Trial Outcomes & Findings for Isatuximab in Combination With Cemiplimab in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (NCT NCT03194867)

NCT ID: NCT03194867

Last Updated: 2024-06-14

Results Overview

Potential DLTs were defined as the occurrence of any of the following adverse reactions at first treatment cycle, unless due to disease progression or obviously unrelated cause: Hematological DLTs: Grade(G) 4 neutropenia (N) for more than 7 consecutive days, G3 to G4 N complicated by 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 associated with clinically significant bleeding requiring clinical intervention or Non-hematological DLTs: G4 non-hematologic AE, G\>=2 uveitis, G3 non-hematological AE lasting greater than (\>)3 days despite optimal care support, delay in initiation of Cycle 2 \>14 days due to treatment related laboratory abnormalities/AE. Any other AE that the investigator/study committee deemed to be dose-limiting, regardless of grade, was also considered as DLT.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

109 participants

Primary outcome timeframe

Cycle 1 Day 1 to Day 28

Results posted on

2024-06-14

Participant Flow

Participants were screened at 30 sites. The study was conducted i.e. participants were randomized at 29 sites in 10 countries. A total of 3 participants in Phase 1 and 106 participants in Phase 2 were enrolled (Phase 1)/randomized (Phase 2) from 21 Feb 2018 to 20 Mar 2019.

The study consisted of 2 phases: Phase 1 confirmed the feasibility of isatuximab/cemiplimab combination and Phase 2 further evaluated safety, efficacy and pharmacokinetics (PK) of combination versus isatuximab monotherapy. Participants in Phase 2 were randomized in a 1:1:1 ratio to receive either isatuximab monotherapy or combination therapy. The duration of study for a participant included a screening period (up to 21 days) and 3-month post treatment follow-up. Each cycle duration was 28 days.

Participant milestones

Participant milestones
Measure	Phase 1: Isatuximab + Cemiplimab Once Every 2 Weeks (Q2W) Participants received isatuximab 10 milligram/ kilogram (mg/kg) intravenous (IV) infusion once weekly for 4 weeks (QWx4) followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable adverse events (AEs), consent withdrawal, or any other reason.	Phase 2: Isatuximab Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W) Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Overall Study STARTED	3	34	36	36
Overall Study Randomized and Treated	3	34	35	36
Overall Study COMPLETED	3	34	35	36
Overall Study NOT COMPLETED	0	0	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase 1: Isatuximab + Cemiplimab Once Every 2 Weeks (Q2W) Participants received isatuximab 10 milligram/ kilogram (mg/kg) intravenous (IV) infusion once weekly for 4 weeks (QWx4) followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable adverse events (AEs), consent withdrawal, or any other reason.	Phase 2: Isatuximab Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W) Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Overall Study Incorrect completion of end of study form	0	0	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=3 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=34 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W n=36 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W n=36 Participants Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Total n=109 Participants Total of all reporting groups
Age, Continuous	64.7 years STANDARD_DEVIATION 2.9 • n=5 Participants	66.1 years STANDARD_DEVIATION 9.3 • n=7 Participants	63.7 years STANDARD_DEVIATION 10.0 • n=5 Participants	66.4 years STANDARD_DEVIATION 9.2 • n=4 Participants	65.4 years STANDARD_DEVIATION 9.4 • n=21 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	16 Participants n=7 Participants	14 Participants n=5 Participants	16 Participants n=4 Participants	47 Participants n=21 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	18 Participants n=7 Participants	22 Participants n=5 Participants	20 Participants n=4 Participants	62 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants	8 Participants n=21 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	29 Participants n=7 Participants	30 Participants n=5 Participants	29 Participants n=4 Participants	91 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants	9 Participants n=21 Participants

PRIMARY outcome

Timeframe: Cycle 1 Day 1 to Day 28

Population: The DLT evaluable population consisted of participants in Phase 1 who received the planned doses of isatuximab and cemiplimab during Cycle 1, and who completed the DLT observation period of Cycle 1 after the first study treatment administration, unless they discontinued the study treatment(s) due to DLT.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=3 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)	0 Participants	—	—	—

PRIMARY outcome

Timeframe: TEAEs were collected from the first dose up to 30 days after the last dose of study treatment, approximately 50 months

Population: Analysis was performed on the Safety population (tabulated according to treatment actually received \[as treated\]). There were 2 participants randomized in group isatuximab and isatuximab + cemiplimabQ4W respectively and who took another treatment/schedule.

