A Phase I/2 Dose Escalation Safety, Pharmacokinetic and Efficacy Study of Multiple Intravenous Administrations of a Humanized Monoclonal Antibody (SAR650984) Against CD38 in Patients With Selected CD38+ Hematological Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Sanofi
- 入组人数
- 351
- 试验地点
- 59
- 主要终点
- Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
Primary Objective:
Phase 1:
To determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) of SAR650984 (Isatuximab).
Phase 2 (stage 1):
To evaluate the activity of single-agent Isatuximab at different doses/schedules and to select dose and regimen to further evaluate the overall response rate (ORR) of Isatuximab as single agent or in combination with dexamethasone.
Phase 2 (stage 2):
To evaluate the activity in terms of overall response rate (ORR) of Isatuximab at the selected dose/schedule from stage1, as single agent (ISA arm) and in combination with dexamethasone (ISAdex arm).
Secondary Objectives:
Phase 1:
- To characterize the global safety profile including cumulative toxicities.
- To evaluate the pharmacokinetic (PK) profile of Isatuximab in the proposed dosing schedule(s).
- To assess the pharmacodynamics (PD), immune response, and preliminary disease response.
Phase 2 (stage 1): to evaluate the following objectives for Isatuximab as single agent:
- Safety
- Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival.
Phase 2 (stage 2): to evaluate the following objectives in each arm (ISA and ISAdex):
- Safety
- Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival.
- Participant-reported changes in health-related quality of life, symptoms of multiple myeloma and generic health status.
- Pharmacokinetic profile of Isatuximab.
- Immunogenicity of Isatuximab.
- Investigate the relationship between CD38 receptor density and CD38 receptor occupancy (Stage 1 only) on multiple myeloma cells and parameters of clinical response.
详细描述
The Phase 1 study duration for an individual participant included a screening period for inclusion of up to 2 weeks, treatment with Isatuximab QW (every week) or Q2W (every 2 weeks) unless discontinued earlier due to safety or disease progression. Participants were followed for a minimum of 30 days following the last use of study drug or more than 30 days in case of unresolved toxicity, or up to initiation of another anticancer treatment.
The Phase 2 study duration for an individual participant included a screening period for inclusion of up to 3 weeks, then a treatment period and a follow up period. Treatment was continued until disease progression, unacceptable adverse reactions or other reasons for discontinuation. Participants were followed every 3 months following the last use of study drug until death or study cutoff, whichever came first.
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
- None
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Phase 1: Isatuximab 20 mg/kg Q2W
Participants with CD38+ HM, received Isatuximab 20 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase 1:Isatuximab <=1 mg/kg Q2W
Participants with CD38+ hematological malignancies (HM), received Isatuximab at any one of the dose less than or equal to (<=) 1 milligram per kilogram (mg/kg) (i.e. either 0.0001 mg/kg or 0.001 mg/kg or 0.01 mg/kg or 0.03 mg/kg or 0.1 mg/kg or 0.3 mg/kg or 1 mg/kg) as intravenous (IV) infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal by participant, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase 1: Isatuximab 3mg/kg Q2W
Participants with CD38+ HM, received Isatuximab 3 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase 1: Isatuximab 5 mg/kg Q2W
Participants with CD38+ HM, received Isatuximab 5 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase1:Isatuximab (CD38+HM and Standard Risk Multiple Myeloma)
Participants with CD38+ HM along with participants with standard risk multiple myeloma were included this arm and, received Isatuximab 10 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase 1:Isatuximab (CD38 + HM and High Risk Multiple Myeloma)
Participants with CD38+ HM along with participants with high risk multiple myeloma, received Isatuximab 10 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase 1: Isatuximab 10 mg/kg QW
Participants with CD38+ HM, received Isatuximab 10 mg/kg, as IV infusion QW, i.e. on Day 1 and 8 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase 1: Isatuximab 20 mg/kg QW
Participants with CD38+ HM, received Isatuximab 20 mg/kg, as IV infusion QW, i.e. on Day 1 and 8 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase 2 Stage 1a: Isatuximab 3 mg/kg Q2W
Participants with multiple Myeloma received Isatuximab 3 mg/kg, as IV infusion on Day 1 and Day 15 of each 28-day cycle until unacceptable adverse event (AE), disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 414 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase 2 Stage 1a: Isatuximab 10 mg/kg Q2W
Participants with multiple Myeloma received Isatuximab 10 mg/kg, as IV infusion on Day 1 and Day 15 of each 28-day cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 414 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase2 Stage1a:Isatuximab 10mg/kg Q2W; Then Q4W
