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.
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
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
58
Pharmaceutical form: solution for infusion Route of administration: intravenous
Pharmaceutical form: solution for infusion Route of administration: intravenous
Investigational Site Number :2500005
Dijon, France
Investigational Site Number :2500004
Montpellier, France
Investigational Site Number :2500002
Nantes, France
Investigational Site Number :2500007
Pessac, France
Investigational Site Number :2500001
Villejuif, France
Investigational Site Number :3800003
Rozzano, Milano, Italy
Investigational Site Number :3800002
Bologna, Italy
Investigational Site Number :3800006
Brescia, Italy
Investigational Site Number :5280002
Amsterdam, Netherlands
Investigational Site Number :5280001
Maastricht, Netherlands
...and 10 more locations
Number of Participants With Dose Limiting Toxicities (DLTs)
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)
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 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)
Number of Participants With Laboratory Abnormalities: Hematological Parameters
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)
Number of Participants With Laboratory Abnormalities: Electrolytes
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)
Number of Participants With Laboratory Abnormalities: Renal Parameters
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)
Number of Participants With Laboratory Abnormalities: Liver Function Parameters
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)
Cohort A1: Percentage of Participants With Complete Response (CR)
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)
Cohort A2, B and C: Percentage of Participants With Objective Response (OR)
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)
Number of Participants With Treatment-Induced and Treatment Boosted Antidrug Antibodies (ADA) Against Isatuximab
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)
Number of Participants With Treatment-Induced and Treatment Boosted Antidrug Antibodies (ADA) Against Cemiplimab
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)
Pharmacokinetics (PK) Parameter: Plasma Concentration of Isatuximab at End of Infusion (CEOI)
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
PK Parameter: Maximum Observed Plasma Concentration (Cmax) After the First Infusion of Isatuximab
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
PK Parameter: Time to Reach Cmax (Tmax) After the First Infusion of Isatuximab
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
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PK Parameter: Area Under the Plasma Concentration (AUClast) Versus Time Curve After the First Infusion of Isatuximab
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
PK Parameter: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab
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
PK Parameter: Time of Clast (Tlast) After the First Infusion of Isatuximab
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
PK Parameter: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUC0-168 Hours) After the First Infusion of Isatuximab
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
PK Parameter: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUC0-144 Hours) After the First Infusion of Isatuximab
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
PK Parameter: Plasma Trough Concentration (Ctrough) of Isatuximab
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
PK Parameter: Serum Concentration of Cemiplimab at End of Infusion (CEOI)
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
PK Parameter: Maximum Observed Concentration (Cmax) After the First Infusion of Cemiplimab
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
PK Parameter: Time to Reach Cmax (Tmax) After the First Infusion of Cemiplimab
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
PK Parameter: Area Under the Serum Concentration (AUClast) Versus Time Curve After the First Infusion of Cemiplimab
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
PK Parameter: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Cemiplimab
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
PK Parameter: Time of Clast (Tlast) After the First Infusion of Cemiplimab
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
PK Parameter: Area Under the Serum Concentration Versus Time Curve Over the Dosing Interval (AUC0-336 Hours) After the First Infusion of Cemiplimab
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
PK Parameter: Serum Trough Concentration (Ctrough) of Cemiplimab
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
Percent Change From Baseline in Tumor Burden
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
Duration of Response (DOR)
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)
Percentage of Participants With Disease Control (DC)
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)
Progression Free Survival (PFS)
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)
Cohort A1 and A2: Percentage of Participants With Objective Response
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)
Cohort A1 and A2: Percentage of Participants With Complete Response
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)