Multiple Myeloma
Conditions
Keywords
Anti-CD38 monoclonal antibody
Brief summary
Primary Objectives: * Phase I: To evaluate safety and tolerability of isatuximab in Japanese participants with relapsed and refractory multiple myeloma. * Phase II: To evaluate efficacy of isatuximab at recommended dose and to further evaluate the overall response rate (ORR) of isatuximab in Japanese participants with relapsed and refractory multiple myeloma. Secondary Objectives: * To evaluate the safety including immunogenicity of isatuximab. The severity, frequency and incidence of all adverse events were assessed. * To evaluate the pharmacokinetic (PK) profile of isatuximab in the proposed dosing schedule. * To assess the efficacy using International Myeloma Working Group (IMWG) uniform response criteria. * To assess the relationship between Baseline cluster of differentiation 38 (CD38) receptor density on multiple myeloma cells and efficacy.
Detailed description
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.
Interventions
Pharmaceutical form: solution Route of administration: intravenous
Sponsors
Sanofi
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females, age 20 years or older. * Participants had a known diagnosis of symptomatic multiple myeloma. * Participants had received at least 3 prior lines of therapies OR participants whose disease was double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI). * Participants had been responsive (i.e., minimal response \[MR\] or better) to at least one prior line of therapy. * Refractory to the most recently received IMiD or PI included therapy. * Participants with measurable disease defined as at least one of the following: * Immunoglobulin G (IgG) Type: Serum M-protein \>=1 gram per deciliter (g/dL) (\>=10 g/L); * Immunoglobulin A (IgA) and D Type: Serum M-protein, quantification should be performed; * Urine M-protein ≥200 mg/24 hours. * Participants with a Eastern Cooperative Oncology Group (ECOG) performance status \<=2.
Exclusion criteria
* Participants treated with any anti-CD38 agent. * Diagnosed or treated for another malignancy within 5 years prior to enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in-situ malignancy, or low-risk prostate cancer after curative therapy. * Prior anticancer therapy (chemotherapy, targeted agents, immunotherapy) within 21 days prior to the first drug infusion unless otherwise specified below: * Alkylating agents (e.g., Melphalan) within 28 days prior to the first dose of study treatment. * Steroids treatment (e.g., prednisone greater than (\>)10 mg/day orally or equivalent except patients being treated for adrenal insufficiency/replacement therapy or treated for inhalation corticosteroids) within 14 days prior to the first dose of study treatment. * Participated in another clinical trial within 30 days prior to the first dose of study treatment. * Participants treated with systemic radiation therapy within 4 weeks prior to the first dose of study treatment OR Localized radiation therapy within 1 week prior to the first dose of study treatment. * Major surgical procedure within 4 weeks prior to the first dose of study treatment. * Any toxicity Grade \>=2 (excluding alopecia, neutropenia or neuropathy) related to any prior anti-cancer therapy according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. * Neuropathy Grade \>=3 or painful peripheral neuropathy Grade \>=2. * History of significant cardiovascular disease unless the disease within the past 6 months was well-controlled. * Previously received an allogenic stem cell transplant. * Diagnosed Crow-Fukase (POEMS) syndrome OR plasma cell leukemia. * Participants with known or suspected amyloidosis. * Participants with Waldenstrom's macroglobulinemia OR Multiple myeloma IgM subtype. * Participants with active infection. * Known human immunodeficiency virus (HIV) or active hepatitis B or C viral infection. * Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation. * Any severe underlying medical conditions including presence of laboratory abnormalities, which could impair the ability to participate in the study or the interpretation of its results. * Hypersensitivity or history of intolerance to boron or mannitol, sucrose, histidine (as base and hydrochloride salt) and polysorbate 80 or any of the components of study therapy that are not amenable to pre-medication with steroids and H2 blockers or would prohibit further treatment with these agents. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | Cycle 1 (28 days) | 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. |
| Phase 2: Percentage of Participants With Overall Response (OR) | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Percentage of Participants With Overall Response (OR) | 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) | 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. |
| Phase 1: Duration of Response (DOR) | 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) | 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. |
| Phase 2: Percentage of Participants With Clinical Benefit (CB) | 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) | 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. |
| Phase 2: Overall Survival (OS) | From date of first study treatment administration to the date of death due to any cause (maximum duration of exposure: up to 248 weeks) | 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. |
| Phase 2: Progression Free Survival (PFS) | 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) | 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. |
| Phase 2: Duration of Response (DOR) | 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) | 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. |
| Phase 2: Time to Progression (TTP) | 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) | 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. |
| Phase 1: Plasma Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab | End of infusion on Day 1 of Cycle 1 | Ceoi is the plasma concentration observed at the end of intravenous infusion. |
| Phase 1: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab | 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) | Cmax was defined as the maximum concentration observed after the first infusion calculated using the non-compartmental analysis. |
| Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | 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) | 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). |
| Phase 1: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-week) After First Infusion of Isatuximab | 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) | AUC was defined as area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval. |
| Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | 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 | Ctrough was the plasma concentration observed just before treatment administration during repeated dosing. |
| Phase 2: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab | Multiple timepoints from Cycle 1 to Cycle 10 | Cmax was predicted using population pharmacokinetic model. |
| Phase 2: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-Week) After First Infusion of Isatuximab | Multiple timepoints from Cycle 1 to Cycle 10 | AUC was predicted using population pharmacokinetic model. |
| Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | 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 | Ctrough was the plasma concentration observed just before treatment administration during repeated dosing. |
| Phase 1 and 2: CD38 Receptor Density at Baseline | At Baseline (Day 1) | CD38 receptor density assessed from bone marrow aspirates for responder and non-responders' participants was reported. |
| Phase 1: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab | 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) | 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. |
| Phase 2: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab | From first dose of study drug up to 30 days after last study drug administration (maximum duration of exposure: up to 248 weeks) | 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. |
| Phase 1: Time to Reach the Maximum Concentration (Tmax) After First Infusion of Isatuximab | 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) | Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion. |
| Phase 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | 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) | 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). |
Countries
Japan
Participant flow
Recruitment details
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.