Participants with multiple Myeloma received Isatuximab 10 mg/kg, as IV infusion Q2W, i.e. on Day 1 and Day 15 of Cycle 1 and 2 (each cycle 28 days), then every 4 week (Q4W), i.e. on Day 1 of each 28-days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 414 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase 2 Stage 1b: Isatuximab 20mg/kg QW and Then Q2W
Participants with multiple Myeloma received Isatuximab 20 mg/kg, as IV infusion QW, i.e. on Day 1, 8, 15 and 22 of Cycle 1 and 2 (each cycle 28 days), then Q2W, i.e. on Day 1 and Day 15 of each 28-days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 92 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase 2 Stage 2: Isatuximab Alone
Participants with relapsed or relapsed/refractory multiple myeloma (RRMM), received Isatuximab 20 mg/kg, as IV infusion on Day 1, 8, 15 and Day 22 of Cycle 1 (28 days) and then on Day 1 and 15 of each subsequent 28-day cycles until unacceptable AE, disease progression, poor compliance to the study protocol, study termination, lost to follow up or investigator's decision (maximum exposure: 301 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase 2 Stage 2: Isatuximab + Dexamethasone
Participants with relapsed or RRMM, received Isatuximab 20 mg/kg, as IV infusion on Day 1, 8, 15 and Day 22 of Cycle 1 (28 days) and then on Day 1 and 15 of each subsequent 28-day cycles along with dexamethasone: tablet or as IV infusion (40 mg/day for less than [<] 75 years of age; 20 mg/day [greater than or equal to [>=] for 75 years of age) on Days 1, 8, 15 and 22 of each 28 days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination, lost to follow up or investigator's decision (maximum exposure: 301 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Phase 2 Stage 2: Isatuximab + Dexamethasone
Participants with relapsed or RRMM, received Isatuximab 20 mg/kg, as IV infusion on Day 1, 8, 15 and Day 22 of Cycle 1 (28 days) and then on Day 1 and 15 of each subsequent 28-day cycles along with dexamethasone: tablet or as IV infusion (40 mg/day for less than [<] 75 years of age; 20 mg/day [greater than or equal to [>=] for 75 years of age) on Days 1, 8, 15 and 22 of each 28 days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination, lost to follow up or investigator's decision (maximum exposure: 301 weeks).
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Day 1 of Cycle 1 up to Day 14 of Cycle 2
DLTs were assessed using the national cancer institute common terminology criteria for adverse events (NCI-CTCAE) version 4.03. DLTs were defined as any Grade 3 or higher non-hematological toxicity (with the exception of allergic reaction/hypersensitivity), Grade 4 neutropenia and/or Grade 4 thrombocytopenia lasting longer than 5 days, attributed to isatuximab. Any other toxicity that the Investigator and the Sponsor deemed to be dose-limiting, regardless of the grade, was also considered as DLT.
Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
时间窗: From Baseline up to 30 days after the last dose (maximum duration: 120 weeks )
Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened during the on-treatment period which was defined as the period from the time of first dose of study treatment until 30 days after the last dose of study treatment.
Phase 2 Stage 1: Percentage of Participants With Overall Response (OR) According to International Myeloma Working Group (IMWG) Uniform Response Criteria
时间窗: From the date of randomization until disease progression or death or data cut-off (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for Stage 1b arm)
OR defined as participants with stringent complete response (sCR) or complete response (CR) or very good partial response (VGPR) or partial response (PR) . Based on IMWG, CR: Negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and \<=5% plasma cells in bone marrow; sCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein and urine M-protein level \<100 mg/24 hours; PR: \>=50% reduction of serum M-Protein and reduction in urinary M-protein by \>=90% or to \<200 mg/24 hours; \>=50% decrease in the difference between involved and uninvolved FLC levels in place of the M-protein criteria or a \>=50% reduction in plasma cells in place of M-protein if present at baseline.
Phase 2 Stage 2: Percentage of Participants With Overall Response According to Updated IMWG Response Criteria
时间窗: From the date of randomization to date of death from any cause (maximum duration: 97 weeks)
OR: participants with sCR or CR or VGPR or PR. As per updated IMWG, CR: Negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and \<=5% plasma cells in bone marrow; normal FLC ratio of 0.26-1.65 in participants with only FLC disease; sCR: CR and normal FLC ratio and no clonal cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein and urine M-protein level \<100 mg/24 hours, \>90% decrease in the difference between involved and uninvolved FLC levels; PR: \>=50% reduction of serum M-Protein and reduction in urinary M-protein by \>=90% or to \<200 mg/24 hours; \>=50% decrease in the difference between involved and uninvolved FLC levels in place of M-protein criteria or \>=50% reduction in plasma cells in place of M-protein if present at baseline.
