A Study of Isatuximab-based Therapy in Participants With Lymphoma

Percentage of participants who had a CR as a best overall response (BOR) using the Lugano response criteria (LRC) 2014 (based on PET-CT and CT responses). Per LRC, CR based on PET-CT response was defined as complete metabolic response (MR) in lymph nodes and extralymphatic sites with a score of 1, 2, or 3 with or without residual mass, on 5-point scale (5PS), where, 1= no uptake above background; 2 = uptake \<=mediastinum; 3 = uptake \> mediastinum but \<= liver; 4 = uptake moderately \> liver; 5 = uptake markedly higher than liver and/or new lesions; no new lesions and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. CR based on CT-response was defined as target nodes/nodal masses of lymph nodes, extralymphatic sites regressed to \<=1.5 cm in longest dimension transverse diameter of lesion (LDi); absence of non-measured lesion; organ enlargement regressed to normal; no new lesions; normal bone marrow morphology; if indeterminate, immunohistochemistry negative.

Time frame: From the date of randomization until disease progression or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks)

Population: Analysis was performed on all treated population. Data for this outcome measure was not planned to be collected and analyzed for Cohort B and C as pre-specified in protocol.

Percentage of participants who had a CR or partial response (PR) as BOR using LRC, 2014. Per LRC, CR (PET-CT): complete MR in lymph nodes and extralymphatic sites with a score of 1, 2, or 3 with or without residual mass; no new lesions and no evidence of FDG-avid disease. CR (CT-response): target nodes/nodal masses of lymph nodes, extralymphatic sites regressed to \<=1.5cm LDi; absence of non-measured lesion; organ enlargement regressed to normal; no new lesions; normal bone marrow morphology. PR (PET-CT): partial MR in lymph nodes and extralymphatic sites; no new lesions and residual uptake higher than uptake. PR (Per CT): lymph nodes, extralymphatic sites\>=50% decrease in sum of product of perpendicular diameters (SPD), extranodal sites; if lesion is too small to measure on CT,assign5mm\*5mm as default; if no longer visible:0\*0mm; Node\>5mm\*5mm but smaller than normal, use actual measurement; absent/regressed non-measured lesions; no increase; spleen regressed by\>50% or no new lesions.

Time frame: From the date of randomization until disease progression, or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks)

Population: Analysis was performed on all treated population.

DLTs: Adverse Events (AEs) occurring during 1st treatment cycle, unless due to disease progression or obviously unrelated cause which included: hematological abnormalities: Grade(G) 4 neutropenia(N) for 7 or more consecutive days, G3 to G4 N with fever (temperature greater than or equal to \[\>=\] 38.5 degree Celsius on more than 1 occasion) or microbiologically/radiographically documented infection, G3 to G4 thrombocytopenia with clinically significant bleeding requiring clinical intervention or non-hematological abnormalities: G 4 non-hematologic AE, G\>=2 uveitis, G3 non-hematological AE lasting greater than (\>)3 days, delay in initiation of Cycle 2 \>14 days due to treatment related laboratory abnormalities/AE. Any other AE that the study committee deemed to be dose-limiting, regardless of grade, was also considered as DLT.

Time frame: Cycle 1 (28 days)

Population: Analysis was performed on DLT evaluable population which included all participants who received the planned doses of isatuximab and cemiplimab during Cycle 1 and completed the DLT observation period after the first administration of the study drug. Here, 0 in the overall number of participants analyzed signifies that no participants were evaluable for DLTs in the Cohort A1 arm.

Electrolyte parameters assessed were hyponatremia, hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypoalbuminemia, hypoglycemia and hyperglycemia. Abnormal criteria was assessed as per the NCI-CTCAE v 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.

Time frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)

Population: Analysis was performed on all treated population. Here number analyzed signifies the participants with available data for each specified parameter.

Hematological parameters assessed were anemia, white blood cell (WBC) decreased, platelet count decreased, lymphocyte count decreased, and neutrophil count decreased. Abnormality criteria was assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 NCI-CTCAE v 5.0), where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.

Time frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)

Population: Analysis was performed on all treated population.