Pre-assignment details
Study consisted of 2 phases: Phase 1 and Phase 2. Phase I (Cohorts 1 and 2) was a dose escalation part to evaluate the safety, pharmacokinetics (PK), and efficacy of isatuximab. Phase 2 was commenced after completion of the DLT observation period in Phase 1 and determination of the recommended dose to be used in Phase 2.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg Participants received Isatuximab 10 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 AEs, disease progression, or any other reason for discontinuation whichever occurs first (maximum duration of exposure: 112 weeks). | 3 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg 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 AEs, disease progression, or any other reason for discontinuation whichever occurs first (maximum duration of exposure: 137 weeks). | 5 |
| Phase 2: Isatuximab 20 mg/kg 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 AEs, disease progression, or any other reason for discontinuation whichever occurs first (maximum duration of exposure: 248 weeks). | 28 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase 1 | Adverse Event | 0 | 2 | 0 |
| Phase 1 | Progressive disease | 3 | 3 | 0 |
| Phase 2 | Adverse Event | 0 | 0 | 2 |
| Phase 2 | Other-Unspecified | 0 | 0 | 4 |
| Phase 2 | Progressive disease | 0 | 0 | 22 |
Baseline characteristics
| Characteristic | Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 2: Isatuximab 20 mg/kg | Total |
|---|---|---|---|---|
| Age, Continuous | 67.3 years STANDARD_DEVIATION 7.6 | 74.4 years STANDARD_DEVIATION 4.7 | 70.6 years STANDARD_DEVIATION 8.1 | 70.9 years STANDARD_DEVIATION 7.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 5 Participants | 28 Participants | 36 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 10 Participants | 16 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 18 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 2 / 5 | 10 / 28 |
| other Total, other adverse events | 3 / 3 | 4 / 5 | 24 / 28 |
| serious Total, serious adverse events | 1 / 3 | 2 / 5 | 11 / 28 |
Outcome results
Primary
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)
Population: Analysis was performed on DLT evaluable population that included subset of participants who completed the first Cycle which consisted of 4 isatuximab administrations of the study drug or they discontinued study drug before completion of first cycle for a DLT.~.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Primary
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)
Population: Analysis was performed on all treated population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Percentage of Participants With Overall Response (OR) | 32.1 percentage of participants |
Secondary
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)
Population: Participants treated with Isatuximab (Phase 1 and 2) and evaluable for CD38 receptor density assessment. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1 and 2: CD38 Receptor Density at Baseline | 113226.2 sMEC | Standard Deviation 93628.7 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1 and 2: CD38 Receptor Density at Baseline | 133378.2 sMEC | Standard Deviation 55518.5 |
Secondary
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)
Population: Analysis was performed on PK population. Here, Overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-week) After First Infusion of Isatuximab | 9300 micrograms*hours per milliliter | Standard Deviation 3010 |
| 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 | 21300 micrograms*hours per milliliter | Standard Deviation 5520 |
Secondary
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)
Population: Analysis was performed on a subset of participants who had response.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Duration of Response (DOR) | 100.64 weeks | Standard Deviation 7.78 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Duration of Response (DOR) | 113.90 weeks | Standard Deviation 18.45 |
Secondary
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)
Population: Analysis was performed on PK population. Here, Overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab | 124 micrograms per milliliter | Standard Deviation 22.9 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab | 280 micrograms per milliliter | Standard Deviation 64.4 |
Secondary
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)
Population: Analysis was performed on ADA population which included all participants that received isatuximab in Phase 1 part of the study, with at least one ADA assessment reportable during the ADA on-study observation periods.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab | Treatment-induced ADA | 0 Participants |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab | Treatment boosted ADA | 0 Participants |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab | Treatment-induced ADA | 0 Participants |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab | Treatment boosted ADA | 0 Participants |
Secondary
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)
Population: Analysis was performed on all treated population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | TEAEs | 3 Participants |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | TESAEs | 1 Participants |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | TESAEs | 2 Participants |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | TEAEs | 4 Participants |
Secondary
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)
Population: Analysis was performed on all treated population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Percentage of Participants With Overall Response (OR) | 66.7 percentage of participants |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Percentage of Participants With Overall Response (OR) | 60.0 percentage of participants |
Secondary
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