次要结局
- Phase 2 Stage 2: Percentage of Participants With Clinical Benefit(From the date of randomization to the date of first documentation of progression or death (maximum duration: 97 weeks ))
- Phase 2 Stage 1: Progression Free Survival (PFS)(From the date of the first dose administration until progression or death, whichever occurred first (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm))
- Phase 2 Stage 2: Progression Free Survival(From the date of the first dose administration until progression or death, whichever occurred first (maximum duration: 97 weeks))
- Phase 2 Stage 2: Overall Survival(From the date of randomization to date of death from any cause (maximum duration: 97 weeks))
- Phase 2 Stage 1: Overall Survival (OS)(From the date of randomization to date of death from any cause (maximum duration 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm))
- Phase 2 Stage 1: Change From Baseline in Health Related Quality of Life (HRQL) European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Scores: Global Health Status(Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10 and End of Treatment (EOT: anytime up to 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm))
- Phase 2 Stage 1: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Multiple Myeloma Specific Module With 20 Items (EORTC QLQ-MY20) Scores: Disease Symptom Subscale Score(Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10 and EOT (anytime up to 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm))
- Phase 2 Stage 1: Change From Baseline in Euro Quality of Life 5 Dimension (EQ-5D) Generic Health Status - Visual Analogue Scale Scores(Baseline, Day 1 of Cycles 4, 7, 10, 13, 16, 19, and EOT (anytime up to 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm))
- Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 1 Week Interval(Pre-dose, at the end of infusion, 1 hour and 168 hours post dose on Day 1 of Cycle 1)
- Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 2 Weeks Interval(Cycle 1, Day 1: pre-dose, at the end of infusion, 168 and 336 hours post-infusion)
- Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 4 Weeks Interval(Cycle 1, Day 1: pre-dose, at the end of infusion, 168, 336, and 672 hours post-infusion)
- Pharmacokinetic Assessment: Phase 2 Stage 2: Plasma Concentration of Isatuximab Before Treatment Administration (Ctrough)(At Days 7, 14 and 28)
- Pharmacokinetic Assessment: Phase 2 Stage 2: Accumulation Ratio of Isatuximab Based on Ctrough(Cycle 2, Day 1; Cycle 1, Day 8; Cycle 4, Day 1)
- Immunogenicity Assessment: Phase 2 Stage 2: Number of Participants With Anti-drug Antibodies to Isatuximab(Up to 97 weeks)
- Pharmacokinetic (PK) Assessment: Phase 1: Plasma Concentration of Isatuximab Observed at the End of an Intravenous Infusion (Ceoi)(Cycle 1 Day 1 and Cycle 3 Day 1: At the end of infusion)
- PK Assessment: Phase 1: Maximum Observed Plasma Concentration (Cmax) of Isatuximab(For Q2W:Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 3, 7, 24, 48 and 168 hr post-infusion; For QW: Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 4, 24, 48, 72 and 168 hr post-infusion)
- PK Assessment: Phase 1: Time to Reach Maximum Plasma Concentration Observed (Tmax) of Isatuximab(For Q2W:Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 3, 7, 24, 48 and 168 hr post-infusion; For QW: Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 4, 24, 48, 72 and 168 hr post-infusion)
- PK Assessment: Phase 1: Plasma Concentration of Isatuximab at Week 1, 2 and 3(Week 1, 2 and 3)
- PK Assessment: Phase 1: Predicted Cumulative Area Under the Plasma Concentration Curve (AUC) of Isatuximab Over the First Week (0-168 Hours) (AUC1W)(For Q2W:Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 3, 7, 24, 48 and 168 hr post-infusion; For QW: Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 4, 24, 48, 72 and 168 hr post-infusion)
- PK Assessment: Phase 1: Predicted Cumulative Area Under the Plasma Concentration Curve (AUC) of Isatuximab Over the First 2 Weeks (0-336 Hours) (AUC2W)(For Q2W:Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 3, 7, 24, 48 and 336 hr post-infusion; For QW: Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 4, 24, 48, 72 and 336 hr post-infusion)
- Pharmacodynamic (PD) Assessment: Phase 1: Change From Baseline in Serum/Plasma Markers(Cycle 1 Day 1)
- Immunogenicity Assessment: Phase 1: Number of Participants With Treatment-Emergent And Treatment-Boosted Anti-drug Antibodies (ADA) Response(Up to 120 weeks)
- Clinical Assessment: Phase 1: Percentage of Participants With Overall Response and Clinical Benefit: Assessed Using European Society for Blood and Marrow Transplantation (EBMT) Criteria(From the date of randomization to the date of first documentation of progression or death (due to any cause) (maximum duration: 120 weeks))
- Clinical Assessment: Phase 1: Duration of Response (DOR)(From the date of first response to the date of first documentation of progression or death (due to any cause) (maximum duration: 120 weeks))
- Clinical Assessment: Phase 1: Time to First Response (TTR)(From the date of first dose administration to the date of first response or death (due to any cause) (maximum duration: 120 weeks))
- Clinical Assessment: Phase 1: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (Karnofsky Performance Status)-Shift From Baseline Value to Best Value During Treatment(At baseline, during treatment (Day 1 up to 120 weeks))
- Clinical Assessment: Phase 1: Number of Participants With Eastern Cooperative Oncology Group Performance Status (Karnofsky Performance Status)-Shift From Baseline Value to Worst Value During Treatment(At baseline, during treatment (up to 120 weeks))
- Phase 2 Stage 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)(From Baseline up to 30 days after the last dose (maximum duration: 414 weeks for Stage 1a and 92 weeks for Stage 1b))
- Phase 2 Stage 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs)(From Baseline up to 30 days after the last dose (maximum duration: 301 weeks))
- Phase 2 Stage 1: Duration of Response(From the date of first response until disease progression or death or data cut-off (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm))
- Phase 2 Stage 2: Duration of Response(From the date of first response until disease progression or death or data cut-off (maximum duration: 97 weeks))
- Phase 2 Stage 1: Percentage of Participants With Clinical Benefit(From the date of randomization to the date of first documentation of progression or death (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm))