A Phase 1/2 Open-label, Multi-center, Safety, Preliminary Efficacy and Pharmacokinetic (PK) Study of Isatuximab in Combination With Other Anti-cancer Therapies in Participants With Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Sanofi
- 入组人数
- 58
- 试验地点
- 20
- 主要终点
- Number of Participants With Laboratory Abnormalities: Electrolytes
研究概览
简要总结
Primary Objectives:
Phase 1
-To characterize the safety and tolerability of isatuximab in combination with cemiplimab in participants with relapsed and refractory classic Hodgkin's lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL) or peripheral T-cell lymphoma (PTCL), and to confirm the recommended Phase 2 dose (RP2D).
Phase 2
- Cohort A1 (anti-programmed cell death protein 1/ligand 1 [PD-1/PD-L1] naïve cHL): To assess the complete remission (CR) rate of isatuximab in combination with cemiplimab.
- Cohort A2 (cHL progressing from PD-1/PD-L1), B (DLBCL) and C (PTCL): To assess the objective response rate (ORR) of isatuximab in combination with cemiplimab.
Secondary Objectives:
- To evaluate the safety of the RP2D of the combination of isatuximab with cemiplimab.
- To evaluate the safety of the combination of isatuximab with cemiplimab and radiotherapy in participants with cHL.
- To evaluate the immunogenicity of isatuximab and cemiplimab when given in combination.
- To characterize the pharmacokinetic (PK) profile of isatuximab and cemiplimab when given in combination.
- To assess overall efficacy of isatuximab in combination with cemiplimab and isatuximab in combination with cemiplimab and radiotherapy.
详细描述
The total study duration per participant was up to 28 months, including an up to 28-day screening period, an up to 96-week treatment period, and a 90-day safety follow up period.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 —（Child, 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 A2: cHL: Isatuximab + Cemiplimab
cHL, anti-PD-1/PD-L1 inhibitor progressor participants received isatuximab 10 mg/kg, IV infusion, QW in Cycle 1 and then Q2W from Cycle 2 to Cycle 6 (each cycle of 28 days) and Q3W from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 mg Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30, with optional radiotherapy until, unacceptable AEs or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of CR, whichever was longer) of delivery of investigational medicinal product(s) without documented PD, or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
干预措施: cemiplimab REGN2810 (Drug)
Cohort A1: cHL: Isatuximab + Cemiplimab
Classic Hodgkin's lymphoma (cHL), anti-programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitor naïve participants received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion once a week (QW) in Cycle 1 and then every 2 weeks (Q2W) from Cycle 2 to Cycle 6 (each cycle of 28 days), and then every 3 weeks (Q3W) from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 milligrams (mg) Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30, with optional radiotherapy until, unacceptable adverse events (AEs) or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of complete response [CR], whichever was longer) of delivery of investigational medicinal product(s) without documented progressive disease (PD), or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
干预措施: isatuximab SAR650984 (Drug)
Cohort A1: cHL: Isatuximab + Cemiplimab
Classic Hodgkin's lymphoma (cHL), anti-programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitor naïve participants received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion once a week (QW) in Cycle 1 and then every 2 weeks (Q2W) from Cycle 2 to Cycle 6 (each cycle of 28 days), and then every 3 weeks (Q3W) from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 milligrams (mg) Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30, with optional radiotherapy until, unacceptable adverse events (AEs) or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of complete response [CR], whichever was longer) of delivery of investigational medicinal product(s) without documented progressive disease (PD), or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
干预措施: cemiplimab REGN2810 (Drug)
Cohort A2: cHL: Isatuximab + Cemiplimab
cHL, anti-PD-1/PD-L1 inhibitor progressor participants received isatuximab 10 mg/kg, IV infusion, QW in Cycle 1 and then Q2W from Cycle 2 to Cycle 6 (each cycle of 28 days) and Q3W from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 mg Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30, with optional radiotherapy until, unacceptable AEs or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of CR, whichever was longer) of delivery of investigational medicinal product(s) without documented PD, or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
干预措施: isatuximab SAR650984 (Drug)
Cohort B: DLBCL: Isatuximab + Cemiplimab
Diffuse large B-cell lymphoma (DLBCL), anti PD-1/PD-L1 naïve participants received isatuximab 10 mg/kg, IV infusion, QW in Cycle 1 and then Q2W from Cycle 2 to Cycle 6 (each cycle of 28 days) and Q3W from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 mg Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30 until, unacceptable AEs or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of CR, whichever was longer) of delivery of investigational medicinal product(s) without documented PD, or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
干预措施: isatuximab SAR650984 (Drug)
Cohort B: DLBCL: Isatuximab + Cemiplimab
Diffuse large B-cell lymphoma (DLBCL), anti PD-1/PD-L1 naïve participants received isatuximab 10 mg/kg, IV infusion, QW in Cycle 1 and then Q2W from Cycle 2 to Cycle 6 (each cycle of 28 days) and Q3W from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 mg Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30 until, unacceptable AEs or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of CR, whichever was longer) of delivery of investigational medicinal product(s) without documented PD, or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
