Randomized, Open Label, Multicenter Study Assessing The Clinical Benefit Of Isatuximab Combined With Carfilzomib (Kyprolis®) And Dexamethasone Versus Carfilzomib With Dexamethasone In Patients With Relapse And/Or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Sanofi
- 入组人数
- 302
- 试验地点
- 70
- 主要终点
- Progression Free Survival as Determined by Independent Response Committee: Final Analysis
研究概览
简要总结
The purpose of this study it to compare the efficacity of isatuximab when combined to carfilzomib and dexamethasone versus carfilzomib and dexamethasone in patients with multiple myeloma already treated with 1 to 3 prior lines of therapy.
详细描述
The duration of the study for a patient will include a period for screening of up to 3 weeks. Patients will be treated until disease progression, unacceptable AE, or patient decision to stop the study treatment. After study treatment discontinuation, patients will have follow-up visits until the analysis of overall survival.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants with MM previously treated with prior 1 to 3 lines and with measurable serum M-protein (>= 0.5 gram/deciliter) and/or urine M-protein (>= 200 milligram/24 hours).
排除标准
- •Participants previously pretreated with carfilzomib, who never achieved at least one minor response during previous therapies and/or last previous therapy completed within 14 last days.
- •Participants with serum free light chain (FLC) measurable disease only.
- •Participants less than 18 years old, participants with Eastern Cooperative Oncology Group performance status more than
- •Participants with inadequate biological tests.
- •Participants with myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association class III or IV congestive heart failure, superior or equal to grade 3 arrhythmias, stroke or transient ischemic attack within last 6 months, and/or left ventricular ejection fraction lower than 40%.
- •Participants with previous cancer unless disease free for more than 5 years or in situ cancer curatively treated.
- •Participants with known acquired immunodeficiency syndrome related illness or human immunodeficiency virus requiring antiretroviral treatment, or hepatitis A, B, or C active infection.
- •Women of childbearing potential or male participant with women of childbearing potential who do not agree to use highly effective method of birth control.
- •The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
研究组 & 干预措施
Isatuximab + Carfilzomib + Dexamethasone (IKd)
Isatuximab (intravenous) on day 1, 8, 15 and 22 of 1st cycle, then on day 1 and 15 of subsequent cycles in combination with carfilzomib (intravenous) on day 1, 2, 8, 9, 15 and 16 + dexamethasone (intravenous or by mouth [po]) on day 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle.
干预措施: isatuximab SAR650984 (Drug)
Isatuximab + Carfilzomib + Dexamethasone (IKd)
Isatuximab (intravenous) on day 1, 8, 15 and 22 of 1st cycle, then on day 1 and 15 of subsequent cycles in combination with carfilzomib (intravenous) on day 1, 2, 8, 9, 15 and 16 + dexamethasone (intravenous or by mouth [po]) on day 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle.
干预措施: carfilzomib (Drug)
Isatuximab + Carfilzomib + Dexamethasone (IKd)
Isatuximab (intravenous) on day 1, 8, 15 and 22 of 1st cycle, then on day 1 and 15 of subsequent cycles in combination with carfilzomib (intravenous) on day 1, 2, 8, 9, 15 and 16 + dexamethasone (intravenous or by mouth [po]) on day 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle.
干预措施: dexamethasone (Drug)
Carfilzomib + Dexamethasone (Kd)
Carfilzomib (intravenous) on day 1, 2, 8, 9, 15, 16 + dexamethasone (intravenous or po) on day 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle.
干预措施: carfilzomib (Drug)
Carfilzomib + Dexamethasone (Kd)
Carfilzomib (intravenous) on day 1, 2, 8, 9, 15, 16 + dexamethasone (intravenous or po) on day 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle.
