A Phase 1/2 interventional study of Isatuximab SAR650984 in Multiple Myeloma, sponsored by Sanofi. Completed at 13 sites in Japan. Open to participants aged 20 Years and older. Per ClinicalTrials.gov, last updated 2024-04-01.
Sponsored by Sanofi · Phase 1/2, Interventional, and Treatment
Primary Objectives:
Secondary Objectives:
The study duration for an individual participant included a screening period for inclusion of up to 21 days, the treatment period consisting of 28-day cycles and a follow-up period. Treatment with isatuximab might continue until disease progression, unacceptable adverse event, or other reason for discontinuation.
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Exclusion criteria:
The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Participants received Isatuximab 10 milligram per kilogram (mg/kg) intravenous (IV) infusion once every week (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1), and then every 2 weeks (Q2W) (i.e., on Day 1 and 15) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events, disease progression, or any other reason for discontinuation whichever occurs first (maximum duration of exposure: 112 weeks).
Drug: Isatuximab SAR650984
Participants received Isatuximab 20 mg/kg IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1), and then Q2W (i.e., on Day 1 and 15) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events, disease progression, or any other reason for discontinuation whichever occurs first (maximum duration of exposure: 137 weeks).
Drug: Isatuximab SAR650984
Participants received Isatuximab 20 mg/kg IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1), and then Q2W (i.e., on Day 1 and 15) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events, disease progression, or any other reason for discontinuation whichever occurs first (maximum duration of exposure: 248 weeks).
Drug: Isatuximab SAR650984
Pharmaceutical form: solution Route of administration: intravenous
Also known as: Sarclisa
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
DLTs: AEs occurring during 1st treatment cycle, assessed per national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) version 4.03. DLTs included: Hematologic DLTs: Grade(G) 4 neutropenia(N) lasting greater than or equal to (\>=) 5 days; G3 to G4 N with fever or microbiologically or radiographically documented infection; G4 thrombocytopenia lasting for \>=5 days; thrombocytopenia, treatment delay greater than (\>)14 days due to hematologic toxicity. Non-hematologic DLTs: G\>=3 non-hematological AE, excluding G3 fatigue, G 3 to 4 electrolyte abnormalities, G3 nausea/vomiting/diarrhea if responsive to optimal medical management within 48 hours or allergic reaction/ hypersensitivity attributed to isatuximab; AE that required treatment delay for \>14 days. Any other toxicity deemed by Investigator or sponsor to be dose-limiting, regardless of the grade, was also considered DLT.
Time frame: Cycle 1 (28 days)
Phase 2: Percentage of Participants With Overall Response (OR)
Percentage of participants with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) assessed by International Myeloma Working Group (IMWG) uniform response criteria. sCR: CR as defined plus normal FLC ratio \& absence of clonal cells in bone marrow. CR: negative immunofixation on serum \& urine; disappearance of any soft tissue plasmacytomas; \<5% plasma cells in bone marrow; normal FLC ratio of 0.26-1.65. VGPR: serum \& urine M-protein detectable by immunofixation; \>=90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 h; \>90% decrease in difference between involved \& uninvolved FLC levels required. PR: \>=50% reduction of serum M-protein \& reduction in 24h urinary M protein by \>=90%/\<200 mg/24 h; if serum \& urine M-protein unmeasurable:\>=50% decrease in difference between involved \& uninvolved FLC; if serum \& urine M-protein not measurable:\>=50% reduction in plasma cells required, in place of M-protein.
Time frame: From the date of the first response until the primary analysis data cut-off date of 31 July 2018 (median duration of follow-up was 24.14 weeks)
Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
An AE was defined as any untoward medical occurrence in a participant or clinical investigation patient administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as 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 develop, worsened or became serious during the on-treatment period (time from first dose of study drug up to 30 days after the last dose of study drug administration).
Time frame: From first dose of study drug up to 30 days after the last dose of study drug administration (maximum duration of exposure: up to 112 weeks for Cohort 1 and 137 weeks for Cohort 2)
Phase 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
An AE was defined as any untoward medical occurrence in a participant or clinical investigation patient administered with a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as 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 are defined as AEs that develop, worsened or became serious during the on-treatment period (time from first dose of study drug up to 30 days after the last dose of study drug administration).