Abnormal liver function parameters assessed were aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, alkaline phosphatase (ALP) increased, blood bilirubin (BB) increased. Abnormal criteria was assessed as per NCI-CTCAE v 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.

Time frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)

Population: Analysis was performed on all treated population.

Abnormal renal parameters assessed were glomerular filtration rate (GFR) by class, creatinine increased and hyperuricemia. GFR by class was assessed in categories:\>=90 milliliter per minute per 1.73 meter square (mL/min/1.73m\^2) (Normal), \>=60 to \<90 mL/min/1.73m\^2 (Mild), \>=30 to \<60 mL/min/1.73m\^2 (Moderate), \>=15 to \<30 mL/min/1.73m\^2 (Severe), and \<15 mL/min/1.73m\^2 (End Stage Renal Disease). Abnormal criteria was assessed as per NCI-CTCAE v 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.

Time frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)

Population: Analysis was performed on all treated population.

An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. Serious adverse events (SAEs) were any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (defined as the time from the first dose of study treatment up to 30 days after the last dose of study treatment).

Time frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)

Population: Analysis was performed on all treated population which included all participants who signed the informed consent and received at least 1 dose of the study treatment, either isatuximab or cemiplimab.

Percentage of participants who had a CR as a BOR using the LRC, 2014 (based on PET-CT and CT responses). Per LRC, CR based on PET-CT was defined as complete MR in lymph nodes and extralymphatic sites with a score of 1, 2, or 3 with or without residual mass, on 5PS, where, 1= no uptake above background; 2 = uptake \<=mediastinum; 3 = uptake \> mediastinum but \<= liver; 4 = uptake moderately \> liver; 5 = uptake markedly higher than liver and/or new lesions; no new lesions and no evidence of FDG-avid disease in bone marrow. CR based on CT-response was defined as target nodes/nodal masses of lymph nodes, extralymphatic sites regressed to \<=1.5 cm in longest dimension transverse diameter of lesion (LDi); absence of non-measured lesion; organ enlargement regressed to normal; no new lesions; normal bone marrow morphology; if indeterminate, immunohistochemistry negative.

Time frame: From the date of randomization until disease progression, or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks)

Population: Analysis was performed on all treated population. Data for this outcome measure was not planned to be collected and analyzed for Cohort B and C as pre-specified.

Percentage of participants who had a CR or PR as BOR using LRC, 2014 (based on PET-CT and CT responses). CR (per PET-CT): complete MR in lymph nodes and extra lymphatic sites with a score of 1, 2, or 3 with or without residual mass; no new lesions and no evidence of FDG-avid disease. CR (CT-response): target nodes/nodal masses of lymph nodes, extralymphatic sites regressed to \<=1.5cm LDi; absence of non-measured lesion; organ enlargement regressed to normal; no new lesions; normal bone marrow morphology. PR (per PET-CT): partial MR in lymph nodes and extral ymphatic sites; no new lesions and residual uptake higher than uptake. PR (per CT): lymph nodes, extralymphatic sites \>=50% decrease in SPD, extranodal sites; if lesion is too small to measure on CT, assign 5mm\*5mm as default; if no longer visible:0\*0mm; Node\>5mm\*5mm but smaller than normal, used actual measurement; absent/regressed non-measured lesions; no increase; spleen regressed by\>50% or no new lesions.

Time frame: From the date of randomization until disease progression, or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks)

Population: Analysis was performed on all treated population. Data for cohort B and C are reported separately.

Time (months) between date of first response to first date that recurrent or radiologically disease progression (PD) was documented, or date of death,whichever was 1st. In absence of PD or death before cut-off date or date of initiation of further anticancer treatment, DOR was censored at date of last valid response not showing PD performed prior to initiation of further anticancer treatment or cut-off date, whichever was earlier. PD(PET-CT): metabolic disease with score 4/5 with inc. in intensity of uptake for target nodes/nodal mass & new FDG-avid foci consistent with lymphoma. PD(CT):any 1 of following: cross product of longest transverse diameter of lesion(LDi) & perpendicular diameter (PPD) progression of nodes/nodal mass, abnormal node/lesion with LDi \>1.5 cm, inc \>=50% from PPD nadir & inc in LDi/ shortest axis perpendicular to LDi(SDi) from nadir 0.5 cm, regrowth of resolved lesions, new splenomegaly,progression of non-measured lesion, new/recurrent involvement of bone marrow.

