Isatuximab in Combination With REGN2810 (Cemiplimab) in Patients With Advanced Malignancies

Study Overview
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Brief Summary
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Primary Objectives: To characterize the safety and tolerability of isatuximab in combination with REGN2810 in participants with metastatic, castration-resistant prostate cancer (mCRPC) who were naïve to anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1)-containing therapy, or non-small cell lung cancer (NSCLC) who progressed on anti-PD-1/PD-L1-containing therapy, and to confirm the recommended Phase 2 dose (RP2D). To assess the response rate of isatuximab in combination with REGN2810 in participants with either mCRPC who were anti-PD-1/PD-L1 therapy naive, or NSCLC who progressed on anti-PD-1/PD-L1 therapy, or of isatuximab as single agent in participants with mCRPC. Secondary Objectives: To evaluate the safety of the combination of isatuximab with REGN2810 or isatuximab monotherapy. To evaluate the immunogenicity of isatuximab and REGN2810. To characterize the pharmacokinetic (PK) profile of isatuximab single agent or in combination with REGN2810, and to characterize the PK of REGN2810 in combination with isatuximab. To assess overall efficacy of isatuximab in combination with REGN2810 or as a single agent.

Detailed Description
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The total study duration per participant was up to 28 months including an up to 28 days screening period, an up to 24 months treatment period, and a 3 months safety follow up period.

Official Title
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A Phase 1/2 Open-label, Multi-center, Safety, Preliminary Efficacy and Pharmacokinetic (PK) Study of Isatuximab (SAR650984) in Combination With REGN2810, or Isatuximab Alone, in Patients With Advanced Malignancies

Conditions
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Prostate Cancer, Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Isatuximab SAR650984
* Drug: Cemiplimab REGN2810