Time frame: From first dose of study drug up to 30 days after the last dose of study drug administration (maximum duration of exposure: up to 248 weeks)
Phase 1: Percentage of Participants With Overall Response (OR)
Percentage of participants with sCR, CR, VGPR, and PR assessed by IMWG uniform response criteria. sCR: CR as defined plus normal FLC ratio \& absence of clonal cells in bone marrow. CR: negative immunofixation on serum \& urine; disappearance of any soft tissue plasmacytomas; \<5 percentage (%) plasma cells in bone marrow; normal FLC ratio of 0.26-1.65. VGPR: serum \& urine M-protein detectable by immunofixation; \>=90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 hour (h); \>90% decrease in difference between involved \& uninvolved FLC levels required. PR: \>=50% reduction of serum M-protein \& reduction in 24h urinary M protein by \>=90%/\<200 mg/24 h; if serum \& urine M-protein unmeasurable:\>=50% decrease in difference between involved \& uninvolved FLC; if serum \& urine M-protein not measurable:\>=50% reduction in plasma cells required, in place of M-protein.
Time frame: From the date of the first response until disease progression, or death due to any cause, whichever comes first (maximum duration of exposure: up to 112 weeks for Cohort 1 and 137 weeks for Cohort 2)
Phase 1: Duration of Response (DOR)
DOR: time (in weeks) from date of first response to date of subsequent progressive disease (PD) or death, whichever happens earlier. In absence of confirmation of subsequent PD or death before cut-off date, DOR was censored at date of last valid assessment performed or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria): increase (inc.) of \>=25% from lowest response value in any one of following: serum M-component (absolute inc.\>=0.5 g/dL) and/or; urine M-component (absolute inc.\>=200 mg/24h) and/or, in participants without measurable serum \& urine M-protein: difference between involved \& uninvolved FLC levels (absolute inc. \>10 mg/dL); in participants without measurable serum \& urine M-protein and without measurable disease by FLC levels, bone marrow plasma cell % (absolute % \>=10%); development of new bone lesions or soft tissue plasmacytomas/definite inc. in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia.
Time frame: From the date of the first response until disease progression, or death due to any cause, whichever comes first (maximum duration of exposure: up to 112 weeks for Cohort 1 and 137 weeks for Cohort 2)
Phase 2: Percentage of Participants With Clinical Benefit (CB)
CB defined as percentage of participants with sCR, CR, VGPR, PR or Minor/minimal response (MR) assessed by IMWG criteria. sCR: CR as defined plus normal FLC ratio \& absence of clonal cells. CR: negative immunofixation on serum \& urine; disappearance of any soft tissue plasmacytomas; \<5% plasma cells in bone marrow; normal FLC ratio: 0.26-1.65. VGPR: serum \& urine M-protein detectable by immunofixation; \>=90% reduction in serum M-protein plus urine M-protein level \<100 mg/24h; \>90% decrease in difference between involved \& uninvolved FLC levels required. PR: \>=50% reduction of serum M-protein \& reduction in 24h urinary M protein by \>=90%/\<200 mg/24 h; if serum \& urine M-protein unmeasurable:\>=50% decrease in difference between involved \& uninvolved FLC; if serum \& urine M-protein not measurable:\>=50% reduction in plasma cells required. MR: \>=25% but \<=49% reduction of serum M protein and reduction in 24h urine M protein by 50-89%; 25-49% reduction in size of soft tissue plasmacytomas.
Time frame: From date of first study treatment administration until first documented response, or death due to any cause, whichever comes first (maximum duration of exposure: up to 248 weeks)
Phase 2: Overall Survival (OS)
Overall survival was defined as the time interval (in months) from the date of first study treatment administration to death due to any cause. In the absence of the confirmation of death before the cut-off date, OS was censored at the last date the participant was known to be alive or at the study cut-off date, whichever was earlier. Analysis was performed by Kaplan-Meier method.
Time frame: From date of first study treatment administration to the date of death due to any cause (maximum duration of exposure: up to 248 weeks)
Phase 2: Progression Free Survival (PFS)
PFS was defined as the time interval (in months) from date of first study treatment administration until disease progression or death due to any cause, whichever comes first. In absence of PD or death, PFS was censored at date of last valid assessment performed before cut-off date or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria): inc. of \>=25% in any one of following: serum M-component absolute (abs.) inc. \>=0.5 g/dL) and/or; urine M-component (abs. inc. \>=200 mg/24h) and/or, in participants without measurable serum \& urine M-protein, difference between involved \& uninvolved FLC levels (abs. inc. \>10 mg/dL); in participants without measurable serum \& urine M-protein \& without measurable disease by FLC levels: bone marrow plasma cell % (abs. % \>=10%); definite development of new bone lesions or soft tissue plasmacytomas or definite inc. in size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia.