An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered with a pharmaceutical product and which did not necessarily have a causal relationship with study treatment. 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 an AE which occurred after the first dose of study treatment administration up to 30 days after the last dose of study treatment administration. The DLT observation period was 1 cycle (28 days). However, all AEs during treatment, unless due to disease progression or an obviously unrelated cause, were taken into consideration by the Study Committee for the determination of the maximum tolerated dose and recommended Phase 2 dose.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=3 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=33 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W n=37 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W n=35 Participants Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 1 and Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) TEAEs	3 Participants	33 Participants	36 Participants	33 Participants
Phase 1 and Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) TESAEs	1 Participants	17 Participants	17 Participants	21 Participants

PRIMARY outcome

Timeframe: From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

Population: The Randomized population consisted of all participants from Phase 2 who gave their informed consent and were assigned a randomization number by the IRT, regardless of whether participants received any study treatment or received a different study treatment from which they were randomized.

ORR by Investigator using international myeloma working group (IMWG) response criteria:percentage of participants with complete response (CR) (including stringent CR \[sCR\]very good partial response \[VGPR\] and partial response \[PR\]).CR:negative immunofixation on serum and urine,disappearance of any soft tissue plasmacytomas,less than (\<)5% plasma cells in bone marrow (BM) aspirates and normal free light chain(FLC)ratio (0.26-1.65).sCR:CR plus no clonal cells in BM biopsy.VGPR:serum and urine M-protein detectable by immunofixation,not electrophoresis;\>=90% reduction in serum M-protein plus urine M-protein level\<100mg/24hour(h);FLC only:\>=90% decrease in difference between involved and uninvolved FLC levels.PR:\>=50% reduction of serum M-protein and reduction in 24h urine M-protein by \>=90% or \<200mg/24h.In addition to above, if present at baseline,\>=50% reduction in size (sum of products of maximal perpendicular diameters of measured lesions \[SPD\]) of soft tissue plasmacytomas required.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=34 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=36 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W n=36 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 2: Percentage of Participants With Overall Response Rate (ORR)	11.8 percentage of participants Interval 3.3 to 27.45	25.0 percentage of participants Interval 12.12 to 42.2	22.2 percentage of participants Interval 10.12 to 39.15	—

SECONDARY outcome

Timeframe: From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

CBR by Investigator using IMWG response criteria: percentage of participants with CR (including sCR), VGPR, PR (all defined in previous OM) or MR. MR was defined as \>= 25% but \<= 49% reduction in serum M-protein and reduction in 24h urine M-protein by 50-89%, which still exceeded 200 mg/24h; if present at baseline, \>=50% reduction in size (SPD) of soft tissue plasmacytomas was also required.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=34 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=36 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W n=36 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 2: Percentage of Participants With Clinical Benefit Rate (CBR)	23.5 percentage of participants Interval 10.75 to 41.17	36.1 percentage of participants Interval 20.82 to 53.78	38.9 percentage of participants Interval 23.14 to 56.54	—

SECONDARY outcome

Timeframe: From the date of randomization up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

Duration of follow-up was defined as the date of randomization to the date of last contact or death, whichever came first. Median duration of follow-up is reported.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=34 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=36 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W n=36 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 2: Duration of Follow-up	10.28 months Interval 8.739 to 11.368	8.84 months Interval 8.016 to 11.072	9.03 months Interval 8.016 to 10.875	—

SECONDARY outcome

Timeframe: From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

DOR: Time from date of first response (\>=PR) that was subsequently confirmed to date of first documented progressive disease (PD) or death.DOR was determined only for participants who achieved a response of PR or better.If progression or death not observed, participant was censored at date of last valid disease assessment not showing disease progression performed prior to initiating further anticancer treatment and analysis cut-off date.PD(IMWG criteria):increase of \>=25% from lowest confirmed value in any 1 of following:serum M-protein (absolute increase\>=0.5 gram/deciliter\[g/dL\]), serum M-protein increase\>=1g/dL if lowest M component \>=5g/dL; urine M-component (absolute increase \>=200mg/24h),appearance of new lesion(s),\>=50% increase from nadir in SPD of \>1 lesion or \>=50% increase in longest diameter of a previous lesion \>1cm in short axis,\>=50% increase in circulating plasma cells (minimum 200 cells/microliter\[c/mcL\]) if that was the only measure of disease. PR: as defined in OM3.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=4 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=9 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W n=8 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 2: Duration of Response (DOR)	5.6 months Interval 4.0 to 7.0	4.7 months Interval 3.0 to 12.0	5.7 months Interval 2.0 to 12.0	—

SECONDARY outcome

Timeframe: From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

TTR was defined as the time from randomization to first response (PR or better) that was subsequently confirmed. PR as per IMWG criteria was defined as \>=50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by \>=90% or to \<200 mg/24 hours. In addition to the above listed criteria, if present at baseline, a \>=50% reduction in the size SPD of soft tissue plasmacytomas was also required.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=4 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=9 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W n=8 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 2: Time to Response (TTR)	1.5 months Interval 1.0 to 2.0	1.0 months Interval 1.0 to 3.0	1.0 months Interval 1.0 to 4.0	—