Population: Analysis was performed on PK population that included all participants who gave their informed consent and received at least one dose (even incomplete) of Isatuximab; with data for at least 1 PK parameter available. Here, Overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Plasma Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab | 122 micrograms per milliliter | Standard Deviation 21.6 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Plasma Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab | 246 micrograms per milliliter | Standard Deviation 51.8 |
Secondary
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)
Population: Analysis was performed on PK population. Here, Overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Time to Reach the Maximum Concentration (Tmax) After First Infusion of Isatuximab | 2.68 hours |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Time to Reach the Maximum Concentration (Tmax) After First Infusion of Isatuximab | 5.56 hours |
Secondary
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
Population: Analysis was performed on PK population. Here, Number analyzed = participants with available data for each specified category and 0 in the number analyzed field signifies that no participants were available for analysis at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 8 Day 15 | 242.50 micrograms per milliliter | Standard Deviation 88.39 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 2 Day 15 | 167.80 micrograms per milliliter | Standard Deviation 154.43 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 1 Day 8 | 23.77 micrograms per milliliter | Standard Deviation 8.98 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 1 Day 15 | 71.33 micrograms per milliliter | Standard Deviation 22.87 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 1 Day 22 | 124.87 micrograms per milliliter | Standard Deviation 69.51 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 3 Day 1 | 174.40 micrograms per milliliter | Standard Deviation 184.7 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 3 Day 15 | 193.50 micrograms per milliliter | Standard Deviation 154.86 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 4 Day 1 | 202.85 micrograms per milliliter | Standard Deviation 172.75 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 4 Day 15 | 184.85 micrograms per milliliter | Standard Deviation 182.65 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 5 Day 1 | 220.40 micrograms per milliliter | Standard Deviation 228.54 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 5 Day 15 | 233.00 micrograms per milliliter | Standard Deviation 237.59 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 6 Day 1 | 267.50 micrograms per milliliter | Standard Deviation 280.72 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 6 Day 15 | 160.60 micrograms per milliliter | Standard Deviation 116.53 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 7 Day 1 | 200.15 micrograms per milliliter | Standard Deviation 165.25 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 7 Day 15 | 254.50 micrograms per milliliter | Standard Deviation 228.4 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 8 Day 1 | 303.00 micrograms per milliliter | Standard Deviation 278.6 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 2 Day 1 | 135.57 micrograms per milliliter | Standard Deviation 125.1 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 9 Day 1 | 269.00 micrograms per milliliter | Standard Deviation 147.08 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 9 Day 15 | 444.00 micrograms per milliliter | Standard Deviation 463.86 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 10 Day 1 | 436.50 micrograms per milliliter | Standard Deviation 441.94 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 10 Day 15 | 684.00 micrograms per milliliter | Standard Deviation 772.16 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 11 Day 1 | 592.00 micrograms per milliliter | — |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 2 Day 1 | 367.75 micrograms per milliliter | Standard Deviation 127.45 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 9 Day 15 | 758.33 micrograms per milliliter | Standard Deviation 393.2 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 2 Day 15 | 419.08 micrograms per milliliter | Standard Deviation 351.57 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 6 Day 1 | 665.67 micrograms per milliliter | Standard Deviation 385.34 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 1 Day 8 | 78.52 micrograms per milliliter | Standard Deviation 38.49 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 8 Day 15 | 789.67 micrograms per milliliter | Standard Deviation 525.08 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 1 Day 15 | 186.33 micrograms per milliliter | Standard Deviation 69.29 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 6 Day 15 | 714.33 micrograms per milliliter | Standard Deviation 451.44 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 1 Day 22 | 254.00 micrograms per milliliter | Standard Deviation 97.45 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 10 Day 15 | 1224.67 micrograms per milliliter | Standard Deviation 719.96 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 3 Day 1 | 500.98 micrograms per milliliter | Standard Deviation 426.78 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 7 Day 1 | 611.67 micrograms per milliliter | Standard Deviation 342.27 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 3 Day 15 | 347.75 micrograms per milliliter | Standard Deviation 259.68 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 9 Day 1 | 722.67 micrograms per milliliter | Standard Deviation 379.5 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 4 Day 1 | 344.30 micrograms per milliliter | Standard Deviation 286.74 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 7 Day 15 | 641.67 micrograms per milliliter | Standard Deviation 246.78 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 4 Day 15 | 392.63 micrograms per milliliter | Standard Deviation 322.7 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 10 Day 1 | 941.67 micrograms per milliliter | Standard Deviation 576.67 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 5 Day 1 | 608.00 micrograms per milliliter | Standard Deviation 351.93 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 8 Day 1 | 874.67 micrograms per milliliter | Standard Deviation 408.85 |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 5 Day 15 | 581.33 micrograms per milliliter | Standard Deviation 356.35 |