Time frame: From date of first study treatment administration until disease progression or death due to any cause, whichever comes first (maximum duration of exposure: up to 248 weeks)
Phase 2: Duration of Response (DOR)
DOR was defined as time (in weeks) from date of first response to date of subsequent progressive disease (PD) or death, whichever happens earlier. In absence of confirmation of subsequent PD or death before cut-off date, DOR was censored at date of last valid assessment performed or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria):inc. of \>=25% from lowest response value in any one of following: serum M-component (absolute inc.\>=0.5 g/dL) and/or; urine M-component (absolute inc.\>=200 mg/24h) and/or, in participants without measurable serum \& urine M-protein: difference between involved \& uninvolved FLC levels (absolute inc.\>10 mg/dL); in participants without measurable serum \& urine M-protein and without measurable disease by FLC levels, bone marrow plasma cell % (absolute% \>=10%); development of new bone lesions or soft tissue plasmacytomas/definite inc. in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia.
Time frame: From the date of first response until disease progression, or death due to any cause, whichever comes first (maximum duration of exposure: up to 248 weeks)
Phase 2: Time to Progression (TTP)
TTP: time interval (in months) from date of first study treatment administration to date of first assessed disease progression. In absence of disease progression, TTP was censored at date of last valid assessment performed before cut-off date or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria): inc. of \>=25% from lowest response value in any one of following: serum M-component (absolute inc.\>=0.5 g/dL) and/or; urine M-component (absolute inc.\>=200 mg/24h) and/or, in participants without measurable serum \& urine M-protein: difference between involved \& uninvolved FLC levels (absolute inc.\>10 mg/dL); in participants without measurable serum \& urine M-protein and without measurable disease by FLC levels, bone marrow plasma cell % (absolute% \>=10%); development of new bone lesions or soft tissue plasmacytomas/definite inc. in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia.
Time frame: From date of first study treatment administration until disease progression, or death due to any cause, whichever comes first (maximum duration of exposure: up to 248 weeks)
Phase 1: Plasma Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab
Ceoi is the plasma concentration observed at the end of intravenous infusion.
Time frame: End of infusion on Day 1 of Cycle 1
Phase 1: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab
Cmax was defined as the maximum concentration observed after the first infusion calculated using the non-compartmental analysis.
Time frame: Cycle 1 Day 1 at 0 hour (pre-dose), mid-infusion (2 hours post-infusion), end of infusion (EOI) and EOI+4-hour, Day 2 (24 hour), Day 3 (48 hour), Day 4 (72 hour) and pre-dose on Day 8 (0 hour)
Phase 1: Time to Reach the Maximum Concentration (Tmax) After First Infusion of Isatuximab
Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion.
Time frame: Cycle 1 Day 1 at 0 hour (pre-dose), mid-infusion (2 hours post-infusion), EOI and EOI+4-hour, Day 2 (24 hour), Day 3 (48 hour), Day 4 (72 hour) and pre-dose on Day 8 (0 hour)
Phase 1: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-week) After First Infusion of Isatuximab
AUC was defined as area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval.
Time frame: Cycle 1 Day 1 at 0 hour (pre-dose), mid-infusion (2 hours post-infusion), EOI and EOI+4-hour, Day 2 (24 hour), Day 3 (48 hour), Day 4 (72 hour) and pre-dose on Day 8 (0 hour)
Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab
Ctrough was the plasma concentration observed just before treatment administration during repeated dosing.
Time frame: Pre-infusion on Cycle 1 Day 8 (C1 D8), C1 D15, C1 D22, C2 D1, C2 D15, C3 D1, C3 D15, C4 D1, C4 D15, C5 D1, C5 D15, C6 D1, C6 D15, C7 D1, C7 D15, C8 D1, C8 D15, C9 D1, C9 D15, C10 D1, C10 D15, C11 D1
Phase 2: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab
Cmax was predicted using population pharmacokinetic model.
Time frame: Multiple timepoints from Cycle 1 to Cycle 10
Phase 2: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-Week) After First Infusion of Isatuximab
AUC was predicted using population pharmacokinetic model.
Time frame: Multiple timepoints from Cycle 1 to Cycle 10
Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab
Ctrough was the plasma concentration observed just before treatment administration during repeated dosing.
Time frame: Pre-infusion on C1 D8, C1 D15, C1 D22, C2 D1, C2 D15, C3 D1, C3 D15, C4 D1, C4 D15, C5 D1, C5 D15, C6 D1, C6 D15, C7 D1, C7 D15, C8 D1, C8 D15, C9 D1, C9 D15, C10 D1, C10 D15
Phase 1 and 2: CD38 Receptor Density at Baseline
CD38 receptor density assessed from bone marrow aspirates for responder and non-responders' participants was reported.
Time frame: At Baseline (Day 1)
Phase 1: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab
ADA were categorized as: treatment induced, and treatment boosted response. Treatment-induced ADA: ADA that developed at any time during the ADA on-study observation period in participants without preexisting ADA (ADA that was present in samples drawn during the ADA pretreatment period). Treatment boosted ADA: Preexisting ADA with an increase in titer value between pretreatment \& posttreatment samples of at least two titer steps, during the ADA on-study observation period.
Time frame: From first dose of study drug up to 30 days after last study drug administration (maximum duration of exposure: up to 112 weeks for Cohort 1, and 137 weeks for Cohort 2)
Phase 2: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab
ADA were categorized as: treatment induced, and treatment boosted response. Treatment-induced ADA: ADA that developed at any time during the ADA on-study observation period in participants without preexisting ADA (ADA that was present in samples drawn during the ADA pretreatment period). Treatment boosted ADA: Preexisting ADA with an increase in titer value between pretreatment \& posttreatment samples of at least two titer steps, during the ADA on-study observation period.
Time frame: From first dose of study drug up to 30 days after last study drug administration (maximum duration of exposure: up to 248 weeks)
The study was conducted at 13 centers in Japan. A total of 36 participants were enrolled between 05 September 2016 and 6 April 2018, and received isatuximab monotherapy.
| Milestone | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 2: Isatuximab 20 mg/kg |
|---|---|---|---|
| Started | 3 | 5 | 0 |
| Completed | 0 | 0 | 0 |
| Not completed | 3 | 5 | 0 |
| Withdrew: Adverse event | 0 | 2 | 0 |
| Withdrew: Progressive disease | 3 | 3 | 0 |
| Milestone | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 2: Isatuximab 20 mg/kg |
|---|---|---|---|
| Started | 0 | 0 | 28 |
| Completed | 0 | 0 | 0 |
| Not completed | 0 | 0 | 28 |
| Withdrew: Adverse event | 0 | 0 | 2 |
| Withdrew: Progressive disease | 0 | 0 | 22 |
| Withdrew: Other-unspecified | 0 | 0 | 4 |
DLTs: AEs occurring during 1st treatment cycle, assessed per national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) version 4.03. DLTs included: Hematologic DLTs: Grade(G) 4 neutropenia(N) lasting greater than or equal to (\>=) 5 days; G3 to G4 N with fever or microbiologically or radiographically documented infection; G4 thrombocytopenia lasting for \>=5 days; thrombocytopenia, treatment delay greater than (\>)14 days due to hematologic toxicity. Non-hematologic DLTs: G\>=3 non-hematological AE, excluding G3 fatigue, G 3 to 4 electrolyte abnormalities, G3 nausea/vomiting/diarrhea if responsive to optimal medical management within 48 hours or allergic reaction/ hypersensitivity attributed to isatuximab; AE that required treatment delay for \>14 days. Any other toxicity deemed by Investigator or sponsor to be dose-limiting, regardless of the grade, was also considered DLT.
| Participants | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg |
|---|---|---|
| Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 | 0 |
Percentage of participants with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) assessed by International Myeloma Working Group (IMWG) uniform response criteria. sCR: CR as defined plus normal FLC ratio \& absence of clonal cells in bone marrow. CR: negative immunofixation on serum \& urine; disappearance of any soft tissue plasmacytomas; \<5% plasma cells in bone marrow; normal FLC ratio of 0.26-1.65. VGPR: serum \& urine M-protein detectable by immunofixation; \>=90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 h; \>90% decrease in difference between involved \& uninvolved FLC levels required. PR: \>=50% reduction of serum M-protein \& reduction in 24h urinary M protein by \>=90%/\<200 mg/24 h; if serum \& urine M-protein unmeasurable:\>=50% decrease in difference between involved \& uninvolved FLC; if serum \& urine M-protein not measurable:\>=50% reduction in plasma cells required, in place of M-protein.
| percentage of participants | Phase 2: Isatuximab 20 mg/kg |
|---|---|
| Phase 2: Percentage of Participants With Overall Response (OR) | 32.1 |
An AE was defined as any untoward medical occurrence in a participant or clinical investigation patient administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as 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 develop, worsened or became serious during the on-treatment period (time from first dose of study drug up to 30 days after the last dose of study drug administration).
| Participants | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg |
|---|---|---|
| TEAEs | 3 | 4 |
| TESAEs | 1 | 2 |
An AE was defined as any untoward medical occurrence in a participant or clinical investigation patient administered with a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as 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 are defined as AEs that develop, worsened or became serious during the on-treatment period (time from first dose of study drug up to 30 days after the last dose of study drug administration).
| Participants | Phase 2: Isatuximab 20 mg/kg |
|---|---|
| TEAEs | 25 |
| TESAEs | 11 |
Percentage of participants with sCR, CR, VGPR, and PR assessed by IMWG uniform response criteria. sCR: CR as defined plus normal FLC ratio \& absence of clonal cells in bone marrow. CR: negative immunofixation on serum \& urine; disappearance of any soft tissue plasmacytomas; \<5 percentage (%) plasma cells in bone marrow; normal FLC ratio of 0.26-1.65. VGPR: serum \& urine M-protein detectable by immunofixation; \>=90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 hour (h); \>90% decrease in difference between involved \& uninvolved FLC levels required. PR: \>=50% reduction of serum M-protein \& reduction in 24h urinary M protein by \>=90%/\<200 mg/24 h; if serum \& urine M-protein unmeasurable:\>=50% decrease in difference between involved \& uninvolved FLC; if serum \& urine M-protein not measurable:\>=50% reduction in plasma cells required, in place of M-protein.
| percentage of participants | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg |
|---|---|---|
| Phase 1: Percentage of Participants With Overall Response (OR) | 66.7 | 60.0 |
DOR: time (in weeks) from date of first response to date of subsequent progressive disease (PD) or death, whichever happens earlier. In absence of confirmation of subsequent PD or death before cut-off date, DOR was censored at date of last valid assessment performed or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria): increase (inc.) of \>=25% from lowest response value in any one of following: serum M-component (absolute inc.\>=0.5 g/dL) and/or; urine M-component (absolute inc.\>=200 mg/24h) and/or, in participants without measurable serum \& urine M-protein: difference between involved \& uninvolved FLC levels (absolute inc. \>10 mg/dL); in participants without measurable serum \& urine M-protein and without measurable disease by FLC levels, bone marrow plasma cell % (absolute % \>=10%); development of new bone lesions or soft tissue plasmacytomas/definite inc. in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia.
| weeks | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg |
|---|---|---|
| Phase 1: Duration of Response (DOR) | 100.64 ± 7.78 | 113.90 ± 18.45 |
CB defined as percentage of participants with sCR, CR, VGPR, PR or Minor/minimal response (MR) assessed by IMWG criteria. sCR: CR as defined plus normal FLC ratio \& absence of clonal cells. CR: negative immunofixation on serum \& urine; disappearance of any soft tissue plasmacytomas; \<5% plasma cells in bone marrow; normal FLC ratio: 0.26-1.65. VGPR: serum \& urine M-protein detectable by immunofixation; \>=90% reduction in serum M-protein plus urine M-protein level \<100 mg/24h; \>90% decrease in difference between involved \& uninvolved FLC levels required. PR: \>=50% reduction of serum M-protein \& reduction in 24h urinary M protein by \>=90%/\<200 mg/24 h; if serum \& urine M-protein unmeasurable:\>=50% decrease in difference between involved \& uninvolved FLC; if serum \& urine M-protein not measurable:\>=50% reduction in plasma cells required. MR: \>=25% but \<=49% reduction of serum M protein and reduction in 24h urine M protein by 50-89%; 25-49% reduction in size of soft tissue plasmacytomas.
| percentage of participants | Phase 2: Isatuximab 20 mg/kg |
|---|---|
| Phase 2: Percentage of Participants With Clinical Benefit (CB) | 53.6 |
Overall survival was defined as the time interval (in months) from the date of first study treatment administration to death due to any cause. In the absence of the confirmation of death before the cut-off date, OS was censored at the last date the participant was known to be alive or at the study cut-off date, whichever was earlier. Analysis was performed by Kaplan-Meier method.
| months | Phase 2: Isatuximab 20 mg/kg |
|---|---|
| Phase 2: Overall Survival (OS) | NA (20.24 to NA) |
PFS was defined as the time interval (in months) from date of first study treatment administration until disease progression or death due to any cause, whichever comes first. In absence of PD or death, PFS was censored at date of last valid assessment performed before cut-off date or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria): inc. of \>=25% in any one of following: serum M-component absolute (abs.) inc. \>=0.5 g/dL) and/or; urine M-component (abs. inc. \>=200 mg/24h) and/or, in participants without measurable serum \& urine M-protein, difference between involved \& uninvolved FLC levels (abs. inc. \>10 mg/dL); in participants without measurable serum \& urine M-protein \& without measurable disease by FLC levels: bone marrow plasma cell % (abs. % \>=10%); definite development of new bone lesions or soft tissue plasmacytomas or definite inc. in size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia.
| months | Phase 2: Isatuximab 20 mg/kg |
|---|---|
| Phase 2: Progression Free Survival (PFS) | 5.6 (3.75 to 12.98) |
DOR was defined as time (in weeks) from date of first response to date of subsequent progressive disease (PD) or death, whichever happens earlier. In absence of confirmation of subsequent PD or death before cut-off date, DOR was censored at date of last valid assessment performed or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria):inc. of \>=25% from lowest response value in any one of following: serum M-component (absolute inc.\>=0.5 g/dL) and/or; urine M-component (absolute inc.\>=200 mg/24h) and/or, in participants without measurable serum \& urine M-protein: difference between involved \& uninvolved FLC levels (absolute inc.\>10 mg/dL); in participants without measurable serum \& urine M-protein and without measurable disease by FLC levels, bone marrow plasma cell % (absolute% \>=10%); development of new bone lesions or soft tissue plasmacytomas/definite inc. in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia.
| weeks | Phase 2: Isatuximab 20 mg/kg |
|---|---|
| Phase 2: Duration of Response (DOR) | 58.70 ± 29.91 |
TTP: time interval (in months) from date of first study treatment administration to date of first assessed disease progression. In absence of disease progression, TTP was censored at date of last valid assessment performed before cut-off date or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria): inc. of \>=25% from lowest response value in any one of following: serum M-component (absolute inc.\>=0.5 g/dL) and/or; urine M-component (absolute inc.\>=200 mg/24h) and/or, in participants without measurable serum \& urine M-protein: difference between involved \& uninvolved FLC levels (absolute inc.\>10 mg/dL); in participants without measurable serum \& urine M-protein and without measurable disease by FLC levels, bone marrow plasma cell % (absolute% \>=10%); development of new bone lesions or soft tissue plasmacytomas/definite inc. in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia.
| months | Phase 2: Isatuximab 20 mg/kg |
|---|---|
| Phase 2: Time to Progression (TTP) | 5.5 (3.745 to 12.977) |
Ceoi is the plasma concentration observed at the end of intravenous infusion.
| micrograms per milliliter | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg |
|---|---|---|
| Phase 1: Plasma Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab | 122 ± 21.6 | 246 ± 51.8 |
Cmax was defined as the maximum concentration observed after the first infusion calculated using the non-compartmental analysis.
| micrograms per milliliter | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg |
|---|---|---|
| Phase 1: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab | 124 ± 22.9 | 280 ± 64.4 |
Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion.
| hours | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg |
|---|---|---|
| Phase 1: Time to Reach the Maximum Concentration (Tmax) After First Infusion of Isatuximab | 2.68 (2.32 to 7.25) | 5.56 (3.28 to 8.48) |
AUC was defined as area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval.
| micrograms*hours per milliliter | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg |
|---|---|---|
| Phase 1: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-week) After First Infusion of Isatuximab | 9300 ± 3010 | 21300 ± 5520 |
Ctrough was the plasma concentration observed just before treatment administration during repeated dosing.