SECONDARY outcome

Timeframe: From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

PFS: Time interval from the randomization date to the date of the first documented disease progression that is subsequently confirmed or the date of death due to any cause, whichever came first. If progression or death was not observed, participant was censored at date of last valid disease assessment not showing disease progression performed prior to initiation of a further anticancer treatment or the analysis cut-off date. Analysis was performed by Kaplan-Meier method. PD (IMWG) criteria: increase of \>=25% from lowest confirmed value in any 1 of following: serum M-protein (absolute increase \>=0.5g/dL), serum M-protein increase \>=1g/dL if lowest M component was \>=5g/dL; urine M-component (absolute increase \>=200mg/24h), appearance of new lesion(s),\>=50% increase from nadir in SPD of \>1 lesion or \>=50% increase in the longest diameter of a previous lesion \>1 cm in short axis or \>=50% increase in circulating plasma cells (minimum of 200 c/mcL) if that was the only measure of disease.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=34 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=36 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W n=36 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 2: Progression Free Survival (PFS)	2.89 months Interval 1.971 to 3.811	3.75 months Interval 1.971 to 5.881	3.02 months Interval 2.793 to 5.158	—

SECONDARY outcome

Timeframe: From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

OS was defined as the time interval from the date of randomization to death from any cause. Participants without death prior to the analysis cut-off date were censored at the last date the participant was known to be alive or the cut-off date, whichever came first. The results provided below corresponds to descriptive OS information at the time of primary analysis completion date of 09 October 2019.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=34 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=36 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W n=36 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 2: Overall Survival (OS)	NA months Interval 7.622 to NA indicates due to the limited follow-up time, most of participants were still alive, so the median OS and upper limit of confidence interval (CI) was not reached.	NA months Interval 6.801 to NA indicates due to the limited follow-up time, most of participants were still alive, so the median OS and upper limit of CI was not reached.	12.78 months Interval 7.392 to NA indicates due to the limited follow-up time, most of participants were still alive, so upper limit of CI was not reached.	—

SECONDARY outcome

Timeframe: At end of infusion (EOI) on Cycle 1 Day 1

Population: Analysis was performed on the PK population. "Isatuximab + Cemiplimab" arm includes 3 and 27 participants from phase 1 and phase 2, respectively. Same dose of isatuximab was administered to all participants in phase 1 and phase 2 part of study in Isatuximab + Cemiplimab Q2W and Q4W arms. Hence PK analysis was combined for phase 1 and phase 2 Isatuximab + Cemiplimab Q2W and Q4W arms.

Plasma samples were collected at specified timepoints and those non-impacted by the bioanalytical issue were used for evaluation of Ceoi. It was calculated using non-compartmental analysis (NCA) after the first administration in Cycle 1. The PK population was defined independently for isatuximab and cemiplimab and consisted of all participants from the all-treated (AT) population with at least 1 available concentration post-baseline (whatever the cycle and even if dosing was incomplete) with adequate documentation of dosing and sampling dates and times.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=10 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=30 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 1 and 2: Plasma Concentration Observed at the End of IV Infusion (Ceoi) of Isatuximab Alone and in Combination With Cemiplimab	255 microgram (mcg)/mL Standard Deviation 72.1	239 microgram (mcg)/mL Standard Deviation 67.7	—	—

SECONDARY outcome

Timeframe: At start of infusion (SOI), EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1

Plasma samples were collected at specified timepoints and those non-impacted by the bioanalytical issue were used for evaluation of Cmax. It was calculated using NCA after the first administration in Cycle 1.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=10 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=30 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 1 and 2: Maximum Observed Concentration (Cmax) of Isatuximab Alone and in Combination With Cemiplimab	264 mcg/mL Standard Deviation 68.0	247 mcg/mL Standard Deviation 65.9	—	—

SECONDARY outcome

Timeframe: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1

Plasma samples were collected at specified timepoints and those non-impacted by the bioanalytical issue were used for evaluation of tmax. It was calculated using NCA after the first administration in Cycle 1.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=10 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=30 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 1 and 2: Time to Reach Cmax (Tmax) of Isatuximab Alone and in Combination With Cemiplimab	5.56 hour Interval 3.25 to 10.5	4.85 hour Interval 2.58 to 13.7	—	—

SECONDARY outcome

Timeframe: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1

Plasma samples were collected at specified timepoints and those non-impacted by the bioanalytical issue were used for evaluation of Clast. It was calculated using NCA after the first administration in Cycle 1.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=10 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=30 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 1 and 2: Last Concentration Observed Above the Lower Limit of Quantitation (Clast) of Isatuximab Alone and in Combination With Cemiplimab	85.7 mcg/mL Standard Deviation 44.9	64.1 mcg/mL Standard Deviation 32.1	—	—