Time frame: From the date of first response until disease progression or death, or study cut-off date whichever occurred first (maximum duration: up to 103 weeks)

Population: Analysis was performed on participants who had a response. DOR was analyzed using Kaplan-Meier method. Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

ADA responses 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.

Time frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)

Population: Analysis was performed on ADA evaluable population. Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

ADA responses 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.

Time frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)

Population: Analysis was performed on Anti-drug antibody (ADA) evaluable population that included all participants who signed informed consent and received at least 1 dose of either isatuximab or cemiplimab, with at least 1 non-missing ADA result after the drug administration. Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

DC defined as percentage of participants who achieved CR, PR or stable disease (SD) as per LRC, 2014. CR (PET-CT): complete MR in lymph nodes and extralymphatic sites; no new lesions and no evidence of FDG-avid disease. CR (CT): target nodes/nodal masses of lymph nodes, extralymphatic sites regressed to \<=1.5cm LDi; absence of non-measured lesion; organ enlargement regressed to normal; no new lesions; normal bone marrow. PR (PET-CT): partial MR in lymph nodes and sites; no new lesions. PR (CT): lymph nodes, sites\>=50% decrease in SPD, sites; if lesion is too small to measure on CT, assign 5mm\*5mm; No longer visible:0\*0mm; Node\>5mm\*5mm, use actual measurement; absent/regressed non-measured lesions; no increase; spleen regressed by\>50% or no new lesions. SD (PET-CT):no metabolic response, target nodes score of 4/5 with no significant change & no new lesions; SD (CT): \<50% dec in SPD, no increase in progression for. 5PS:1: non-measured lesions, organ enlargement & no new lesions.

Time frame: From the date of first response until disease progression or death, or study cut-off date whichever occurred first (maximum duration: up to 103 weeks)

Population: Analysis was performed on all treated population.

Tumor burden change was defined as the best percent-change from baseline in a sum of product of lesion diameters (longest for non-nodal lesion, short axis for nodal lesions) for all target lesions.

Time frame: Up to 103 weeks

Population: Analysis was performed on all treated population. Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab.

Time frame: End of infusion (EOI up to 3 hours) on Day 2 of Cycle 1

Population: Analysis was performed on PK population (for isatuximab) which included participants who signed informed consent and received at least 1 dose of the drug with at least one reportable concentration after the study drug (isatuximab) administration. Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

AUC0-144 hours was defined as the area under the plasma concentration versus time curve from time 0 to 144 hours post dose calculated for isatuximab.

Time frame: At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1

Population: Analysis was performed on PK population (for isatuximab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

AUC0-168 hours was defined as the area under the plasma concentration versus time curve from time 0 to 168 hours post dose calculated for isatuximab. Samples for this outcome measure were collected up to 144 hours post-dose. No sample was collected at 168 hours post-dose; and thus, the samples collected up to 144 hours post-dose were extrapolated to derive data for 168 hours post-dose.

Time frame: At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1

Population: Analysis was performed on PK population (for isatuximab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

AUClast was defined as area under the plasma concentration versus time curve calculated from time 0 to last quantifiable concentration, calculated for isatuximab.

Time frame: At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1

Population: Analysis was performed on PK population (for isatuximab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

AUClast was defined as area under the serum concentration versus time curve calculated from time 0 to last quantifiable concentration calculated for cemiplimab.

Time frame: At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1

Population: Analysis was performed on PK population (for Cemiplimab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

AUC0-336 hours was defined as the area under the serum concentration versus time curve from time 0 to 336 hours post dose for cemiplimab.

Time frame: At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1

Population: Analysis was performed on PK population (for Cemiplimab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

Clast was defined as the last concentration of cemiplimab observed above the lower limit of quantification.

Time frame: At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1

Population: Analysis was performed on PK population (for Cemiplimab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

Clast was defined as the last concentration of isatuximab observed above the lower limit of quantification.

Time frame: At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1

Population: Analysis was performed on PK population (for isatuximab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

Cmax was defined as the maximum concentration observed after the first administration.