干预措施: cemiplimab REGN2810 (Drug)
Cohort C: PTCL: Isatuximab + Cemiplimab
Peripheral T-cell lymphoma (PTCL), anti PD-1/PD-L1 naïve participants received isatuximab 10 mg/kg, IV infusion, QW in Cycle 1 and then Q2W from Cycle 2 to Cycle 6 (each cycle of 28 days) and Q3W from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 mg Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30 until, unacceptable AEs or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of CR, whichever was longer) of delivery of investigational medicinal product(s) without documented PD, or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
干预措施: isatuximab SAR650984 (Drug)
Cohort C: PTCL: Isatuximab + Cemiplimab
Peripheral T-cell lymphoma (PTCL), anti PD-1/PD-L1 naïve participants received isatuximab 10 mg/kg, IV infusion, QW in Cycle 1 and then Q2W from Cycle 2 to Cycle 6 (each cycle of 28 days) and Q3W from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 mg Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30 until, unacceptable AEs or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of CR, whichever was longer) of delivery of investigational medicinal product(s) without documented PD, or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
干预措施: cemiplimab REGN2810 (Drug)
结局指标
主要结局
Number of Participants With Laboratory Abnormalities: Electrolytes
时间窗: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)
Electrolyte parameters assessed were hyponatremia, hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypoalbuminemia, hypoglycemia and hyperglycemia. Abnormal criteria was assessed as per the NCI-CTCAE v 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.
Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Cycle 1 (28 days)
DLTs: Adverse Events (AEs) occurring during 1st treatment cycle, unless due to disease progression or obviously unrelated cause which included: hematological abnormalities: Grade(G) 4 neutropenia(N) for 7 or more consecutive days, G3 to G4 N with fever (temperature greater than or equal to \[\>=\] 38.5 degree Celsius on more than 1 occasion) or microbiologically/radiographically documented infection, G3 to G4 thrombocytopenia with clinically significant bleeding requiring clinical intervention or non-hematological abnormalities: G 4 non-hematologic AE, G\>=2 uveitis, G3 non-hematological AE lasting greater than (\>)3 days, delay in initiation of Cycle 2 \>14 days due to treatment related laboratory abnormalities/AE. Any other AE that the study committee deemed to be dose-limiting, regardless of grade, was also considered as DLT.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs)
时间窗: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)
An 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. 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 treatment up to 30 days after the last dose of study treatment).
Number of Participants With Laboratory Abnormalities: Hematological Parameters
时间窗: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)
Hematological parameters assessed were anemia, white blood cell (WBC) decreased, platelet count decreased, lymphocyte count decreased, and neutrophil count decreased. Abnormality criteria was assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 NCI-CTCAE v 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.
Number of Participants With Laboratory Abnormalities: Renal Parameters
时间窗: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)
Abnormal renal parameters assessed were glomerular filtration rate (GFR) by class, creatinine increased and hyperuricemia. GFR by class was assessed in categories:\>=90 milliliter per minute per 1.73 meter square (mL/min/1.73m\^2) (Normal), \>=60 to \<90 mL/min/1.73m\^2 (Mild), \>=30 to \<60 mL/min/1.73m\^2 (Moderate), \>=15 to \<30 mL/min/1.73m\^2 (Severe), and \<15 mL/min/1.73m\^2 (End Stage Renal Disease). Abnormal criteria was assessed as per NCI-CTCAE v 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.
Cohort A2, B and C: Percentage of Participants With Objective Response (OR)
时间窗: From the date of randomization until disease progression, or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks)
Percentage of participants who had a CR or partial response (PR) as BOR using LRC, 2014. Per LRC, CR (PET-CT): complete MR in lymph nodes and extralymphatic sites with a score of 1, 2, or 3 with or without residual mass; no new lesions and no evidence of FDG-avid disease. CR (CT-response): target nodes/nodal masses of lymph nodes, extralymphatic sites regressed to \<=1.5cm LDi; absence of non-measured lesion; organ enlargement regressed to normal; no new lesions; normal bone marrow morphology. PR (PET-CT): partial MR in lymph nodes and extralymphatic sites; no new lesions and residual uptake higher than uptake. PR (Per CT): lymph nodes, extralymphatic sites\>=50% decrease in sum of product of perpendicular diameters (SPD), extranodal sites; if lesion is too small to measure on CT,assign5mm\*5mm as default; if no longer visible:0\*0mm; Node\>5mm\*5mm but smaller than normal, use actual measurement; absent/regressed non-measured lesions; no increase; spleen regressed by\>50% or no new lesions.
Number of Participants With Laboratory Abnormalities: Liver Function Parameters
时间窗: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)
Abnormal liver function parameters assessed were aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, alkaline phosphatase (ALP) increased, blood bilirubin (BB) increased. Abnormal criteria was assessed as per NCI-CTCAE v 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.
