A Study of Isatuximab-based Therapy in Participants With Lymphoma

• ClinicalTrials.gov Identifier: NCT03769181
• Recruitment Status: Terminated
• First Posted: December 7, 2018
• Results First Posted: October 17, 2023
• Last Update Posted: October 17, 2023
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: November 29, 2018
• First Posted Date: December 7, 2018
• Results First Submitted Date: August 15, 2023
• Results First Posted Date: October 17, 2023
• Last Update Posted Date: October 17, 2023
• Actual Study Start Date: December 11, 2018
• Actual Primary Completion Date: November 8, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 15, 2023)

• Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (28 days) ]
  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.
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs) [ Time Frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks) ]
  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).
• Number of Participants With Laboratory Abnormalities: Hematological Parameters [ Time Frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks) ]
  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.
• Number of Participants With Laboratory Abnormalities: Electrolytes [ Time Frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks) ]
  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.
• Number of Participants With Laboratory Abnormalities: Renal Parameters [ Time Frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks) ]
  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.
• Number of Participants With Laboratory Abnormalities: Liver Function Parameters [ Time Frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks) ]
  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.
• Cohort A1: Percentage of Participants With Complete Response (CR) [ 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) ]
  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.
• Cohort A2, B and C: Percentage of Participants With Objective Response (OR) [ 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) ]
  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.

Original Primary Outcome Measures (submitted: December 5, 2018)

• Phase 1 - Dose limiting toxicities (DLTs); Recommended Phase 2 dose (RP2D) [ Time Frame: 1st Cycle - 28 days ]
  DLTs as observed during DLT-observation period; Dose selected for the Phase 2 portion
• Phase 2 - Cohort A1 (anti-PD-1/PD-L1 naive cHL): Complete Remission Rate [ Time Frame: Up to 24 weeks after last patient treated in a given cohort ]
  The proportion of participants who have a Complete Remission as a best overall response during the isatuximab + cemiplimab therapy period using the 5-point scale per the Lugano classification where 1 is No uptake, 2 is Uptake ≤ mediastinum, 3 is Uptake > mediastinum but ≤ liver, 4 is Moderately increased uptake compared to the liver and 5 is Markedly increased uptake compared to the liver and/or new lesions
• Phase 2 - Cohort A2 (cHL progressing from PD-1/PD-L1), B (DLBCL) and C (PTCL): Response Rate [ Time Frame: Up to 24 weeks after last patient treated in a given cohort ]
  The proportion of participants who have a Complete Response or Partial Response as a best overall response during isatuximab + cemiplimab therapy period using the 5-point scale per the Lugano classification where 1 is No uptake, 2 is Uptake ≤ mediastinum, 3 is Uptake > mediastinum but ≤ liver, 4 is Moderately increased uptake compared to the liver and 5 is Markedly increased uptake compared to the liver and/or new lesions

Current Secondary Outcome Measures (submitted: August 15, 2023)

• Number of Participants With Treatment-Induced and Treatment Boosted Antidrug Antibodies (ADA) Against Isatuximab [ Time Frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks) ]
  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.
• Number of Participants With Treatment-Induced and Treatment Boosted Antidrug Antibodies (ADA) Against Cemiplimab [ Time Frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks) ]
  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.
• Pharmacokinetics (PK) Parameter: Plasma Concentration of Isatuximab at End of Infusion (CEOI) [ Time Frame: End of infusion (EOI up to 3 hours) on Day 2 of Cycle 1 ]
  Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab.
• PK Parameter: Maximum Observed Plasma Concentration (Cmax) After the First Infusion of Isatuximab [ 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 ]
  Cmax was defined as the maximum plasma concentration observed after the first administration of drug.
• PK Parameter: Time to Reach Cmax (Tmax) After the First 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 ]
  Tmax was defined as the time to reach Cmax, after the intravenous infusion of isatuximab.
• PK Parameter: Area Under the Plasma Concentration (AUClast) Versus Time Curve After the First 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 ]
  AUClast was defined as area under the plasma concentration versus time curve calculated from time 0 to last quantifiable concentration, calculated for isatuximab.
• PK Parameter: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First 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 ]
  Clast was defined as the last concentration of isatuximab observed above the lower limit of quantification.
• PK Parameter: Time of Clast (Tlast) After the First 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 ]
  Tlast was defined as the time of last concentration observed above the lower limit of quantification for isatuximab.
• PK Parameter: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUC0-168 Hours) After the First 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 ]
  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.
• PK Parameter: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUC0-144 Hours) After the First 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 ]
  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.
• PK Parameter: Plasma Trough Concentration (Ctrough) of Isatuximab [ 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 ]
  Ctrough was the plasma concentration of isatuximab observed just before treatment administration during repeated dosing.
• PK Parameter: Serum Concentration of Cemiplimab at End of Infusion (CEOI) [ Time Frame: EOI (up to 30 minutes [min]) on Day 1 of Cycle 1 ]
  Ceoi is the plasma concentration observed at the end of intravenous infusion of cemiplimab.
• PK Parameter: Maximum Observed Concentration (Cmax) After the First 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 ]
  Cmax was defined as the maximum concentration observed after the first administration.
• PK Parameter: Time to Reach Cmax (Tmax) After the First 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 ]
  Tmax was defined as the time to reach Cmax after the intravenous infusion of cemiplimab.
• PK Parameter: Area Under the Serum Concentration (AUClast) Versus Time Curve After the First 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 ]
  AUClast was defined as area under the serum concentration versus time curve calculated from time 0 to last quantifiable concentration calculated for cemiplimab.
• PK Parameter: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First 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 ]
  Clast was defined as the last concentration of cemiplimab observed above the lower limit of quantification.
• PK Parameter: Time of Clast (Tlast) After the First 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 ]
  Tlast was defined as the time of last concentration observed above the lower limit of quantification for cemiplimab.
• PK Parameter: Area Under the Serum Concentration Versus Time Curve Over the Dosing Interval (AUC0-336 Hours) After the First 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 ]
  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.
• PK Parameter: Serum Trough Concentration (Ctrough) of Cemiplimab [ 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 ]
  Ctrough was the serum concentration of cemiplimab observed just before treatment administration during repeated dosing.
• Percent Change From Baseline in Tumor Burden [ Time Frame: Up to 103 weeks ]
  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.
• Duration of Response (DOR) [ 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) ]
  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.
• Percentage of Participants With Disease Control (DC) [ 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) ]
  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.
• Progression Free Survival (PFS) [ 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) ]
  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.
• Cohort A1 and A2: Percentage of Participants With Objective Response [ 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) ]
  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.
• Cohort A1 and A2: Percentage of Participants With Complete Response [ 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) ]
  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.

Original Secondary Outcome Measures (submitted: December 5, 2018)

• Adverse Events (AEs)/Serious Adverse Events (SAEs) for isatuximab + cemiplimab [ Time Frame: Up to 90 days after last study treatment administration (Up to approximately 27 months after first study treatment administration) ]
  Number of patients with AEs/SAEs
• Adverse Events/Serious Adverse Events for isatuximab + cemiplimab + radiotherapy [ Time Frame: Up to 90 days after last study treatment administration (Up to approximately 27 months after first study treatment administration) ]
  Number of patients with AEs/SAEs in cohorts A1 and A2
• Immunogenicity: Anti-drug antibody levels [ Time Frame: Up to 90 days following the last administration of study treatment or at the primary analysis cut-of date, whichever comes first ]
  Anti-drug antibody (ADA) levels against isatuximab and against cemiplimab
• Pharmacokinetic evaluation: Cmax [ Time Frame: Up to 90 days following the last administration of study treatment or at the primary analysis cut-of date, whichever comes first ]
  Maximum concentration observed after the first infusion
• Pharmacokinetic evaluation: Ctrough [ Time Frame: Up to 90 days following the last administration of study treatment or at the primary analysis cut-of date, whichever comes first ]
  Concentrations observed just before treatment administration during repeated dosing
• Pharmacokinetic evaluation: AUC0-T [ Time Frame: Up to 90 days following the last administration of study treatment or at the primary analysis cut-of date, whichever comes first ]
  Area under the concentration versus time curve calculated using the trapezoidal method over the dosing interval (ie, 6 days for isatuximab or 21 days for cemiplimab)
• Tumor burden change [ Time Frame: Up to 24 weeks after last patient treated in a given cohort ]
  The best percent-change from baseline
• Disease control rate [ Time Frame: Up to 24 weeks after last patient treated in a given cohort ]
  The sum of complete responses (CR) + partial responses (PR) + stable disease (SD)
• Duration of response [ Time Frame: Up to 24 weeks after last patient treated in a given cohort ]
  The time from the date of the first response (PR or CR in radiographic objective response) that is subsequently confirmed to the date of first confirmed disease progression or death, whichever occurs first
• Progression free survival [ Time Frame: Up to 24 weeks after last patient treated in a given cohort ]
  The time from the first study treatment administration to the date of first documentation of progressive disease or death, whichever comes first

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Isatuximab-based Therapy in Participants With Lymphoma
• Official Title: A Phase 1/2 Open-label, Multi-center, Safety, Preliminary Efficacy and Pharmacokinetic (PK) Study of Isatuximab in Combination With Other Anti-cancer Therapies in Participants With Lymphoma

Brief Summary

Primary Objectives:

Phase 1

-To characterize the safety and tolerability of isatuximab in combination with cemiplimab in participants with relapsed and refractory classic Hodgkin's lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL) or peripheral T-cell lymphoma (PTCL), and to confirm the recommended Phase 2 dose (RP2D).

Phase 2

• Cohort A1 (anti-programmed cell death protein 1/ligand 1 [PD-1/PD-L1] naïve cHL): To assess the complete remission (CR) rate of isatuximab in combination with cemiplimab.
• Cohort A2 (cHL progressing from PD-1/PD-L1), B (DLBCL) and C (PTCL): To assess the objective response rate (ORR) of isatuximab in combination with cemiplimab.

Secondary Objectives:

• To evaluate the safety of the RP2D of the combination of isatuximab with cemiplimab.
• To evaluate the safety of the combination of isatuximab with cemiplimab and radiotherapy in participants with cHL.
• To evaluate the immunogenicity of isatuximab and cemiplimab when given in combination.
• To characterize the pharmacokinetic (PK) profile of isatuximab and cemiplimab when given in combination.
• To assess overall efficacy of isatuximab in combination with cemiplimab and isatuximab in combination with cemiplimab and radiotherapy.

• Detailed Description: The total study duration per participant was up to 28 months, including an up to 28-day screening period, an up to 96-week treatment period, and a 90-day safety follow up period.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Lymphoma

Intervention

• Drug: isatuximab SAR650984

  Pharmaceutical form: solution for infusion

  Route of administration: intravenous

  Other Name: Sarclisa
• Drug: cemiplimab REGN2810

  Pharmaceutical form: solution for infusion

  Route of administration: intravenous

Study Arms

• Experimental: Cohort A1: cHL: Isatuximab + Cemiplimab
  Classic Hodgkin's lymphoma (cHL), anti-programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitor naïve participants received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion once a week (QW) in Cycle 1 and then every 2 weeks (Q2W) from Cycle 2 to Cycle 6 (each cycle of 28 days), and then every 3 weeks (Q3W) from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 milligrams (mg) Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30, with optional radiotherapy until, unacceptable adverse events (AEs) or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of complete response [CR], whichever was longer) of delivery of investigational medicinal product(s) without documented progressive disease (PD), or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
  Interventions:

  • Drug: isatuximab SAR650984
  • Drug: cemiplimab REGN2810
• Experimental: Cohort A2: cHL: Isatuximab + Cemiplimab
  cHL, anti-PD-1/PD-L1 inhibitor progressor participants received isatuximab 10 mg/kg, IV infusion, QW in Cycle 1 and then Q2W from Cycle 2 to Cycle 6 (each cycle of 28 days) and Q3W from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 mg Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30, with optional radiotherapy until, unacceptable AEs or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of CR, whichever was longer) of delivery of investigational medicinal product(s) without documented PD, or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
  Interventions:

  • Drug: isatuximab SAR650984
  • Drug: cemiplimab REGN2810
• Experimental: Cohort B: DLBCL: Isatuximab + Cemiplimab
  Diffuse large B-cell lymphoma (DLBCL), anti PD-1/PD-L1 naïve participants received isatuximab 10 mg/kg, IV infusion, QW in Cycle 1 and then Q2W from Cycle 2 to Cycle 6 (each cycle of 28 days) and Q3W from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 mg Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30 until, unacceptable AEs or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of CR, whichever was longer) of delivery of investigational medicinal product(s) without documented PD, or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
  Interventions:

  • Drug: isatuximab SAR650984
  • Drug: cemiplimab REGN2810
• Experimental: Cohort C: PTCL: Isatuximab + Cemiplimab
  Peripheral T-cell lymphoma (PTCL), anti PD-1/PD-L1 naïve participants received isatuximab 10 mg/kg, IV infusion, QW in Cycle 1 and then Q2W from Cycle 2 to Cycle 6 (each cycle of 28 days) and Q3W from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 mg Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30 until, unacceptable AEs or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of CR, whichever was longer) of delivery of investigational medicinal product(s) without documented PD, or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
  Interventions:

  • Drug: isatuximab SAR650984
  • Drug: cemiplimab REGN2810

• Publications *: Carlo-Stella C, Zinzani PL, Sureda A, Araujo L, Casasnovas O, Carpio C, Yeh SP, Bouabdallah K, Cartron G, Kim WS, Cordoba R, Koh Y, Re A, Alves D, Chamuleau M, Le Gouill S, Lopez-Guillermo A, Moreira I, van der Poel MWM, Abbadessa G, Meng R, Ji R, Lepine L, Saleem R, Ribrag V. A phase 1/2, open-label, multicenter study of isatuximab in combination with cemiplimab in patients with lymphoma. Hematol Oncol. 2023 Feb;41(1):108-119. doi: 10.1002/hon.3089. Epub 2022 Oct 31.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 28, 2022): 58
• Original Estimated Enrollment (submitted: December 5, 2018): 130
• Actual Study Completion Date: November 8, 2022
• Actual Primary Completion Date: November 8, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

• Participants greater than or equal to (>=) 12 years of age inclusive, at the time of signing the informed consent.
• Disease location amenable to tumor biopsy at Baseline.
• Measurable disease.
• For Cohort A1 (cHL anti-programmed cell death protein 1/ligand 1 [PD-1/PD-L1] inhibitor naïve): Histologically confirmed advanced cHL that had relapsed or progressed after at least 3 lines of systemic therapy that included autologous hematopoietic stem cell transplant (auto-HSCT) or auto-HSCT and brentuximab vedotin (BV).
• For Cohort A2 (cHL anti-PD-1/PD-L1 inhibitor progressor): Histologically confirmed advanced cHL which had relapsed or progressed after one previous anti-PD-1/PD-L1 containing regimen as the most recent prior therapy but no more than 4 lines of previous chemotherapy including the anti-PD-1/PD-L1 containing regimen and documentation of benefit during or after the anti-PD-1/PD-L1 containing regimen within 4 months prior to initiation of investigational medicinal product.
• For Cohort B (diffuse large B-cell lymphoma [DLBCL]): Histologically confirmed advanced DLBCL that had relapsed or progressed after 2 lines of systemic therapy including auto-HSCT or 2 lines of systemic therapy for participants who were not eligible for auto-HSCT.
• For Cohort C (peripheral T-cell lymphoma [PTCL]): Histologically confirmed advanced PTCL that had relapsed or progressed after either first-line chemotherapy and auto-HSCT as consolidation of first remission or first-line chemotherapy if participants were ineligible for auto-HSCT.
• Body weight of greater than (>) 45 kilograms for participants with age less than (<)18 years.

Exclusion criteria:

• Prior exposure to agent that blocks CD38.
• For participants with cHL (PD-1/PD-L1 naïve), DLBCL or PTCL prior exposure to any agent (approved or investigational) that blocks the PD-1/PD-L1, PD-L2, CD137, cytotic T-lymphocyte-associated protein 4 or LAG-3.
• Evidence of other immune related disease/conditions.
• Had received a live-virus vaccination within 28 days of planned treatment start; seasonal flu vaccines that do not contain live virus are permitted.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) >=2.
• Poor bone marrow reserve.
• Poor organ function.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Italy, Korea, Republic of, Netherlands, Portugal, Spain, Taiwan

Administrative Information

• NCT Number: NCT03769181
• Other Study ID Numbers: ACT15320; 2018-002442-37 ( EudraCT Number ); U1111-1211-9010 ( Registry Identifier: ICTRP )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

• Current Responsible Party: Sanofi
• Original Responsible Party: Same as current
• Current Study Sponsor: Sanofi
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: September 2023