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must had a known diagnosis of either metastatic castration-resistant prostate cancer (mCRPC) or non-small cell lung cancer (NSCLC) with evidence of measurable disease. Failure of, inability to, or refusal to receive standard of care. Greater than or equal to (>=) 18 years of age. Exclusion Criteria: Prior exposure to isatuximab or participation in clinical studies with isatuximab. For participants with mCRPC, prior exposure to any agent (approved or investigational) that blocks the PD-1/PD-L1 pathway. Evidence of other immune related disease /conditions. History of non-infectious pneumonitis requiring steroids or current pneumonitis; history of the thoracic radiation. Had received a live-virus vaccination within 28 days of planned treatment start. Seasonal flu vaccines that do not contain live virus were permitted. Prior solid organ or hematologic transplant. Eastern Cooperative Oncology Group performance status (PS) >=2. Poor bone marrow reserve. Poor organ function. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Random assignment used only for allocation to Cohort A-1 or A-2
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: mCRPC/NSCLC<br>Isatuximab dose 1 and REGN2810 predefined dose | Drug: Isatuximab SAR650984<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>* Other names: Sarclisa;Drug: Cemiplimab REGN2810<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>|
| Experimental: Cohort A-1: mCRPC, isatuximab and REGN2810 combination<br>Participants with mCRPC will be given isatuximab dose determined in Phase 1 arm of study and REGN2810 predefined dose | Drug: Isatuximab SAR650984<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>* Other names: Sarclisa;Drug: Cemiplimab REGN2810<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>|
| Experimental: Cohort A-2: mCRPC, isatuximab monotherapy<br>Participants with mCRPC will be given isatuximab dose 2 | Drug: Isatuximab SAR650984<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>* Other names: Sarclisa;|
| Experimental: Phase 2 Cohort B: NSCLC<br>Participants with NSCLC will be given isatuximab dose determined in Phase 1 arm of study and REGN2810 predefined dose | Drug: Isatuximab SAR650984<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>* Other names: Sarclisa;Drug: Cemiplimab REGN2810<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>|
| Experimental: Possibly Phase 2 Cohort C: mCRPC<br>Isatuximab dose 3 will be given in combination with REGN2810 predefined dose or isatuximab dose 3 will be given as monotherapy in participants with mCRPC | Drug: Isatuximab SAR650984<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>* Other names: Sarclisa;Drug: Cemiplimab REGN2810<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>|
| Experimental: Possibly Phase 2 Cohort D: NSCLC<br>Isatuximab dose 3 will be given in combination with REGN2810 predefined dose | Drug: Isatuximab SAR650984<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>* Other names: Sarclisa;Drug: Cemiplimab REGN2810<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | DLTs: adverse events occurring during 1st treatment cycle, unless due to disease progression/to cause obviously unrelated to investigational medicinal product (IMP) which included:hematological abnormalities: Grade(G) 4 neutropenia(N) for 7/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. Non-hematological abnormalities: G4 non-hematologic AE, G>=2 uveitis, G3 non-hematological AE lasting greater than (>)3 days (except G3 fatigue, allergic reaction/hypersensitivity attributed to isatuximab or REGN2810 and G3 or G4 clinically non-significant laboratory abnormality), delay in initiation of Cycle 2 >14 days due to treatment related laboratory abnormalities/AE. Any other toxicity that Investigator and Sponsor deemed to be dose-limiting, regardless of grade, was also considered as DLT. | Cycle 1 (21 days) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | 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) was 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). TEAEs included both SAEs and non-SAEs. | From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years) | 
| Number of Participants With Laboratory Abnormalities: Hematological Parameters | Hematological parameters assessed were anemia, white blood cell (WBC) decreased, platelet count decreased, lymphocyte count decreased and neutrophil count decreased. Abnormality criteria was based on National Cancer Institute Common Terminology Criteria for Adverse Event version 4.03 (NCI-CTCAE v 4.03), where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Only those categories in which at least 1 participant had data were reported. | From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years) | 
| Number of Participants With Laboratory Abnormalities: Electrolytes | Abnormal electrolytes parameters assessed were hyponatremia, hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypoalbuminemia and hyperglycemia. Abnormality criteria was based on NCI-CTCAE v 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Only those categories in which at least 1 participant had data were reported. | From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years) | 
| Number of Participants With Laboratory Abnormalities: Renal Parameters | Abnormal renal parameters assessed were creatinine clearance (CrCl), creatinine increased and hyperuricemia. Creatinine clearance was assessed in categories: >=60 - less than (<) 90 milliliters per minute per 1.73 square meter (mL/min/1.73m^2), >=30 - <60 mL/min/1.73m^2, >=15 - <30 mL/min/1.73m^2 and <15 mL/min/1.73m^2. Creatinine increased and hyperuricemia abnormality criteria was based on NCI-CTCAE v 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. For all these 3 parameters, only those categories in which at least 1 participant had data were reported. | From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years) | 
| Number of Participants With Laboratory Abnormalities: Liver Function Parameters | Abnormal liver function parameters assessed were aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, alkaline phosphatase (ALP) increased, blood bilirubin (BB) increased. Abnormality criteria was based on NCI-CTCAE v 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Only those categories in which at least 1 participant had data were reported. | From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years) | 
