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Multinational Clinical Study Comparing Isatuximab, Carfilzomib And Dexamethasone To Carfilzomib And Dexamethasone In Relapse And/Or Refractory Multiple Myeloma Patients (IKEMA)

Primary Purpose

Plasma Cell Myeloma

Status

Active

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

isatuximab SAR650984

carfilzomib

dexamethasone

About this trial

This is an interventional treatment trial for Plasma Cell Myeloma focused on measuring Anti-CD38 monoclonal antibody

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Patients with multiple myeloma previously treated with prior 1 to 3 lines and with measurable serum M-protein (≥ 0.5 g/dL) and/or urine M-protein (≥ 200 mg/24 hours).

Exclusion criteria:

Patients previously pretreated with carfilzomib, who never achieved at least one minor response during previous therapies and/or last previous therapy completed within 14 last days.
Patients with serum free light chain (FLC) measurable disease only.
Patients less than 18 years old, patients with Eastern Cooperative Oncology Group performance status more than 2.
Patients with inadequate biological tests.
Patients with myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association class III or IV congestive heart failure, superior or equal to grade 3 arrhythmias, stroke or transient ischemic attack within last 6 months, and/or left ventricular ejection fraction lower than 40%.
Patients with previous cancer unless disease free for more than 5 years or in situ cancer curatively treated.
Patients with known acquired immunodeficiency syndrome related illness (AIDS) or human immunodeficiency virus (HIV) requiring antiretroviral treatment, or hepatitis A, B, or C active infection.
Women of childbearing potential or male patient with women of childbearing potential who do not agree to use highly effective method of birth control.

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Isatuximab + Carfilzomib + Dexamethasone (IKd)

Carfilzomib + Dexamethasone (Kd)

Arm Description

Isatuximab (intravenous) on day 1, 8, 15 and 22 of 1st cycle, then on day 1 and 15 of subsequent cycles in combination with carfilzomib (intravenous) on day 1, 2, 8, 9, 15 and 16 + dexamethasone (intravenous or by mouth [po]) on day 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle.

Carfilzomib (intravenous) on day 1, 2, 8, 9, 15, 16 + dexamethasone (intravenous or po) on day 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle.

Outcomes

Primary Outcome Measures

Progression Free Survival (PFS) As Determined by Independent Response Committee (IRC): Primary Analysis

Time (in months) from randomization to date of 1st documentation of progressive disease (PD)/date of death from any cause, whichever comes 1st. If PD & death are not observed before cut-off date/date of initiation of further anti-myeloma treatment, PFS was censored at date of last valid disease assessment not showing PD performed prior to initiation of further anti-myeloma treatment/cut-off date, whichever comes 1st. PD(IMWG criteria):any 1 of following:Increase(inc) of >=25% in serum M-component from nadir; serum M component inc >=1 g/dL in 2 consecutive assessment, if starting M component >=5 g/dL; and/or inc of >=25% in urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion if >1 lesion/ >=50% increase in longest diameter of previous soft tissue extramedullary disease lesion >1 cm in short axis. Estimated by Kaplan-Meier method.

Progression Free Survival as Determined by Independent Response Committee: [Event Censored if Occurred >8 Weeks From Last Disease Assessment]: Primary Analysis

Time (in months) from randomization to date of 1st PD documentation/death date, whichever is 1st. If PD & death not observed before cut-off date/date of further anti-myeloma treatment initiation, PFS censored at date of last valid disease assessment not showing PD performed prior to initiation of further anti-myeloma treatment/cut-off date, whichever was 1st. Progression/deaths occurring >8 weeks after last disease assessment censored at earliest date of last disease assessment without evidence of progression before initiation of new anti-myeloma treatment & cut-off date. PD (IMWG criteria): meeting any 1: Inc >=25% in Serum M-component from nadir; serum M component inc >=1 g/dL in 2 consecutive assessment, if starting M component >=5 g/dL; and/or inc >=25% in Urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion >1 cm short axis.