Cohort A1: Percentage of Participants With Complete Response (CR)
时间窗: From the date of randomization until disease progression or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks)
Percentage of participants who had a CR as a best overall response (BOR) using the Lugano response criteria (LRC) 2014 (based on PET-CT and CT responses). Per LRC, CR based on PET-CT response was defined as complete metabolic response (MR) in lymph nodes and extralymphatic sites with a score of 1, 2, or 3 with or without residual mass, on 5-point scale (5PS), where, 1= no uptake above background; 2 = uptake \<=mediastinum; 3 = uptake \> mediastinum but \<= liver; 4 = uptake moderately \> liver; 5 = uptake markedly higher than liver and/or new lesions; no new lesions and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. CR based on CT-response was defined as target nodes/nodal masses of lymph nodes, extralymphatic sites regressed to \<=1.5 cm in longest dimension transverse diameter of lesion (LDi); absence of non-measured lesion; organ enlargement regressed to normal; no new lesions; normal bone marrow morphology; if indeterminate, immunohistochemistry negative.
次要结局
- Pharmacokinetics (PK) Parameter: Plasma Concentration of Isatuximab at End of Infusion (CEOI)(End of infusion (EOI up to 3 hours) on Day 2 of Cycle 1)
- PK Parameter: Time to Reach Cmax (Tmax) After the First Infusion of Isatuximab(At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1)
- PK Parameter: Time of Clast (Tlast) After the First Infusion of Isatuximab(At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1)
- PK Parameter: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUC0-144 Hours) After the First Infusion of Isatuximab(At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1)
- PK Parameter: Serum Concentration of Cemiplimab at End of Infusion (CEOI)(EOI (up to 30 minutes [min]) on Day 1 of Cycle 1)
- PK Parameter: Area Under the Serum Concentration (AUClast) Versus Time Curve After the First Infusion of Cemiplimab(At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1)
- Percent Change From Baseline in Tumor Burden(Up to 103 weeks)
- Percentage of Participants With Disease Control (DC)(From the date of first response until disease progression or death, or study cut-off date whichever occurred first (maximum duration: up to 103 weeks))
- Number of Participants With Treatment-Induced and Treatment Boosted Antidrug Antibodies (ADA) Against Cemiplimab(From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks))
- PK Parameter: Maximum Observed Plasma Concentration (Cmax) After the First Infusion of Isatuximab(At Start of infusion (SOI; 0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1)
- PK Parameter: Area Under the Plasma Concentration (AUClast) Versus Time Curve After the First Infusion of Isatuximab(At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1)
- PK Parameter: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab(At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1)
- Number of Participants With Treatment-Induced and Treatment Boosted Antidrug Antibodies (ADA) Against Isatuximab(From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks))
- PK Parameter: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUC0-168 Hours) After the First Infusion of Isatuximab(At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1)
- PK Parameter: Plasma Trough Concentration (Ctrough) of Isatuximab(Pre-infusion on Cycle1:Day 2, 8, 15, & 22, Cycle 2:Day 1 &15, Cycle 3:Day 1 &15, Cycle 4:Day 1 &15, Cycle 5 Day1,Cycle 6 Day1,Cycle 7 Day 1, Cycle 8 Day1, Cycle 9 Day1, Cycle 10 Day1, Cycle 11 Day1, Cycle14 Day1, Cycle 17 Day1, Cycle 20 Day1,Cycle 23 Day1)
- PK Parameter: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Cemiplimab(At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1)
- PK Parameter: Serum Trough Concentration (Ctrough) of Cemiplimab(Pre-infusion on Cycle 1:Day 1 & Day15,Cycle 2:Day 1 & Day 15,Cycle 3:Day 1 & Day 15,Cycle 4:Day 1 & Day15,Cycle 5 Day 1,Cycle 6 Day 1,Cycle7 Day1,Cycle 8 Day 1,Cycle 9 Day1,Cycle 10 Day1,Cycle11 Day1,Cycle14 Day 1,Cycle 17 Day1,Cycle20 Day 1,Cycle 23 Day1)
- Cohort A1 and A2: Percentage of Participants With Objective Response(From the date of randomization until disease progression, or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks))
- PK Parameter: Maximum Observed Concentration (Cmax) After the First Infusion of Cemiplimab(At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1)
- PK Parameter: Area Under the Serum Concentration Versus Time Curve Over the Dosing Interval (AUC0-336 Hours) After the First Infusion of Cemiplimab(At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1)
- Duration of Response (DOR)(From the date of first response until disease progression or death, or study cut-off date whichever occurred first (maximum duration: up to 103 weeks))
- PK Parameter: Time to Reach Cmax (Tmax) After the First Infusion of Cemiplimab(At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1)
- PK Parameter: Time of Clast (Tlast) After the First Infusion of Cemiplimab(At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1)
- Progression Free Survival (PFS)(From the date of randomization until disease progression, or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks))
- Cohort A1 and A2: Percentage of Participants With Complete Response(From the date of randomization until disease progression, or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks))