Safety, Preliminary Efficacy and PK of Isatuximab (SAR650984) Alone or in Combination With Atezolizumab in Patients With Advanced Malignancies

MTD was defined as the highest dose level at which no more than 1 out of 6 participants (starting dose or DL-1) or 2 out of 12 participants (starting dose) experienced a DLT related to the investigational medicinal product. DLTs: AE occurring during 1st treatment cycle, unless due to disease progression/obviously unrelated cause included: hematological abnormalities: G4 N for 7 or more consecutive days, G3 to G4 N with fever, G3 or G4 thrombocytopenia. Non-hematological abnormalities: G\>=2 AST/ ALT elevation simultaneous with G \>=2 total bilirubin elevation without cholestasis or any other reason found, G4 non-hematologic AE, G3 to 4 cytokine release syndrome, G3 non-hematological AE lasting \>3 days, delay in initiation of Cycle 2 \>14 days due to treatment related laboratory abnormalities or AEs.

Time frame: Cycle 1 (21 days)

Population: Analysis was performed on DLT evaluable population.

Electrolyte parameters assessed were hyponatremia, hypernatremia, hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypoalbuminemia, hypoglycemia and hyperglycemia. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03, 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 Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

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

DLTs: AEs occurring during 1st treatment cycle, unless due to disease progression/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 thrombocytopenia with clinically significant bleeding/ G4 thrombocytopenia. Non-hematological abnormalities: G \>=2 Aspartate transaminase (AST)/ Alanine transaminase (ALT) elevation simultaneous with G \>=2 total bilirubin elevation without initial findings of cholestasis or any other reason found, G4 non-hematologic AE, G3 to 4 cytokine release syndrome, 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 study committee deemed to be dose-limiting, regardless of grade, was also considered DLT.

Time frame: Cycle 1 (21 days)

Population: Analysis was performed on DLT evaluable population that included participants who received planned doses of isatuximab and atezolizumab during Cycle 1 and who completed the DLT observation period.

Hematological parameters assessed were anemia, white blood cell (WBC) decreased, platelet count decreased, lymphocyte count decreased, and neutrophil count decreased. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03, 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 Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

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

Abnormal liver function parameters assessed were AST increased, ALT increased, alkaline phosphatase (ALP) increased, blood bilirubin (BB) increased. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03, 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 Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

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

Abnormal renal parameters assessed were creatinine clearance (CrCl), creatinine increased and hyperuricemia. Creatinine clearance was assessed in categories: \>=60 - less than (\<) 90 milliliters per minute per 1.73 square meter (mL/min/1.73m\^2), \>=30 - \<60 mL/min/1.73m\^2, \>=15 - \<30 mL/min/1.73m\^2 and \<15 mL/min/1.73m\^2. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03, 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 Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

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

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 Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

Population: Analysis was performed on all-treated population.

OR was defined as the percentage of participants with complete response (CR) and partial response (PR) as best overall response, assessed per RECIST 1.1 criteria. Best overall response was derived per RECIST 1.1 criteria using disease assessments performed from the first dose of treatment throughout the study excluding any assessments performed after the cut-off date or following the initiation of a further anticancer treatment. CR was defined as the disappearance of all target lesions, pathological lymph nodes (target/non-target)- reduction in short axis \<10 mm; PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. Disease progression was defined as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum, sum with an absolute increase of diameter of at least 5 mm and appearance of \>1 new lesion.

Time frame: From randomization until disease progression, or death or study cut-off whichever occurred first (maximum duration of exposure: up to 108 weeks)

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

PFS-6 was defined as the probability of participants alive without disease progression at 6 months as assessed by RANO criteria. Participants who didn't experience documented progression or death before analysis cut-off date or date of initiation of new anticancer treatment, PFS was censored at date of last valid disease assessment not showing progression performed prior to initiation of further anticancer treatment or analysis cut-off date, whichever was 1st. Per RANO criteria, progressive disease was defined as \>=25% increase size of T1- gadolinium enhancing disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status. PFS-6 was evaluated by Kaplan-Meier method.

Time frame: From randomization until 6 months after the last participant's first treatment in the GBM Cohort D-1

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

RP2D was the starting dose selected for Phase 2 part of the study. RP2D was the selected dose at which no more than 1 out of 6 participants (starting dose or dose level minus -1 \[DL-1\]) or 2 out of 12 participants (starting dose) experienced a DLT related to the investigational medicinal product. DLTs: Adverse Event (AE) occurring during 1st treatment cycle, unless due to disease progression/obviously unrelated cause included: hematological abnormalities: G4 N for 7/ more consecutive days, G3 to G4 N with fever, G3/G4 thrombocytopenia. Non-hematological abnormalities: G\>=2 AST/ALT elevation simultaneous with G \>=2 total bilirubin elevation without cholestasis or any other reason found, G4 non-hematologic AE, G3 to 4 cytokine release syndrome, G3 non-hematological AE lasting \>3 days, delay in initiation of Cycle 2 \>14 days due to treatment related laboratory abnormalities/AE.

Time frame: Cycle 1 (21 days)

Population: Analysis was performed on DLT evaluable population.

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

Time frame: From randomization until progression or death or study cut-off date whichever occurred first (maximum duration of exposure: up to 108 weeks)

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

Time from date of 1st response until date of first documented recurrent/progressive disease (PD) or death whichever occurred 1st. In absence of disease progression or death before analysis cut-off date or date of initiation of further anticancer treatment, DOR was censored at date of last valid response. RECIST 1.1 criteria was used for assessment in HCC/SCCHN/EOC Cohorts and RANO criteria for GBM Cohort. Per RECIST 1.1, CR: disappearance of all target lesions; PR: at least 30% decrease in sum of diameters of target lesions, PD: at least 20% increase in sum of diameters of target lesions. Per RANO criteria; CR: no change in size of T1-Gd+ disease, stable/reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable/improved status; PR: \>=50% change in size of T1-Gd+, stable/reduced T2/FLAIR signal, no new lesion, stable/reduced corticosteroid use, and stable/improved status. PD:\>=25% increase size of T1-Gd+/increased T2/FLAIR signal/presence of new lesion/worsening status.

Time frame: From the date of first response until disease progression or death, or study cut-off date whichever occurred first (maximum duration of exposure: up to 108 weeks)

Population: Analysis was performed on all treated population. Here 'overall number of participants analyzed' signifies participants with available data for this outcome measure and '0' in 'overall number of participants analyzed' signifies that no participant in the Cohort D-1 achieved any response, and hence, no DOR was analyzed.

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 (including participants without pretreatment samples).

Time frame: From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

Population: Analysis was performed on ADA evaluable population. Here 'overall number of participants analyzed' signifies 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 (including participants without pretreatment samples).

Time frame: From Baseline up to 30 days after last study treatment administration (maximum duration of exposure:106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

Population: Analysis was performed on ADA evaluable population which included all participants who received at least 1 dose of study treatment with at least 1 non-missing ADA result after the drug administration. Here 'overall number of participants analyzed' signifies participants with available data for this outcome measure.

DC: percentage of participants with complete response (CR), partial response (PR) & stable disease (SD) rate. RANO criteria, CR: no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable/ reduced (red) T2/FLAIR signal, no new lesion (NL), no corticosteroid use (CU) & stable/ red clinical status (CS); PR: \>=50% change in size of T1-Gd+ disease, stable/red T2/FLAIR signal, no NL, stable/ red CU & stable/ improved CS (ICS). SD: \<50% reduction to \<25% increase (inc) size of T1-Gd+ disease, stable/red T2/FLAIR signal, no NL, stable/red CU & stable/ICS. Progressive disease (PD): \>=25% inc size of T1-Gd+ disease/ inc T2/FLAIR signal/ presence of NL/ worsening CS. RECIST criteria: CR: Disappearance of target lesions. Reduction in short axis to \<10 mm of lymph nodes; PR: 30% decrease in sum of diameters of target lesions; PD: 20% inc in sum of diameters of target lesions; SD: Neither sufficient shrinkage from baseline study to qualify for PR nor sufficient inc to qualify for PD.