Progression Free Survival as Determined by Independent Response Committee: Final Analysis

PFS: time (in months) from randomization to date of first documentation of PD or date of death from any cause, whichever comes first. If PD and death are not observed before analysis cut-off date or date of initiation of further anti-myeloma treatment, PFS was censored at date of last valid disease assessment or analysis cut-off date, whichever comes first. PD as per IMWG criteria: any 1 of following: Inc of >=25% in Serum M-component from nadir; serum M component increase >=1 g/dL in 2 consecutive assessment, if starting M component was >=5 g/dL; and/or inc of >=25% in Urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion if >1 lesion/ >=50% inc in longest diameter of previous soft tissue extramedullary disease lesion >1 cm in short axis. PFS estimated by Kaplan-Meier method.

Progression Free Survival as Determined by Independent Response Committee [Event Censored if Occurred >8 Weeks From Last Disease Assessment]: Final Analysis

Time (in months) from randomization to date of 1st documentation of PD/date of death from any cause, whichever comes 1st. If PD & death are not observed before cut-off date/date of initiation of further anti-myeloma treatment, PFS was censored at date of last valid disease assessment not showing PD/cut-off date, whichever comes 1st. Progressions/deaths occurring >8 weeks after last disease assessment were censored at earliest date of last valid disease assessment not showing PD before initiation of further anti-myeloma treatment & cut-off date. PD (per IMWG criteria): meeting any 1 criteria: Inc of >=25% in serum M-component from nadir; serum M component inc >=1 g/dL in 2 consecutive assessment, if starting M component was >=5 g/dL; and/or inc of >=25% in urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion >1 cm in short axis.

Secondary Outcome Measures

Percentage of Participants With Overall Response (OR) as Determined by Independent Response Committee: Primary Analysis

OR: participants with sCR, CR, VGPR & partial response (PR) as best overall response assessed by IRC using IMWG response criteria (from start of treatment until disease progression, death, initiation of further anti-myeloma treatment/cutoff date, whichever occurs 1st). sCR: negative immunofixation on serum & urine, disappearance of soft tissue plasmacytoma, <5% plasma cells in bone marrow aspirate (BMA) + normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum & urine, disappearance of soft tissue plasmacytoma, <5% plasma cells in BMA. VGPR: serum & urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein + urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma. PR:>=50% reduction of serum M-protein & decrease in 24h urinary M-protein by >=90%/<200mg/24h, if present at baseline,>=50% decrease in SPD of soft tissue plasmacytoma.

Percentage of Participants With Very Good Partial Response (VGPR) or Better as Determined by Independent Response Committee: Primary Analysis

VGPR or better: defined as participants with sCR, CR and VGPR as the best overall response (defined as best response from start of treatment until disease progression, death, initiation of further anti-myeloma treatment or cut-off date whichever occurs first) as per IRC. As per IMWG response criteria: sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs plus normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs. VGPR: serum and urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma.

Percentage of Participants With VGPR or Better With Minimal Residual Disease (MRD) Negativity: Primary Analysis

Percentage of participants with sCR, CR and VGPR for whom MRD assessed by sequencing was negative at any time after first dose of study treatment. MRD was assessed centrally by next-generation sequencing in bone marrow aspiration samples from participants who achieve VGPR or better, to determine depth of response at molecular level. VGPR or better: percentage of participants with sCR, CR and VGPR. sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs plus normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs. VGPR: serum and urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma.

Percentage of Participants With VGPR or Better With Minimal Residual Disease (MRD) Negativity: Final Analysis

Percentage of participants with sCR, CR and VGPR for whom MRD assessed by sequencing was negative at any time after first dose of study treatment. MRD was assessed centrally by next-generation sequencing in BM aspiration samples from participants who achieve VGPR or better, to determine depth of response at molecular level. VGPR or better: percentage of participants with sCR, CR and VGPR. sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal FLC ratio, absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. VGPR: serum and urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma.