干预措施: dexamethasone (Drug)
结局指标
主要结局
Progression Free Survival as Determined by Independent Response Committee: Final Analysis
时间窗: From randomization until the final analysis data cut-off date of 14 January 2022 (the median duration of follow-up was 43.96 months)
PFS: time (in months) from randomization to date of first documentation of PD or date of death from any cause, whichever comes first. If PD and death are not observed before analysis cut-off date or date of initiation of further anti-myeloma treatment, PFS was censored at date of last valid disease assessment or analysis cut-off date, whichever comes first. PD as per IMWG criteria: any 1 of following: Inc of \>=25% in Serum M-component from nadir; serum M component increase \>=1 g/dL in 2 consecutive assessment, if starting M component was \>=5 g/dL; and/or inc of \>=25% in Urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc \>=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion if \>1 lesion/ \>=50% inc in longest diameter of previous soft tissue extramedullary disease lesion \>1 cm in short axis. PFS estimated by Kaplan-Meier method.
Progression Free Survival as Determined by Independent Response Committee [Event Censored if Occurred >8 Weeks From Last Disease Assessment]: Final Analysis
时间窗: From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)
Time (in months) from randomization to date of 1st documentation of PD/date of death from any cause, whichever comes 1st. If PD \& death are not observed before cut-off date/date of initiation of further anti-myeloma treatment, PFS was censored at date of last valid disease assessment not showing PD/cut-off date, whichever comes 1st. Progressions/deaths occurring \>8 weeks after last disease assessment were censored at earliest date of last valid disease assessment not showing PD before initiation of further anti-myeloma treatment \& cut-off date. PD (per IMWG criteria): meeting any 1 criteria: Inc of \>=25% in serum M-component from nadir; serum M component inc \>=1 g/dL in 2 consecutive assessment, if starting M component was \>=5 g/dL; and/or inc of \>=25% in urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc \>=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion \>1 cm in short axis.
Progression Free Survival (PFS) As Determined by Independent Response Committee (IRC): Primary Analysis
时间窗: From randomization until the primary analysis data cut-off date of 7 Feb 2020 (median duration of follow-up was 20.73 months)
Time (in months) from randomization to date of 1st documentation of progressive disease (PD)/date of death from any cause, whichever comes 1st. If PD \& death are not observed before cut-off date/date of initiation of further anti-myeloma treatment, PFS was censored at date of last valid disease assessment not showing PD performed prior to initiation of further anti-myeloma treatment/cut-off date, whichever comes 1st. PD(IMWG criteria):any 1 of following:Increase(inc) of \>=25% in serum M-component from nadir; serum M component inc \>=1 g/dL in 2 consecutive assessment, if starting M component \>=5 g/dL; and/or inc of \>=25% in urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc \>=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion if \>1 lesion/ \>=50% increase in longest diameter of previous soft tissue extramedullary disease lesion \>1 cm in short axis. Estimated by Kaplan-Meier method.
Progression Free Survival as Determined by Independent Response Committee: [Event Censored if Occurred >8 Weeks From Last Disease Assessment]: Primary Analysis
时间窗: From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
Time (in months) from randomization to date of 1st PD documentation/death date, whichever is 1st. If PD \& death not observed before cut-off date/date of further anti-myeloma treatment initiation, PFS censored at date of last valid disease assessment not showing PD performed prior to initiation of further anti-myeloma treatment/cut-off date, whichever was 1st. Progression/deaths occurring \>8 weeks after last disease assessment censored at earliest date of last disease assessment without evidence of progression before initiation of new anti-myeloma treatment \& cut-off date. PD (IMWG criteria): meeting any 1: Inc \>=25% in Serum M-component from nadir; serum M component inc \>=1 g/dL in 2 consecutive assessment, if starting M component \>=5 g/dL; and/or inc \>=25% in Urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc \>=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion \>1 cm short axis.
