Isatuximab in Combination With Cemiplimab in Relapsed/Refractory Multiple Myeloma (RRMM) Patients

Study Overview
=================
Brief Summary
-----------------
Primary Objectives: To evaluate the safety and tolerability of the combination of isatuximab (also known as SAR650984) and cemiplimab (also known as REGN2810) in patients with relapse/refractory multiple myeloma. To compare the overall response of the combination of isatuximab and cemiplimab versus isatuximab alone in patients with RRMM based on International Myeloma Working Group (IMWG) criteria. Secondary Objectives: To evaluate the efficacy as assessed by clinical benefit rate (CBR), duration of response (DOR), time to response (TTR), progression free survival (PFS), and overall survival (OS). To assess the pharmacokinetics (PK) of isatuximab and cemiplimab when given in combination. To assess the immunogenicity of isatuximab and cemiplimab when given in combination.

Detailed Description
-----------------
The duration of the study for a patient will include a period for screening of up to 21 days and 3-month post treatment follow up. The cycle duration is 28 days. Patients will continue treatment until disease progression, unacceptable adverse events, consent withdrawal, or any other reason.

Official Title
-----------------
A Phase 1/2 Study to Evaluate Safety, Pharmacokinetics and Efficacy of Isatuximab in Combination With Cemiplimab in Patients With Relapsed/Refractory Multiple Myeloma

Conditions
-----------------
Plasma Cell Myeloma

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Patients must have a known diagnosis of multiple myeloma with evidence of measurable disease, as defined below: Serum M-protein ≥1 g/dL (≥0.5 g/dL in case of immunoglobulin A [IgA] disease), AND/OR Urine M-protein ≥200 mg/24 hours, OR In the absence of measurable M-protein, serum immunoglobulin free light chain ≥10 mg/dL, and abnormal serum immunoglobulin kappa lambda free light chain ratio (<0.26 or >1.65). Patients must have received prior treatment with an immunomodulatory drug (IMiD) (for ≥2 cycles or ≥2 months of treatment) and a proteasome inhibitor (PI) (for ≥2 cycles or ≥2 months of treatment). Patients must have received at least 3 prior lines of therapy (Note: Induction therapy and stem cell transplant ± maintenance will be considered as one line). Patient must have achieved MR or better with any anti-myeloma therapy (ie, primary refractory disease is not eligible). Exclusion criteria: Prior exposure to isatuximab or participated clinical studies with isatuximab. Prior exposure to any agent (approved or investigational) that blocks the programmed cell death-1 (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. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted. Has allogenic haemopoietic stem cell (HSC) transplant. Prior treatment with idelalisib (a PI3K inhibitor). Eastern Cooperative Oncology Group (ECOG) performance status (PS) >2. Poor bone marrow reserve. Poor organ function. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isatuximab/cemiplimab (Regimen 1)<br>Isatuximab on Days 1, 8, 15, and 22, then Days 1 and 15 in 28-day cycles up to disease progression. Cemiplimab on Days 1 and 15 in 28-day cycle up to disease progression. | 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: Isatuximab/cemiplimab (Regimen 2)<br>Isatuximab on Days 1, 8, 15, and 22, then Days 1 and 15 in 28-day cycles up to disease progression. Cemiplimab on Day 1 in 28-day cycle up to disease progression. | 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>|
| Active Comparator: Isatuximab<br>Isatuximab on Days 1, 8, 15 and 22, then Day 1 and 15 in 28-day cycles up to disease progression. | Drug: Isatuximab SAR650984<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>* Other names: Sarclisa;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLTs) | DLTs are following AEs in Cycle 1 unless due to disease progression or an obviously unrelated cause: Grade (G) 4 neutropenia >7 days; G 3 to 4 neutropenia with fever or documented infection; G 3 to 4 thrombocytopenia with bleeding requiring intervention; G 4 non-hematological AE; G ≥2 uveitis; G 3 non-hematological AE >3 days despite supportive care (with defined exceptions); Delay in initiation of the 2nd cycle >14 days for related laboratory abnormalities/AE | Up to 4 weeks | 
| Adverse events (AEs) and changes in laboratory tests and vital signs | Number of patients with AEs and changes in laboratory tests and vital signs according to the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) version 4.03 Grade scaling | Up to 90 days following the last administration of study treatment for ongoing related AE, ongoing serious AE and new related AE until resolution or stabilization | 
| Overall Response Rate (ORR) | ORR is defined as the proportion of patients with complete response (CR) (including sCR [stringent complete response]), very good partial response (VGPR) and partial response (PR) | Up to 6 months from last patient in (LPI) for primary efficacy analysis, and up to 12 months from LPI for the final analysis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) | CBR is defined as the proportion of patients with CR (including sCR), VGPR, PR and minimal response (MR) | Up to 6 months from LPI for primary efficacy analysis, and up to 12 months from LPI for the final analysis | 
| Duration of Response (DOR) | DOR is defined as the time from the date of the first response (≥PR) that is subsequently confirmed to the date of first confirmed disease progression or death, whichever happens first | Up to 6 months from LPI for primary efficacy analysis, and up to 12 months from LPI for the final analysis | 
| Time to Response (TTR) | TTR is defined as time from first study treatment administration to first response (≥PR) that is subsequently confirmed | Up to 6 months from LPI for primary efficacy analysis, and up to 12 months from LPI for the final analysis | 
| Progression Free Survival (PFS) | PFS is defined as time from the first study treatment administration to the date of first documentation of progressive disease that is subsequently confirmed or the date of death from any cause | Up to 6 months from LPI for primary efficacy analysis, and up to 12 months from LPI for the final analysis | 
| Overall Survival (OS) | OS defined as the time from the first study treatment administration to death from any cause | Up to 12 months from LPI for the final analysis | 
| Assessment of PK parameter: partial AUC | AUC is area under the drug concentration versus time curve | Up to 4 weeks | 
| Assessment of PK parameter: Cmax | Cmax is maximum drug concentration observed | Up to 4 weeks | 
| Antibodies to isatuximab | Levels of anti isatuximab antibodies in plasma samples will be determined | Up to 12 months from LPI for the final analysis | 
| Antibodies to cemiplimab | Levels of anti cemiplimab antibodies in serum samples will be determined | Up to 12 months from LPI for the final analysis | 

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