Time frame: From the date of first response to disease progression or death, or study cut-off whichever occurred first (maximum duration of exposure: up to 108 weeks)

Population: Analysis was performed on all-treated population.

Response rate for participants with GBM was defined as percentage of participants with CR & PR as best overall response (BOR), assessed by Investigators using RANO criteria. BOR was derived per RANO criteria using disease assessments performed from 1st dose of treatment through study excluding any assessments performed after cut-off date or following initiation of further anticancer treatment. Per RANO criteria; CR was defined as no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; PR was defined as \>=50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status. Progressive disease was defined as \>=25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.

Time frame: From randomization until progression, or death, or study cut-off whichever occurred first (maximum duration of exposure: 54 weeks for Cohort D-1)

Population: Analysis was performed on all-treated population. Data for this outcome measure was not collected and analyzed for Cohort A, B and C because the RANO criteria for the assessment of response could not be used to assess the response for solid tumors such as HCC, SCCHN and EOC.

AUClast was defined as area under the plasma concentration versus time curve calculated from time 0 to last quantifiable concentration. AUClast was calculated using the non-compartmental analysis after the intravenous infusion of isatuximab.

Time frame: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1

Population: Analysis was performed on PK population.

AUC0-168h was defined as the area under the plasma concentration versus time curve from time 0 to 168 hours post dose calculated using non-compartmental analysis after first infusion of isatuximab.

Time frame: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1

Population: Analysis was performed on PK population.

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

Time frame: At end of infusion on Cycle 1 Day 1

Population: Analysis was performed on PK population.

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

Time frame: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1

Population: Analysis was performed on PK population.

Cmax was defined as the maximum concentration observed after the first administration calculated using the noncompartmental analysis after the intravenous infusion of isatuximab.

Time frame: At start of infusion (SOI), end of infusion (EOI), EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1

Population: Analysis was performed on PK population which included all participants who received at least 1 dose of the study treatment with at least one reportable concentration after the study drug administration.

Tlast was defined as the time of last concentration observed above the lower limit of quantification, calculated using the non-compartmental analysis after the intravenous infusion of isatuximab.

Time frame: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1

Population: Analysis was performed on PK population.

Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion of isatuximab.

Time frame: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1

Population: Analysis was performed on PK population.

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

Time frame: Pre-infusion on Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 1 Day 15

Population: Analysis was performed on participants who received at least 1 dose of the study treatment with at least one reportable concentration after drug administration; and were ADA negative (i.e., participants without any treatment induced or treatment boosted ADA-positive sample during the treatment or follow-up observation period). Here 'Number analyzed' signifies participants with available data for each specified category.

Time frame: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 8 Day 1 and Cycle 16 Day 1

Population: Data for the plasma concentration of atezolizumab is not reported because no sample was collected after study termination and analyzed as the study did not fulfil the predefined criteria for Atezolizumab PK analysis.

PFS was defined as time (in months) from 1st study treatment administration to date of 1st documented radiographic progression or date of death from any cause, whichever was 1st. Participants who didn't experience progression or death before analysis cut-off date/date of initiation of new anticancer treatment, PFS was censored at date of last valid disease assessment not showing progression performed prior to initiation of further anticancer treatment or analysis cut-off date, whichever was 1st. RECIST 1.1 criteria was used for assessment in HCC/SCCHN/EOC Cohorts and RANO criteria for GBM Cohort. Per RECIST 1.1 criteria, PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. Appearance of 1 or more new lesions was also considered progression. Per RANO criteria, PD: \>=25% increase in product of perpendicular diameters of any target lesion, or worsening neurologic status not explained by causes unrelated to tumor progression.

Time frame: From date of first study treatment administration until disease progression or death or study cut-off whichever occurred first (maximum duration of exposure: up to 108 weeks)

Population: Analysis was performed on all-treated population. Kaplan-Meier method was used for analysis.