A Phase 1b/2 Study to Evaluate the Safety, Pharmacokinetics, and Preliminary Efficacy of Isatuximab (SAR650984) in Patients Awaiting Kidney Transplantation
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Sanofi
- 入组人数
- 23
- 试验地点
- 6
- 主要终点
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs)
研究概览
简要总结
Primary Objectives:
- Phase 1: To characterize the safety and tolerability of isatuximab in kidney transplant candidates.
- Phase 2: To evaluate the efficacy of isatuximab in desensitization of participants awaiting kidney transplantation.
Secondary Objectives:
- Phase 2: To characterize the safety profile of isatuximab in kidney transplant candidates.
- To characterize the pharmacokinetic (PK) profile of isatuximab in kidney transplant candidates.
- To evaluate the immunogenicity of isatuximab.
- To assess the overall efficacy of isatuximab in desensitization of participants awaiting kidney transplantation.
详细描述
The study had a screening period of up to 28 days, a treatment period of up to 12 weeks, a site visit FUP of up to 26 weeks, and an extended follow-up (FUP) until study cut-off.
The study duration involved site visit per participant (i.e., screening, treatment, site visit FUP was approximately 42 weeks.
The study duration included extended FUP per participant was approximately 97.7 weeks (depending on when the participant was enrolled).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（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
Cohort A: Participants with cPRA >=99.90%
Participants with calculated panel reactive antibodies (cPRA) >=99.90% (indicating active candidates on kidney transplant waitlist) received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion, once weekly (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then every 2 weeks (Q2W) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events (AEs) or participant's decision to stop the treatment (maximum treatment duration: 13 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Cohort A: Participants with cPRA >=99.90%
Participants with calculated panel reactive antibodies (cPRA) >=99.90% (indicating active candidates on kidney transplant waitlist) received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion, once weekly (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then every 2 weeks (Q2W) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events (AEs) or participant's decision to stop the treatment (maximum treatment duration: 13 weeks).
干预措施: Acetaminophen (paracetamol) or equivalent (Drug)
Cohort A: Participants with cPRA >=99.90%
Participants with calculated panel reactive antibodies (cPRA) >=99.90% (indicating active candidates on kidney transplant waitlist) received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion, once weekly (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then every 2 weeks (Q2W) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events (AEs) or participant's decision to stop the treatment (maximum treatment duration: 13 weeks).
干预措施: Ranitidine or equivalent (Drug)
Cohort A: Participants with cPRA >=99.90%
Participants with calculated panel reactive antibodies (cPRA) >=99.90% (indicating active candidates on kidney transplant waitlist) received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion, once weekly (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then every 2 weeks (Q2W) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events (AEs) or participant's decision to stop the treatment (maximum treatment duration: 13 weeks).
干预措施: Diphenhydramine or equivalent (Drug)
Cohort A: Participants with cPRA >=99.90%
Participants with calculated panel reactive antibodies (cPRA) >=99.90% (indicating active candidates on kidney transplant waitlist) received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion, once weekly (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then every 2 weeks (Q2W) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events (AEs) or participant's decision to stop the treatment (maximum treatment duration: 13 weeks).
干预措施: Methylprednisolone or equivalent (Drug)
Cohort A: Participants with cPRA >=99.90%
Participants with calculated panel reactive antibodies (cPRA) >=99.90% (indicating active candidates on kidney transplant waitlist) received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion, once weekly (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then every 2 weeks (Q2W) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events (AEs) or participant's decision to stop the treatment (maximum treatment duration: 13 weeks).
干预措施: Montelukast or equivalent (Drug)
Cohort B: Participants with cPRA 80.00% to 99.89%
Participants with cPRA between 80.00% to 99.89% (indicating active candidates on kidney transplant waitlist with no living donor cleared for donation) received isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days) until unacceptable AEs or participant's decision to stop the treatment (maximum treatment duration: 13 weeks).
干预措施: Isatuximab SAR650984 (Drug)
Cohort B: Participants with cPRA 80.00% to 99.89%
Participants with cPRA between 80.00% to 99.89% (indicating active candidates on kidney transplant waitlist with no living donor cleared for donation) received isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days) until unacceptable AEs or participant's decision to stop the treatment (maximum treatment duration: 13 weeks).
干预措施: Acetaminophen (paracetamol) or equivalent (Drug)
Cohort B: Participants with cPRA 80.00% to 99.89%
Participants with cPRA between 80.00% to 99.89% (indicating active candidates on kidney transplant waitlist with no living donor cleared for donation) received isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days) until unacceptable AEs or participant's decision to stop the treatment (maximum treatment duration: 13 weeks).
干预措施: Ranitidine or equivalent (Drug)
Cohort B: Participants with cPRA 80.00% to 99.89%
Participants with cPRA between 80.00% to 99.89% (indicating active candidates on kidney transplant waitlist with no living donor cleared for donation) received isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days) until unacceptable AEs or participant's decision to stop the treatment (maximum treatment duration: 13 weeks).
干预措施: Diphenhydramine or equivalent (Drug)
Cohort B: Participants with cPRA 80.00% to 99.89%
Participants with cPRA between 80.00% to 99.89% (indicating active candidates on kidney transplant waitlist with no living donor cleared for donation) received isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days) until unacceptable AEs or participant's decision to stop the treatment (maximum treatment duration: 13 weeks).