SECONDARY outcome

Timeframe: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1

Plasma samples were collected at specified timepoints and those non-impacted by the bioanalytical issue were used for evaluation of tlast. It was calculated using NCA after the first administration in Cycle 1.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=10 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=30 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 1 and 2: Time of Clast (Tlast) of Isatuximab Alone and in Combination With Cemiplimab	155.00 hour Interval 72.4 to 169.0	165.00 hour Interval 70.2 to 239.0	—	—

SECONDARY outcome

Timeframe: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1

AUClast was defined as the area under the plasma concentration versus time curve from time 0 to real time tlast calculated using the trapezoidal method over the dosing interval after the first administration in Cycle 1.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=10 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=30 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 1 and 2: Area Under the Concentration Versus Time Curve (AUC) From Time Zero to Tlast (AUClast) of Isatuximab Alone and in Combination With Cemiplimab	21000 (mcg*hour)/mL Standard Deviation 7220	20200 (mcg*hour)/mL Standard Deviation 6590	—	—

SECONDARY outcome

Timeframe: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1

AUC1week was defined as the area under the plasma concentration versus time curve from time 0 to 1 week post dose calculated using the trapezoidal method over the dosing interval after the first administration in Cycle 1.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=10 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=29 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 1 and 2: AUC From Time 0 to Week 1 (AUC1week) of Isatuximab Alone and in Combination With Cemiplimab	23000 (mcg*hour)/mL Standard Deviation 7250	21100 (mcg*hour)/mL Standard Deviation 6450	—	—

SECONDARY outcome

Timeframe: From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 20 months

Population: Analysis was performed on the ADA evaluable population."Isatuximab + CemiplimabQ2W" arm includes 3 and 36 participants from phase 1 and phase 2, respectively. Same dose of isatuximab was administered to all participants in phase 1 and phase 2 part of study in Isatuximab + Cemiplimab Q2W arms. Hence analysis was combined for phase 1 and phase 2 Isatuximab + Cemiplimab Q2W arms.

ADA responses were categorized as treatment-induced ADA and treatment boosted ADA. Pre-existing ADA was defined as ADA that were present in samples drawn during the pre-treatment period. 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. 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. The ADA evaluable population was defined independently for isatuximab and cemiplimab and consisted of all participants from AT population with at least 1 ADA result (negative, positive, or inconclusive) post-baseline.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=32 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=39 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W n=34 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 1 and 2: Number of Participants With Anti-Drug Antibodies (ADA) to Isatuximab Pre-existing ADA	0 Participants	1 Participants	0 Participants	—
Phase 1 and 2: Number of Participants With Anti-Drug Antibodies (ADA) to Isatuximab Treatment-induced	0 Participants	0 Participants	0 Participants	—
Phase 1 and 2: Number of Participants With Anti-Drug Antibodies (ADA) to Isatuximab Treatment boosted	0 Participants	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 20 months

Population: Analysis was performed on the ADA evaluable population. "Isatuximab + CemiplimabQ2W" arm includes 3 and 36 participants from phase 1 and phase 2, respectively. Same dose of isatuximab was administered to all participants in phase 1 and phase 2 part of study in Isatuximab + Cemiplimab Q2W arms. Hence analysis was combined for phase 1 and phase 2 Isatuximab + Cemiplimab Q2W arms.

Outcome measures

Outcome measures
Measure	Phase 1: Isatuximab + CemiplimabQ2W n=39 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 in all cycles every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab n=34 Participants Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ2W Participants received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.	Phase 2: Isatuximab + CemiplimabQ4W Participants isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.
Phase 1 and 2: Number of Participants With ADA to Cemiplimab Pre-existing ADA	1 Participants	0 Participants	—	—
Phase 1 and 2: Number of Participants With ADA to Cemiplimab Treatment-induced	2 Participants	0 Participants	—	—
Phase 1 and 2: Number of Participants With ADA to Cemiplimab Treatment boosted	0 Participants	0 Participants	—	—

Adverse Events

Phase 1: Isatuximab+Cemiplimab Q2W

Serious events: 1 serious events

Other events: 3 other events

Deaths: 1 deaths

Phase 2: Isatuximab

Serious events: 17 serious events

Other events: 31 other events

Deaths: 20 deaths

Phase 2: Isatuximab + CemiplimabQ2W

Serious events: 17 serious events

Other events: 34 other events

Deaths: 23 deaths

Phase 2:Isatuximab + CemiplimabQ4W

Serious events: 21 serious events

Other events: 27 other events

Deaths: 22 deaths

Serious adverse events

Other adverse events

Additional Information

Trial Transparency Team

Sanofi aventis recherche & développement

Phone: 800-633-1610

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.
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Restriction type: OTHER