Secondary
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
Population: Analysis was performed on PK population. Here, Overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-Week) After First Infusion of Isatuximab | 65071 micrograms * hours per milliliter | Standard Deviation 55554 |
Secondary
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)
Population: Analysis was performed on a subset of participants who had response.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Duration of Response (DOR) | 58.70 weeks | Standard Deviation 29.91 |
Secondary
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
Population: Analysis was performed on PK population. Here, Overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab | 747.83 micrograms per milliliter | Standard Deviation 743.83 |
Secondary
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)
Population: Analysis was performed on ADA population which included all participants that received isatuximab in Phase 2 part of the study, with at least one ADA assessment reportable during the ADA on-study observation periods.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab | Treatment-induced ADA | 6 Participants |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab | Treatment boosted ADA | 0 Participants |
Secondary
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)
Population: Analysis was performed on all treated population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | TEAEs | 25 Participants |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | TESAEs | 11 Participants |
Secondary
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)
Population: Analysis was performed on all treated population. Data for this outcome measure was not planned to be collected and analyzed for Phase 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Overall Survival (OS) | NA months |
Secondary
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)
Population: Analysis was performed on all treated population. Data for this outcome measure was not planned to be collected and analyzed for Phase 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Percentage of Participants With Clinical Benefit (CB) | 53.6 percentage of participants |
Secondary
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)
Population: Analysis was performed on all treated population. Analysis was performed by Kaplan-Meier method. Data for this outcome measure was not planned to be collected and analyzed for Phase 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Progression Free Survival (PFS) | 5.6 months |
Secondary
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)
Population: Analysis was performed on all treated population. Analysis was performed by Kaplan-Meier method. Data for this outcome measure was not planned to be collected and analyzed for Phase 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Time to Progression (TTP) | 5.5 months |
Secondary
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
Population: Analysis was performed on PK population. Here, Number analyzed = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 1 Day 8 | 376.34 micrograms per milliliter | Standard Deviation 666.4 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 1 Day 15 | 662.52 micrograms per milliliter | Standard Deviation 1283.39 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 1 Day 22 | 604.17 micrograms per milliliter | Standard Deviation 996.78 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 2 Day 1 | 927.63 micrograms per milliliter | Standard Deviation 1194.16 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 2 Day 15 | 826.15 micrograms per milliliter | Standard Deviation 958.75 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 3 Day 1 | 734.39 micrograms per milliliter | Standard Deviation 675.85 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 3 Day 15 | 689.85 micrograms per milliliter | Standard Deviation 715.21 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 4 Day 1 | 723.76 micrograms per milliliter | Standard Deviation 802.83 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 4 Day 15 | 619.35 micrograms per milliliter | Standard Deviation 356.21 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 5 Day 1 | 647.24 micrograms per milliliter | Standard Deviation 338.97 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 5 Day 15 | 683.90 micrograms per milliliter | Standard Deviation 391.48 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 6 Day 1 | 674.20 micrograms per milliliter | Standard Deviation 439.78 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 6 Day 15 | 742.93 micrograms per milliliter | Standard Deviation 420.34 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 7 Day 1 | 733.83 micrograms per milliliter | Standard Deviation 373.26 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 7 Day 15 | 786.27 micrograms per milliliter | Standard Deviation 331.38 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 8 Day 1 | 870.09 micrograms per milliliter | Standard Deviation 443.79 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 8 Day 15 | 1004.00 micrograms per milliliter | Standard Deviation 463.82 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 9 Day 1 | 946.25 micrograms per milliliter | Standard Deviation 369.91 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 9 Day 15 | 878.63 micrograms per milliliter | Standard Deviation 313.39 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 10 Day 1 | 823.75 micrograms per milliliter | Standard Deviation 314.95 |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab | Cycle 10 Day 15 | 845.38 micrograms per milliliter | Standard Deviation 322.48 |