Percentage of Participants With Complete Response (CR) as Per Independent Response Committee: Final Analysis

Complete response was defined as the participants with sCR and CR. IMWG response criteria for sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal free light chain (FLC) ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. Complete response at the time of the final analysis was assessed with hydrashift isatuximab immunofixation electrophoresis (IFE) assay, which separated immunoglobulin G (IgG) isatuximab from IgG M protein.

Percentage of Participants With Complete Response With MRD Negativity: Final Analysis

MRD negativity was defined as the percentage of participants for whom MRD was negative by next-generation sequencing at any timepoint after first dose of study treatment. Threshold for negativity is 10^-5. MRD status in a participant was negative if at least one result of the assessment was negative in the participant otherwise MRD was considered as positive (MRD status reported as positive, missing or unevaluable). CR: participants with sCR and CR. IMWG response criteria for sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. Complete response at the time of the final analysis was assessed with Hydrashift isatuximab IFE assay, which separated IgG isatuximab from IgG M protein.

Overall Survival (OS): Final Analysis

Data for this outcome measure will be reported at the time of anticipated last participant last visit results posting (February 2024) as the study is still ongoing.

Duration of Response (DOR): Primary Analysis

DOR: time (in months) from date of 1st IRC determined response for participants achieving PR/better to date of 1st documented PD determined by IRC/death, whichever happens 1st. If disease progression/death before analysis cut-off date was not observed, DOR was censored at date of last valid disease assessment performed prior to initiation of further anti-myeloma treatment/data cut-off date, whichever was 1st. PD (IMWG criteria): inc of >=25% from lowest confirmed value in any 1 of following criteria: serum M-protein (absolute inc must be >=0.5 g/dL), serum M-protein inc >=1g/dL if lowest M component was >=5g/dL; urine M-component (absolute inc must be >=200mg/24 hour),appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >=50% inc in the longest diameter of previous lesion >1 cm in short axis. PR: >=50% reduction of serum M-protein & reduction in 24h urinary M-protein by >=90%/<200mg/24 h. Estimated by Kaplan Meier method.

Time to Progression (TTP): Primary Analysis

TTP was defined as time in months from randomization to the date of first documentation of PD (as determined by the IRC). If progression was not observed before the analysis cut-off date or the date of initiation of further anti-myeloma treatment, TTP was censored at the date of the last valid disease assessment not showing disease progression performed prior to initiation of a further anti-myeloma treatment (if any) or the analysis cut-off date, whichever comes first. As per IMWG criteria, PD was defined for participants with inc of >= 25% from lowest confirmed value in any one of the following criteria: serum M-protein (the absolute inc must be >= 0.5 g/dL), serum M-protein inc >=1 g/dL if the lowest M component was >=5 g/dL; urine M-component (the absolute inc must be >=200 mg/24hour), appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >=50% inc in the longest diameter of a previous lesion >1 centimeter in short axis.

Time to First Response: Primary Analysis

Time to first response was defined as the time (in months) from randomization to the date of first IRC determined response (PR or better) that is subsequently confirmed. In the absence of response, participants were censored at the earliest of the date of the last valid disease assessment before disease progression or death, the date of the last valid disease assessment before initiation of a further anti-myeloma treatment (if any) or the analysis cut-off date, whichever comes first. PR per IMWG criteria was defined as >=50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >=90% or to <200 mg/24 h. In addition to the above listed criteria, if present at baseline, a >=50% reduction in the size (SPD) of soft tissue plasmacytomas was also required.

