up to 161 days)