| micrograms per milliliter | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg |
|---|---|---|
| Cycle 1 Day 8 | 23.77 ± 8.98 | 78.52 ± 38.49 |
| Cycle 1 Day 15 | 71.33 ± 22.87 | 186.33 ± 69.29 |
| Cycle 1 Day 22 | 124.87 ± 69.51 | 254.00 ± 97.45 |
| Cycle 2 Day 1 | 135.57 ± 125.10 | 367.75 ± 127.45 |
| Cycle 2 Day 15 | 167.80 ± 154.43 | 419.08 ± 351.57 |
| Cycle 3 Day 1 | 174.40 ± 184.70 | 500.98 ± 426.78 |
| Cycle 3 Day 15 | 193.50 ± 154.86 | 347.75 ± 259.68 |
| Cycle 4 Day 1 | 202.85 ± 172.75 | 344.30 ± 286.74 |
| Cycle 4 Day 15 | 184.85 ± 182.65 | 392.63 ± 322.70 |
| Cycle 5 Day 1 | 220.40 ± 228.54 | 608.00 ± 351.93 |
| Cycle 5 Day 15 | 233.00 ± 237.59 | 581.33 ± 356.35 |
| Cycle 6 Day 1 | 267.50 ± 280.72 | 665.67 ± 385.34 |
| Cycle 6 Day 15 | 160.60 ± 116.53 | 714.33 ± 451.44 |
| Cycle 7 Day 1 | 200.15 ± 165.25 | 611.67 ± 342.27 |
| Cycle 7 Day 15 | 254.50 ± 228.40 | 641.67 ± 246.78 |
| Cycle 8 Day 1 | 303.00 ± 278.60 | 874.67 ± 408.85 |
| Cycle 8 Day 15 | 242.50 ± 88.39 | 789.67 ± 525.08 |
| Cycle 9 Day 1 | 269.00 ± 147.08 | 722.67 ± 379.50 |
| Cycle 9 Day 15 | 444.00 ± 463.86 | 758.33 ± 393.20 |
| Cycle 10 Day 1 | 436.50 ± 441.94 | 941.67 ± 576.67 |
| Cycle 10 Day 15 | 684.00 ± 772.16 | 1224.67 ± 719.96 |
| Cycle 11 Day 1 | 592.00 | — |
Cmax was predicted using population pharmacokinetic model.
| micrograms per milliliter | Phase 2: Isatuximab 20 mg/kg |
|---|---|
| Phase 2: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab | 747.83 ± 743.83 |
AUC was predicted using population pharmacokinetic model.
| micrograms * hours per milliliter | Phase 2: Isatuximab 20 mg/kg |
|---|---|
| Phase 2: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-Week) After First Infusion of Isatuximab | 65071 ± 55554 |
Ctrough was the plasma concentration observed just before treatment administration during repeated dosing.
| micrograms per milliliter | Phase 2: Isatuximab 20 mg/kg |
|---|---|
| Cycle 1 Day 8 | 376.34 ± 666.40 |
| Cycle 1 Day 15 | 662.52 ± 1283.39 |
| Cycle 1 Day 22 | 604.17 ± 996.78 |
| Cycle 2 Day 1 | 927.63 ± 1194.16 |
| Cycle 2 Day 15 | 826.15 ± 958.75 |
| Cycle 3 Day 1 | 734.39 ± 675.85 |
| Cycle 3 Day 15 | 689.85 ± 715.21 |
| Cycle 4 Day 1 | 723.76 ± 802.83 |
| Cycle 4 Day 15 | 619.35 ± 356.21 |
| Cycle 5 Day 1 | 647.24 ± 338.97 |
| Cycle 5 Day 15 | 683.90 ± 391.48 |
| Cycle 6 Day 1 | 674.20 ± 439.78 |
| Cycle 6 Day 15 | 742.93 ± 420.34 |
| Cycle 7 Day 1 | 733.83 ± 373.26 |
| Cycle 7 Day 15 | 786.27 ± 331.38 |
| Cycle 8 Day 1 | 870.09 ± 443.79 |
| Cycle 8 Day 15 | 1004.00 ± 463.82 |
| Cycle 9 Day 1 | 946.25 ± 369.91 |
| Cycle 9 Day 15 | 878.63 ± 313.39 |
| Cycle 10 Day 1 | 823.75 ± 314.95 |
| Cycle 10 Day 15 | 845.38 ± 322.48 |
CD38 receptor density assessed from bone marrow aspirates for responder and non-responders' participants was reported.
| sMEC | Non-responder | Responder |
|---|---|---|
| Phase 1 and 2: CD38 Receptor Density at Baseline | 113226.2 ± 93628.7 | 133378.2 ± 55518.5 |
ADA were categorized as: treatment induced, and treatment boosted response. Treatment-induced ADA: ADA that developed at any time during the ADA on-study observation period in participants without preexisting ADA (ADA that was present in samples drawn during the ADA pretreatment period). Treatment boosted ADA: Preexisting ADA with an increase in titer value between pretreatment \& posttreatment samples of at least two titer steps, during the ADA on-study observation period.