Time to Best Response: Primary Analysis

Time to best response was defined as time (in months) from randomization to the date of first occurrence of IRC determined as best overall response (PR or better) that is subsequently confirmed. In absence of response, participants were censored at earliest date of last valid disease assessment before disease progression/death, date of last valid disease assessment before initiation of further anti-myeloma treatment (if any)/ analysis cut-off date, whichever was 1st. PR (IMWG criteria) was defined as >=50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >=90% or to <200 mg/24 h. In addition to above listed criteria, if present at baseline, a >=50% reduction in the size (SPD) of soft tissue plasmacytomas was also required. Best Overall Response was defined as the best response, using the IRC's assessment of response, from start of treatment until disease progression, death, initiation of further anti-myeloma treatment or cut-off date, whichever occurs 1st.

Second Progression Free Survival (PFS2): Final Analysis

PFS2 defined as time (in months) from date of randomization to date of 1st documentation of PD (as assessed by investigator) after initiation of further anti-myeloma treatment /death from any cause, whichever comes 1st. Participants alive without progression after initiation of further anti-myeloma treatment before analysis cut-off date, PFS2 censored at date of last follow-up visit not showing disease progression after initiation of further anti-myeloma treatment /analysis cut-off date, whichever comes 1st. As per IMWG criteria, PD: defined for participants with increase of >= 25% from lowest confirmed value in any 1 of following criteria: serum M-protein (absolute increase must be >= 0.5 g/dL), serum M-protein increase >=1 g/dL if lowest M component was >=5 g/dL; urine M-component (absolute increase must be >=200 mg/24hour), appearance of new lesion(s), >=50% increase from nadir in SPD of >1 lesion, or >=50% increase in longest diameter of previous lesion >1 centimeter short axis.

Number of Participants With Renal Response (RR): Primary Analysis

RR comprises of complete RR (CR renal), partial RR (PR renal) & minor RR (MR renal). CR renal was defined as an improvement in estimated glomerular filtration rate (eGFR) from <50 mL/min/1.73m^2 at Baseline to >=60 mL/min/1.73m^2 in at least 1 assessment during the treatment period (time from first dose of study treatment up to 30 days after last dose of study treatment); PR renal was defined as improvement in eGFR from <15 mL/min/1.73m^2 at baseline to at least 1 assessment in the range of 30 to 60 mL/min/1.73m^2 during the on-treatment-period and MR renal was defined as an improvement in eGFR from <15 mL/min/1.73m^2 at Baseline to at least 1 assessment in the range of 15 to 30 mL/min/1.73m^2 during the on-treatment-period or from 15 to 30 mL/min/1.73m^2 at Baseline to at least 1 assessment in the range of 30 to 60 mL/min/1.73m^2 during the on-treatment-period.

Health Related Quality of Life (HRQL): Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 30 Items (EORTC QLQ-C30): Global Health Status Score at Specified Timepoints

EORTC QLQ-C30 is a cancer-specific instrument that contains 30 items & provides multidimensional assessment of HRQL. EORTC QLQ-C30 includes global health status/quality of life (GHS/QOL), functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), and 6 single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Most questions from QLQ-C30 are 4-point scale (1/Not at All to 4/Very Much), except Items 29-30, which comprise GHS scale & are 7-point scale (1/Very Poor to 7/Excellent). GHS total score is calculated as ([{Q29+Q30}/2]-1)/6*100. Answers are converted into grading scale, with values between 0 (worse outcome) to100 (best outcome). High score represents a favorable outcome with best quality of life for participant. Results reported for primary analysis with data cut-off date 7-Feb-2020.

HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Disease Symptoms Domain Score at Specified Timepoints: Primary Analysis

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. Disease symptoms domain is one of the four domain scores. Disease symptoms domain consist of 6 questions and the score uses 4-point scale (1 'Not at All' to 4 'Very Much'). Disease Symptoms Domain Score is calculated as ([{Q31+Q32+Q33+Q34+Q35+Q36}/6]-1)/3*100. Scores are averaged, and transformed to 0-100 scale, where higher scores = more symptoms and lower HRQL.

HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Side Effects of Treatment at Specified Timepoints: Primary Analysis

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. Side effects of treatment domain is one of the four domain scores. Side effects of treatment domain consists of 10 questions and the score uses a 4-point scale (1 'Not at All' to 4 'Very Much'). Side Effects of Treatment Score (MYSE) is calculated as ([{Q37+Q38+Q39+Q40+Q41+Q42+Q43+Q44+Q45+Q46}/10]-1)/3*100. Scores are averaged, and transformed to 0-100 scale, where higher scores = more side effects and lower HRQL and lower scores = less side effects and better HRQL.

HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Body Image Score at Specified Timepoints: Primary Analysis

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. It consists of one question and scores are based on the 4-point Likert scale ranging from "Not at all" to "Very much". Body image score is calculated as: (1 - [Q47-1]/3)*100. Scores are averaged, and transformed to scale ranging from 0 to 100. A higher score represents a better quality of life.

HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Future Perspective at Specified Timepoints: Primary Analysis

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. It consists of three questions and the scores are based on the 4-point Likert scale ranging from "Not at all" to "Very much". Future Perspective score is calculated as (1 - ([{Q48+Q49+Q50}/3] -1)/3)*100. Scores are averaged and transformed to scale ranging from 0 to 100. A higher score represents a better quality of life.

HRQL: Change From Baseline in European Quality of Life Group Questionnaire With 5 Dimensions and 5 Levels Per Dimension (EQ-5D-5L): Health State Utility Index Value at Specified Timepoints: Primary Analysis

The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health utility and consist in 2 sections a descriptive system comprising 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and Visual Analog Scale (VAS). Each dimension has a 5-level response: no problems, slight problems, moderate problems, severe problems, and extreme problems. Response options are measured with a 5-point Likert scale. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state and lower score indicate worse health state.

HRQL: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Score: Visual Analogic Scale (VAS) at Specified Timepoints: Primary Analysis

The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health utility and consist of 2 sections; descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and a VAS. The VAS records the respondent's self-rated health on a 20 centimeter (cm) vertical VAS; the scale went from 0 (worst imaginable health state) to 100 (best imaginable health state). This information can be used as a quantitative measure of health as judged by the individual respondents.

Pharmacokinetics: Plasma Concentration at End of Infusion (Ceoi) of Isatuximab: Primary Analysis

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

Pharmacokinetics: Plasma Concentration of Isatuximab at Ctrough: Primary Analysis

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

Pharmacokinetics: Maximum Observed Concentration (Cmax) of Carfilzomib: Primary Analysis

Cmax was defined as the maximum concentration observed after the first infusion calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.

Pharmacokinetics: Clast of Carfilzomib: Primary Analysis

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

Pharmacokinetics: Tmax of Carfilzomib: Primary Analysis

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

Pharmacokinetics: Tlast of Carfilzomib: Primary Analysis

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

Pharmacokinetics: Area Under the Plasma Concentration Time Curve (AUC) of Carfilzomib: Primary Analysis

AUC was defined as area under the plasma concentration-time curve extrapolated to infinity according to the equation: AUC= AUClast + Clast/λz. AUC was calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.

Pharmacokinetics: Area Under the Plasma Concentration Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) of Carfilzomib: Primary Analysis

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

Pharmacokinetics: Percentage of Extrapolation of AUC (AUCext) of Carfilzomib: Primary Analysis

AUCext was defined as the percentage of the extrapolation of AUC, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.

Pharmacokinetics: Terminal Half-life (t1/2z) of Carfilzomib: Primary Analysis

T1/2 was defined as the time required for the concentration of the drug to reach half of its original value, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.

Pharmacokinetics: Clearance at Steady State (CLss) of Carfilzomib: Primary Analysis

CLss was defined as a quantitative measure of the rate at which a drug substance is removed from the body at steady state, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.

Pharmacokinetics: Volume of Distribution at Steady State (Vss) of Carfilzomib: Primary Analysis

Volume of Distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.