Time frame: At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1

Population: Analysis was performed on PK population (for Cemiplimab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

Cmax was defined as the maximum plasma concentration observed after the first administration of drug.

Time frame: At Start of infusion (SOI; 0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1

Population: Analysis was performed on PK population (for isatuximab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

Ctrough was the plasma concentration of isatuximab observed just before treatment administration during repeated dosing.

Time frame: Pre-infusion on Cycle1:Day 2, 8, 15, & 22, Cycle 2:Day 1 &15, Cycle 3:Day 1 &15, Cycle 4:Day 1 &15, Cycle 5 Day1,Cycle 6 Day1,Cycle 7 Day 1, Cycle 8 Day1, Cycle 9 Day1, Cycle 10 Day1, Cycle 11 Day1, Cycle14 Day1, Cycle 17 Day1, Cycle 20 Day1,Cycle 23 Day1

Population: Analysis was performed on PK population (for isatuximab). Here, '0' in the number analyzed field signifies that none of the participants were available for the specified timepoints.

Ceoi is the plasma concentration observed at the end of intravenous infusion of cemiplimab.

Time frame: EOI (up to 30 minutes [min]) on Day 1 of Cycle 1

Population: Analysis was performed on PK population (for Cemiplimab) which included all participants who signed informed consent and received at least 1 dose of the drug with at least one reportable concentration after the study drug (cemiplimab) administration. Here 'overall number of participants analyzed signifies the participants evaluable for this outcome measure.

Ctrough was the serum concentration of cemiplimab observed just before treatment administration during repeated dosing.

Time frame: Pre-infusion on Cycle 1:Day 1 & Day15,Cycle 2:Day 1 & Day 15,Cycle 3:Day 1 & Day 15,Cycle 4:Day 1 & Day15,Cycle 5 Day 1,Cycle 6 Day 1,Cycle7 Day1,Cycle 8 Day 1,Cycle 9 Day1,Cycle 10 Day1,Cycle11 Day1,Cycle14 Day 1,Cycle 17 Day1,Cycle20 Day 1,Cycle 23 Day1

Population: Analysis was performed on PK population (for Cemiplimab). Here, '0' in the number analyzed field signifies that none of the participants were available for the specified timepoint.

Tlast was defined as the time of last concentration observed above the lower limit of quantification for cemiplimab.

Time frame: At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1

Population: Analysis was performed on PK population (for Cemiplimab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

Tlast was defined as the time of last concentration observed above the lower limit of quantification for isatuximab.

Time frame: At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1

Population: Analysis was performed on PK population (for isatuximab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

Tmax was defined as the time to reach Cmax after the intravenous infusion of cemiplimab.

Time frame: At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1

Population: Analysis was performed on PK population (for Cemiplimab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

Tmax was defined as the time to reach Cmax, after the intravenous infusion of isatuximab.

Time frame: At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1

Population: Analysis was performed on PK population (for isatuximab). Here, overall number of participants analyzed signifies the participants with available data for this outcome measure.

PFS: time (in months) from 1st study treatment administration to date of 1st documented radiographic progression or date of death from any cause, whichever occurs 1st. Per LRC, 2014 PD (per PET-CT): metabolic disease with score 4/5 with increase (inc) in intensity of uptake for individual target nodes/nodal mass & new FDG-avid foci consistent with lymphoma at interim/ end-of-treatment assessment for extra nodal lesions, new FDG-avid foci consistent with lymphoma rather; new/recurrent FDG-avid foci bone marrow. PD (per CT response): any 1 of following: cross product of longest transverse diameter of lesion (LDi) & perpendicular diameter (PPD) progression of nodes/nodal mass, abnormal node/lesion with LDi \>1.5 cm, inc \>=50% from PPD nadir & inc in LDi/ shortest axis perpendicular to LDi from nadir 0.5 cm for lesion \<= 2 cm, regrowth of resolved lesions, new splenomegaly,progression of preexisting non measured lesion, new/recurrent involvement of bone marrow.

Time frame: From the date of randomization until disease progression, or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks)

Population: Analysis was performed on all treated population. PFS was analyzed using Kaplan-Meier method.