干预措施: Methylprednisolone or equivalent (Drug)
Cohort B: Participants with cPRA 80.00% to 99.89%
Participants with cPRA between 80.00% to 99.89% (indicating active candidates on kidney transplant waitlist with no living donor cleared for donation) received isatuximab 10 mg/kg, IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then Q2W for subsequent treatment cycles (each cycle of 28 days) until unacceptable AEs or participant's decision to stop the treatment (maximum treatment duration: 13 weeks).
干预措施: Montelukast or equivalent (Drug)
结局指标
主要结局
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs)
时间窗: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had to have a causal relationship with the treatment. Serious adverse events (SAEs) were any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (defined as the time from the first dose of study drug until study cut-off date).
Number of Participants With Hematological Abnormalities
时间窗: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Abnormal hematological parameters assessed were anemia, platelet count decreased, neutrophil count decreased, lymphocyte count decreased and monocytes. The hematological abnormality grades were based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. Monocytes were assessed as per potentially clinically significant abnormality (PCSA) criteria defined as: greater than (\>) 0.7\*10\^9/L.
Number of Participants With Renal Function Abnormalities
时间窗: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Abnormal renal parameters assessed were creatinine increased and estimated Glomerular Filtration Rate (eGFR). The renal function abnormality grades were based on NCI-CTCAE, Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. eGFR was assessed as per PCSA criteria: 60 (less than equal to) \<= to less than (\<) 90 milliliter/minute/1.73 meter square (mL/min/1.73m\^2) (Mild), 30\<= to \<60 mL/min/1.73m\^2 (Moderate), 15\<=to \<30 mL/min/1.73m\^2 (Severe), \<15 mL/min/1.73m\^2 (End Stage Renal Disease).
Number of Participants With Abnormal Electrolytes Parameters
时间窗: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Abnormal electrolyte parameters assessed were hypernatremia, hyponatremia, hyperkalemia, hypokalemia, hypercalcemia, hypocalcemia, blood bicarbonate decreased, hypermagnesemia, hypomagnesemia and chloride. The abnormal grades were based on NCI-CTCAE, Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. Chloride was estimated as per PCSA criteria: \<80 millimoles per liter (mmol/L) and \>115 mmol/L.
Number of Participants With Abnormal Metabolism Parameters
时间窗: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Abnormal metabolism parameters assessed were hypoglycemia, hypoalbuminemia and glycated Hemoglobin (HbA1c). The abnormal grades were based on NCI-CTCAE, Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. HbA1c was estimated as per PCSA criteria: \>8%.
Number of Participants With Liver Function Abnormalities
时间窗: From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks)
Abnormal liver function parameters assessed were Alanine aminotransferase (ALT) increased, Aspartate aminotransferase (AST) increased, Alkaline phosphatase (ALP) increased, and Total bilirubin (TB) increased. The abnormal grades were based on NCI-CTCAE, Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.
Percentage of Participants With Response
时间窗: From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks)
Response was defined as the percentage of participants meeting at least one of the predefined desensitization efficacy criteria as measured by single antigen bead (SAB) assay as follows: reduction in cPRA resulting in at least 100% increase of likelihood of finding a compatible donor; reduction in antibody titer (\>=75% reduction from Baseline) to achieve target cPRA; elimination of \>=1 human leukocyte antigen (HLA) antibody (i.e., mean fluorescence intensity \[MFI\] reduced to \<2000) as measured by a SAB assay, for antibodies with Baseline MFI \>=3000.
次要结局
- Pharmacokinetics (PK) Parameters: Concentration Observed at the End of First Intravenous Infusion (Ceoi) of Isatuximab(At End of infusion on Cycle 1 Day 1)
- PK Parameters: Maximum Concentration Observed (Cmax) After the First Infusion of Isatuximab(At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1)
- PK Parameters: Time Taken to Reach Cmax (Tmax) After the First Infusion of Isatuximab(At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1)
- PK Parameters: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab(At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1)
- PK Parameters: Time of Clast (Tlast) After First Infusion of Isatuximab(At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1)
- PK Parameters: Trough Plasma Concentrations (Ctrough) of Isatuximab(Cycle 2 Day 1)
- PK Parameters: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 168 Hours Over the Dosing Interval (AUC0-168 Hours) After First Infusion of Isatuximab(At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1)
- Number of Participants With Anti-drug Antibodies (ADA) Against Isatuximab(From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks))
- Duration of Response (DOR)(From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks))
- Number of Participants Achieving Target cPRA(From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks))
- Duration for Achieving Target cPRA(From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks))
- Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction(From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks))
- Time to First Transplant Offer(From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks))
- Time to Transplant(From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks))
- Number of Kidney Transplant Offers(From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks))
- Time to First Antibody Mediated Rejection (AMR) Episode(From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks))
- Percentage of Participants Who Experienced Any Antibody Mediated Rejection (AMR)(From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks))
- Number of Participants With Graft Survival at 6 Months Post-Transplant(At 6 Months post-transplant)