| Overall Response Rate (ORR): Percentage of Participants With Overall Response | For participants with mCRPC, response was defined as achieving complete response (CR) or partial response (PR) as best overall response (BOR) for soft tissue assessed and confirmed by the Investigators and/or a prostate-specific antigen (PSA) decline of >=50 percent (%) from Baseline that was subsequently confirmed per Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. For participants with NSCLC, ORR was defined as the percentage of participants with CR or PR as BOR according to RECIST 1.1. criteria. Per RECIST 1.1. criteria, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to <10 millimeters (mm) and PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters. | From the date of randomization to the date of first documentation of progression or death due to any cause, whichever occurred first (maximum duration: up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab, Post Treatment | ADA response were categorized as treatment boosted ADA and treatment-induced ADA. Treatment boosted ADA was defined as pre-existing ADAs with a significant increase in the ADA titer during the study compared to the Baseline titer. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in participants without pre-existing ADA (including participants without pretreatment samples). | From Baseline up to 2 years | 
| Number of Participants With Anti-drug Antibodies (ADA) Response Against REGN2810, Post Treatment | ADA response were categorized as treatment boosted ADA and treatment-induced ADA. Treatment boosted ADA was defined as pre-existing ADAs with a significant increase in the ADA titer during the study compared to the Baseline titer. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in participants without pre-existing ADA (including participants without pretreatment samples). | From Baseline up to 2 years | 
| Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) After the First Infusion of Isatuximab | Cmax was defined as the maximum observed plasma concentration. Cmax analysis was done separately for isatuximab for participants with mCRPC and NSCLC. | At start of infusion (SOI), before actual end of infusion (EOI), EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1 | 
| Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) After the First Infusion of REGN2810 | Cmax was defined as the maximum observed plasma concentration. Cmax analysis was done separately for REGN2810 for participants with mCRPC and NSCLC. | At SOI, before actual EOI, EOI+4 hours, 72 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1 | 
| Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 168 Hours (AUC0-168 hr) After the First Administration of Isatuximab | AUC0-168 hr was defined as the area under the plasma concentration-time curve from time zero to 168h and was calculated using the trapezoidal method over the dosing interval (i.e., 7 days) for isatuximab alone. | At SOI, before actual EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1 | 
| Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 504 Hours (AUC0-504 hr) After the First Administration of REGN2810 | AUC0-504 hr was defined as the area under the plasma concentration-time curve from time zero to 504h and was calculated using the trapezoidal method over the dosing interval (i.e., 21 days) for REGN2810 alone. | At SOI, before actual EOI, EOI+4 hours, 72 hours, 168 hours, 336 hours and 504 hours post-dose on Day 1 of Cycle 1 | 
| Best Percent-change From Baseline in Tumor Burden | Tumor burden change was defined as the best percent-change from Baseline in a sum of the diameters (longest for non-nodal lesion, short axis for nodal lesions) for all target lesions. | Up to 2 years | 
| Duration of Response (DOR) | DOR: defined as time (in months) from date of first response (PR or CR in radiographic objective response, or PSA decline >=50% for participants with mCRPC) that was subsequently confirmed to the date of first disease progression (PD) or death, whichever occurred first. PD included radiographic disease progression or unequivocal clinical progression. RECIST 1.1 criteria was used to assess radiographic PD in participants with NSCLC and PCWG3 criteria for participants with mCRPC. Per RECIST 1.1 criteria, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target/non-target) must had reduction in short axis to <10 mm and PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (Baseline sum if that was smallest), sum with an absolute increase of at least 5 mm and appearance of 1 or more new lesions. | From the date of first response until disease progression or death, whichever occurred first (maximum duration: up to 2 years) | 
| Progression-free Survival (PFS) | For mCRPC participants, PFS was defined as the time (in months) from first study treatment administration to the date of first documented disease progression or the date of death from any cause, whichever occurred first. Disease progression included radiographic disease progression (per PCWG3 criteria) or unequivocal clinical progression. For NSCLC participants, PFS was defined as the time from first study treatment administration to the date of first documented radiographic progression (PD) (per RECIST 1.1) or the date of death from any cause, whichever occurred first. Per RECIST 1.1 criteria, PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the Baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5 mm. Appearance of 1 or more new lesions was also considered as progression. Analysis was performed using Kaplan-Meier method. | From the date of the first study treatment administration to the date of first documented disease progression or death of any cause, whichever occurred first (maximum duration: up to 2 years) | 
| Percentage of Participants With Disease Control (DC) >=6 Months | Disease control: defined as percentage of participants with confirmed CR/PR/stable disease (SD), as assessed by Investigator PCWG3 modified RECIST 1.1 criteria relative to total number of participants in analysis population. Per PCWG3 modified RECIST 1.1 criteria, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target/non-target) must had reduction in short axis to <10 mm, PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference Baseline sum diameters and SD: neither sufficient shrinkage from the Baseline to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum diameters while on study. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study, sum with an absolute increase of diameter of at least 5 mm and appearance of 1 or more new lesions. | From the date of first response to the date of first documented disease progression or death (due to any cause) (maximum duration: up to 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-CD38 monoclonal antibody