Outcome
| Type |
Measure |
Description |
Time frame |
Safety issue |
| Primary |
Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs) |
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. |
Cycle 1 Day 1 to Day 28 |
|
| Primary |
Phase 1 and Phase 2: 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 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. |
TEAEs were collected from the first dose up to 30 days after the last dose of study treatment, approximately 50 months |
|
| Primary |
Phase 2: Percentage of Participants With Overall Response Rate (ORR) |
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. |
From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months |
|
| Secondary |
Phase 2: Percentage of Participants With Clinical Benefit Rate (CBR) |
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. |
From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months |
|
| Secondary |
Phase 2: Duration of Follow-up |
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. |
From the date of randomization up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months |
|
| Secondary |
Phase 2: Duration of Response (DOR) |
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. |
From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months |
|
| Secondary |
Phase 2: Time to Response (TTR) |
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. |
From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months |
|
| Secondary |
Phase 2: Progression Free Survival (PFS) |
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. |
From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months |
|
| Secondary |
Phase 2: Overall Survival (OS) |
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. |
From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months |
|
| Secondary |
Phase 1 and 2: Plasma Concentration Observed at the End of IV Infusion (Ceoi) of Isatuximab Alone and in Combination With Cemiplimab |
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. |
At end of infusion (EOI) on Cycle 1 Day 1 |
|
| Secondary |
Phase 1 and 2: Maximum Observed Concentration (Cmax) of Isatuximab Alone and in Combination With Cemiplimab |
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. |
At start of infusion (SOI), EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1 |
|
| Secondary |
Phase 1 and 2: Time to Reach Cmax (Tmax) of Isatuximab Alone and in Combination With Cemiplimab |
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. |
At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1 |
|
| Secondary |
Phase 1 and 2: Last Concentration Observed Above the Lower Limit of Quantitation (Clast) of Isatuximab Alone and in Combination With Cemiplimab |
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. |
At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1 |
|
| Secondary |
Phase 1 and 2: Time of Clast (Tlast) of Isatuximab Alone and in Combination With Cemiplimab |
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. |
At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1 |
|
| Secondary |
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 |
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. |
At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1 |
|
| Secondary |
Phase 1 and 2: AUC From Time 0 to Week 1 (AUC1week) of Isatuximab Alone and in Combination With Cemiplimab |
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. |
At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1 |
|
| Secondary |
Phase 1 and 2: Number of Participants With Anti-Drug Antibodies (ADA) to Isatuximab |
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. |
From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 20 months |
|
| Secondary |
Phase 1 and 2: Number of Participants With ADA to Cemiplimab |
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. |
From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 20 months |
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