次要结局
- HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Side Effects of Treatment at Specified Timepoints: Primary Analysis(Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks))
- HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Body Image Score at Specified Timepoints: Primary Analysis(Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks))
- Percentage of Participants With VGPR or Better With Minimal Residual Disease (MRD) Negativity: Final Analysis(From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months))
- Percentage of Participants With Overall Response (OR) as Determined by Independent Response Committee: Primary Analysis(From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months))
- Percentage of Participants With Very Good Partial Response (VGPR) or Better as Determined by Independent Response Committee: Primary Analysis(From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months))
- Percentage of Participants With VGPR or Better With Minimal Residual Disease (MRD) Negativity: Primary Analysis(From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months))
- Percentage of Participants With Complete Response (CR) as Per Independent Response Committee: Final Analysis(From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months))
- Percentage of Participants With Complete Response With MRD Negativity: Final Analysis(From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months))
- Overall Survival (OS)(From randomization until the final analysis data cut-off date of 7 Feb 2023 (the median duration of follow-up was 56.61 months))
- Duration of Response (DOR): Primary Analysis(From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months))
- Time to Progression (TTP): Primary Analysis(From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months))
- Time to First Response: Primary Analysis(From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months))
- Time to Best Response: Primary Analysis(From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months))
- Second Progression Free Survival (PFS2): Final Analysis - Data Cut-off Date of 14 Jan 2022(From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months))
- Second Progression Free Survival (PFS2): Overal Survival Analysis - Data Cut-off Date of 07 Feb 2023(From randomization until the overal survival analysis data cut-off date of 07 Feb 2023 (the median duration of follow-up was 56.61 months))
- HRQL: Change From Baseline in European Quality of Life Group Questionnaire With 5 Dimensions and 5 Levels Per Dimension (EQ-5D-5L): Health State Utility Index Value at Specified Timepoints: Primary Analysis(Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks))
- HRQL: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Score: Visual Analogic Scale (VAS) at Specified Timepoints: Primary Analysis(Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks))
- Number of Participants With Renal Response (RR): Primary Analysis(From the first dose of study treatment to 30 days following the last administration of study treatment (maximum duration: up to 114 weeks))
- HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Future Perspective at Specified Timepoints: Primary Analysis(Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks))
- Health Related Quality of Life (HRQL): Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 30 Items (EORTC QLQ-C30): Global Health Status Score at Specified Timepoints(Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks))
- HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Disease Symptoms Domain Score at Specified Timepoints: Primary Analysis(Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks))
- Pharmacokinetics: Plasma Concentration at End of Infusion (Ceoi) of Isatuximab: Primary Analysis(End of infusion on Cycle 1 Day 1 and Cycle 1 Day 15; Cycle 2 Day 1)
- Pharmacokinetics: Plasma Concentration of Isatuximab at Ctrough: Primary Analysis(Pre-infusion on Cycle 1 Day 1, Day 8, Day 15 and Day 22, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 7 Day 1, Cycle 8 Day 1, Cycle 9 Day 1 and Cycle 10 Day 1)
- Pharmacokinetics: Maximum Observed Concentration (Cmax) of Carfilzomib: Primary Analysis(Cycle 1: pre-dose (0 hour), 30 minutes (min), 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15)
- Pharmacokinetics: Clast of Carfilzomib: Primary Analysis(Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15)
- Pharmacokinetics: Tmax of Carfilzomib: Primary Analysis(Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15)
- Pharmacokinetics: Tlast of Carfilzomib: Primary Analysis(Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15)
- Pharmacokinetics: Area Under the Plasma Concentration Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) of Carfilzomib: Primary Analysis(Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15)
- Pharmacokinetics: Percentage of Extrapolation of AUC (AUCext) of Carfilzomib: Primary Analysis(Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15)
- Pharmacokinetics: Clearance at Steady State (CLss) of Carfilzomib: Primary Analysis(Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15)
- Pharmacokinetics: Volume of Distribution at Steady State (Vss) of Carfilzomib: Primary Analysis(Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15)
- Pharmacokinetics: Area Under the Plasma Concentration Time Curve (AUC) of Carfilzomib: Primary Analysis(Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15)
- Pharmacokinetics: Terminal Half-life (t1/2z) of Carfilzomib: Primary Analysis(Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15)
- Number of Participants With Anti-Drug Antibodies (ADA): Primary Analysis(From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: 111 weeks))
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs): LPLV Analysis(From first dose of study treatment administration (Day 1) up to 30 days post last dose of study treatment administration, up to 349 weeks for Kd arm and 356 weeks for IKd arm (maximum duration of treatment exposure))