| Participants | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg |
|---|---|---|
| Treatment-induced ADA | 0 | 0 |
| Treatment boosted ADA | 0 | 0 |
ADA were categorized as: treatment induced, and treatment boosted response. Treatment-induced ADA: ADA that developed at any time during the ADA on-study observation period in participants without preexisting ADA (ADA that was present in samples drawn during the ADA pretreatment period). Treatment boosted ADA: Preexisting ADA with an increase in titer value between pretreatment \& posttreatment samples of at least two titer steps, during the ADA on-study observation period.
| Participants | Phase 2: Isatuximab 20 mg/kg |
|---|---|
| Treatment-induced ADA | 6 |
| Treatment boosted ADA | 0 |
Collected over AE data was collected from first dose of study drug up to 30 days after last dose of study drug administration (maximum duration of exposure: up to 112 weeks for Cohort 1, and 137 weeks for Cohort 2 for Phase 1 part; and up to 248 weeks for Phase 2 part). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | 1/3 (33.3%) | 1/3 (33.3%) | 3/3 (100%) |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | 2/5 (40%) | 2/5 (40%) | 4/5 (80%) |
| Phase 2: Isatuximab 20 mg/kg | 10/28 (35.7%) | 11/28 (39.3%) | 24/28 (85.7%) |
| Event | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 2: Isatuximab 20 mg/kg |
|---|---|---|---|
| PneumoniaInfections and infestations | 1/3 | 0/5 | 2/28 |
| Deep Vein ThrombosisVascular disorders | 1/3 | 0/5 | 0/28 |
| Disease ProgressionGeneral disorders | 0/3 | 1/5 | 0/28 |
| DiplegiaNervous system disorders | 0/3 | 1/5 | 0/28 |
| Subarachnoid HaemorrhageNervous system disorders | 0/3 | 1/5 | 0/28 |
| Neurogenic BladderRenal and urinary disorders | 0/3 | 1/5 | 0/28 |
| Disseminated Intravascular CoagulationBlood and lymphatic system disorders | 0/3 | 0/5 | 1/28 |
| CataractEye disorders | 0/3 | 0/5 | 1/28 |
| IleusGastrointestinal disorders | 0/3 | 0/5 | 1/28 |
| Large Intestine PolypGastrointestinal disorders | 0/3 | 0/5 | 1/28 |
| Event | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 2: Isatuximab 20 mg/kg |
|---|---|---|---|
| NasopharyngitisInfections and infestations | 2/3 | 1/5 | 6/28 |
| Infusion Related ReactionInjury, poisoning and procedural complications | 2/3 | 1/5 | 12/28 |
| VomitingGastrointestinal disorders | 1/3 | 2/5 | 2/28 |
| ConjunctivitisInfections and infestations | 1/3 | 0/5 | 1/28 |
| Hand-Foot-And-Mouth DiseaseInfections and infestations | 1/3 | 0/5 | 0/28 |
| PharyngitisInfections and infestations | 1/3 | 0/5 | 2/28 |
| SinusitisInfections and infestations | 1/3 | 0/5 | 1/28 |
| Upper Respiratory Tract InfectionInfections and infestations | 1/3 | 0/5 | 1/28 |
| LeukopeniaBlood and lymphatic system disorders | 1/3 | 0/5 | 2/28 |
| LymphopeniaBlood and lymphatic system disorders | 1/3 | 0/5 | 1/28 |
Analysis was performed on all treated population which included all participants who gave their informed consent and received at least one dose (even incomplete) of isatuximab.
| Age, Continuous(years) | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 2: Isatuximab 20 mg/kg | Total |
|---|---|---|---|---|
| Mean | 67.3 ± 7.6 | 74.4 ± 4.7 | 70.6 ± 8.1 | 70.9 ± 7.7 |
| Sex: Female, Male(Participants) | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 2: Isatuximab 20 mg/kg | Total |
|---|---|---|---|---|
| Female | 2 | 4 | 10 | 16 |
| Male | 1 | 1 | 18 | 20 |
| Race (NIH/OMB)(Participants) | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 2: Isatuximab 20 mg/kg | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 3 | 5 | 28 | 36 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 | 0 |
| White | 0 | 0 | 0 | 0 |
| More than one race | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — 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
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