Number of Participants With Anti-Drug Antibodies (ADA): Primary Analysis

ADA were categorized as: pre-existing, treatment induced, and treatment boosted response. Pre-existing ADA was defined as ADA that were present in samples drawn during the pretreatment period (i.e., before the first isatuximab administration). Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in participants without pre-existing ADA, including participants without pretreatment samples. Treatment boosted ADA was defined as pre-existing ADA with an increase in titer during the ADA on-study observation period.

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs): Final Analysis

Adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAEs were defined as AEs that developed, worsened, or became serious during the treatment period (time from the first dose of study treatments up to 30 days after last dose of study treatments). An SAE was 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.

Full Information

NCT ID

NCT03275285

First Posted

September 5, 2017

Last Updated

April 20, 2023

Sponsor

Sanofi

1. Study Identification

Unique Protocol Identification Number

NCT03275285

Brief Title

Multinational Clinical Study Comparing Isatuximab, Carfilzomib And Dexamethasone To Carfilzomib And Dexamethasone In Relapse And/Or Refractory Multiple Myeloma Patients

Acronym

IKEMA

Official Title

Randomized, Open Label, Multicenter Study Assessing The Clinical Benefit Of Isatuximab Combined With Carfilzomib (Kyprolis®) And Dexamethasone Versus Carfilzomib With Dexamethasone In Patients With Relapse And/Or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

October 25, 2017 (Actual)

Primary Completion Date

January 14, 2022 (Actual)

Study Completion Date

April 26, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sanofi

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study it to compare the efficacity of isatuximab when combined to carfilzomib and dexamethasone versus carfilzomib and dexamethasone in patients with multiple myeloma already treated with 1 to 3 prior lines of therapy.

Detailed Description

The duration of the study for a patient will include a period for screening of up to 3 weeks. Patients will be treated until disease progression, unacceptable AE, or patient decision to stop the study treatment. After study treatment discontinuation, patients will have follow-up visits until the analysis of overall survival.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Plasma Cell Myeloma

Keywords

Anti-CD38 monoclonal antibody

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

302 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Isatuximab + Carfilzomib + Dexamethasone (IKd)

Arm Type

Experimental

Arm Description

Arm Title

Carfilzomib + Dexamethasone (Kd)

Arm Type

Active Comparator

Arm Description

Carfilzomib (intravenous) on day 1, 2, 8, 9, 15, 16 + dexamethasone (intravenous or po) on day 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle.

Intervention Type

Drug

Intervention Name(s)

isatuximab SAR650984

Other Intervention Name(s)

Sarclisa

Intervention Description

Pharmaceutical form: solution for infusion Route of administration: intravenous

Intervention Type

Drug

Intervention Name(s)

carfilzomib

Other Intervention Name(s)

Kyprolis

Intervention Description

Pharmaceutical form: solution for infusion Route of administration: intravenous

Intervention Type

Drug

Intervention Name(s)

dexamethasone

Intervention Description

Pharmaceutical form: tablets or solution for infusion Route of administration: oral or intravenous

Primary Outcome Measure Information:

Title

Progression Free Survival (PFS) As Determined by Independent Response Committee (IRC): Primary Analysis

Description

Time Frame

From randomization until the primary analysis data cut-off date of 7 Feb 2020 (median duration of follow-up was 20.73 months)

Title

Progression Free Survival as Determined by Independent Response Committee: [Event Censored if Occurred >8 Weeks From Last Disease Assessment]: Primary Analysis

Description

Time Frame

From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)

Title

Progression Free Survival as Determined by Independent Response Committee: Final Analysis

Description

Time Frame

From randomization until the final analysis data cut-off date of 14 January 2022 (the median duration of follow-up was 43.96 months)

Title

Progression Free Survival as Determined by Independent Response Committee [Event Censored if Occurred >8 Weeks From Last Disease Assessment]: Final Analysis

Description

Time Frame

From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)

Secondary Outcome Measure Information:

Title

Percentage of Participants With Overall Response (OR) as Determined by Independent Response Committee: Primary Analysis

Description

Time Frame

From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)

Title

Percentage of Participants With Very Good Partial Response (VGPR) or Better as Determined by Independent Response Committee: Primary Analysis

Description

Time Frame

From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)

Title

Percentage of Participants With VGPR or Better With Minimal Residual Disease (MRD) Negativity: Primary Analysis

Description

Time Frame

From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)

Title

Percentage of Participants With VGPR or Better With Minimal Residual Disease (MRD) Negativity: Final Analysis

Description

Percentage of participants with sCR, CR and VGPR for whom MRD assessed by sequencing was negative at any time after first dose of study treatment. MRD was assessed centrally by next-generation sequencing in BM aspiration samples from participants who achieve VGPR or better, to determine depth of response at molecular level. VGPR or better: percentage of participants with sCR, CR and VGPR. sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal FLC ratio, absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. VGPR: serum and urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma.

Time Frame

From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)

Title

Percentage of Participants With Complete Response (CR) as Per Independent Response Committee: Final Analysis

Description

Time Frame

From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)

Title

Percentage of Participants With Complete Response With MRD Negativity: Final Analysis

Description

Time Frame

From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)

Title

Overall Survival (OS): Final Analysis

Description

Data for this outcome measure will be reported at the time of anticipated last participant last visit results posting (February 2024) as the study is still ongoing.

Time Frame

Up to approximately 6 years

Title

Duration of Response (DOR): Primary Analysis

Description

Time Frame

From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)

Title

Time to Progression (TTP): Primary Analysis

Description

Time Frame

From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)

Title

Time to First Response: Primary Analysis

Description

Time Frame

From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)

Title

Time to Best Response: Primary Analysis

Description

Time Frame

From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)

Title

Second Progression Free Survival (PFS2): Final Analysis

Description

Time Frame

From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)

Title

Number of Participants With Renal Response (RR): Primary Analysis

Description

Time Frame

From the first dose of study treatment to 30 days following the last administration of study treatment (maximum duration: up to 114 weeks)

Title

Description

Time Frame

Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)

Title

Description

Time Frame

Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)

Title

Description

Time Frame

Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)

Title

Description

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. It consists of one question and scores are based on the 4-point Likert scale ranging from "Not at all" to "Very much". Body image score is calculated as: (1 - [Q47-1]/3)*100. Scores are averaged, and transformed to scale ranging from 0 to 100. A higher score represents a better quality of life.

Time Frame

Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)

Title

Description

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. It consists of three questions and the scores are based on the 4-point Likert scale ranging from "Not at all" to "Very much". Future Perspective score is calculated as (1 - ([{Q48+Q49+Q50}/3] -1)/3)*100. Scores are averaged and transformed to scale ranging from 0 to 100. A higher score represents a better quality of life.

Time Frame

Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)

Title

Description

Time Frame

Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)

Title

Description

Time Frame

Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)

Title

Pharmacokinetics: Plasma Concentration at End of Infusion (Ceoi) of Isatuximab: Primary Analysis

Description

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

Time Frame

End of infusion on Cycle 1 Day 1 and Cycle 1 Day 15; Cycle 2 Day 1

Title

Pharmacokinetics: Plasma Concentration of Isatuximab at Ctrough: Primary Analysis

Description

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

Time Frame

Pre-infusion on Cycle 1 Day 1, Day 8, Day 15 and Day 22, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 7 Day 1, Cycle 8 Day 1, Cycle 9 Day 1 and Cycle 10 Day 1

Title

Pharmacokinetics: Maximum Observed Concentration (Cmax) of Carfilzomib: Primary Analysis

Description

Cmax was defined as the maximum concentration observed after the first infusion calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.

Time Frame

Cycle 1: pre-dose (0 hour), 30 minutes (min), 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15

Title

Pharmacokinetics: Clast of Carfilzomib: Primary Analysis

Description

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

Time Frame