Safety, Pharmacokinetics, and Preliminary Efficacy of Isatuximab in Patients Awaiting Kidney Transplantation

Study Overview
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Brief Summary
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Primary Objectives: Phase 1: To characterize the safety and tolerability of isatuximab in kidney transplant candidates. Phase 2: To evaluate the efficacy of isatuximab in desensitization of participants awaiting kidney transplantation. Secondary Objectives: Phase 2: To characterize the safety profile of isatuximab in kidney transplant candidates. To characterize the pharmacokinetic (PK) profile of isatuximab in kidney transplant candidates. To evaluate the immunogenicity of isatuximab. To assess the overall efficacy of isatuximab in desensitization of participants awaiting kidney transplantation.

Detailed Description
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The study had a screening period of up to 28 days, a treatment period of up to 12 weeks, a site visit FUP of up to 26 weeks, and an extended follow-up (FUP) until study cut-off. The study duration involved site visit per participant (i.e., screening, treatment, site visit FUP was approximately 42 weeks. The study duration included extended FUP per participant was approximately 97.7 weeks (depending on when the participant was enrolled).

Official Title
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A Phase 1b/2 Study to Evaluate the Safety, Pharmacokinetics, and Preliminary Efficacy of Isatuximab (SAR650984) in Patients Awaiting Kidney Transplantation

Conditions
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Immune System Disorder

Intervention / Treatment
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* Drug: Isatuximab SAR650984
* Drug: Acetaminophen (paracetamol) or equivalent
* Drug: Ranitidine or equivalent
* Drug: Diphenhydramine or equivalent
* Drug: Methylprednisolone or equivalent
* Drug: Montelukast or equivalent


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of chronic kidney disease (CKD) and active candidate on the kidney donor waitlist at the time of screening. Body mass index (BMI) </=40 kg/m^2. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Capable of giving signed informed consent. For Participants in Cohort A: active candidates on the kidney waitlist with living donor. For Participants in Cohort B: active candidates on the kidney waitlist with no living donor cleared for donation. Exclusion criteria: Significant cardiac dysfunction. Known active, recurrent, or chronic infection. Active lupus or uncontrolled diabetes. Prior treatment with rituximab within 6 months from SAR650984 administration. Inadequate organ and bone marrow function at screening. Pregnant or breastfeeding women or women who intend to become pregnant during participation in the study. Known intolerance or hypersensitivity to any component of SAR650984 or pre-medications. Participants who were not suitable for participation as judged by the Investigator. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Participants with cPRA >=99.90%<br>Participants with calculated panel reactive antibodies (cPRA) >=99.90% (indicating active candidates on kidney transplant waitlist) received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion, once weekly (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1) and then every 2 weeks (Q2W) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events (AEs) or participant's decision to stop the treatment (maximum treatment duration: 13 weeks). | Drug: Isatuximab SAR650984<br>* Pharmaceutical form: Solution for infusion Route of administration: Intravenous<br>* Other names: Sarclisa;Drug: Acetaminophen (paracetamol) or equivalent<br>* Pharmaceutical form: Tablets Route of administration: Oral<br>Drug: Ranitidine or equivalent<br>* Pharmaceutical form: Solution Route of administration: Intravenous<br>Drug: Diphenhydramine or equivalent<br>* Pharmaceutical form: Solution Route of administration: Intravenous<br>Drug: Methylprednisolone or equivalent<br>* Pharmaceutical form: Solution Route of administration: Intravenous<br>Drug: Montelukast or equivalent<br>* Pharmaceutical form: Tablets Route of administration: Oral<br>|
| Experimental: Cohort B: Participants with cPRA 80.00% to 99.89%<br>Participants with cPRA between 80.00% to 99.89% (indicating active candidates on kidney transplant waitlist with no living donor cleared for donation) 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 for subsequent treatment cycles (each cycle of 28 days) until unacceptable AEs or participant's decision to stop the treatment (maximum treatment duration: 13 weeks). | Drug: Isatuximab SAR650984<br>* Pharmaceutical form: Solution for infusion Route of administration: Intravenous<br>* Other names: Sarclisa;Drug: Acetaminophen (paracetamol) or equivalent<br>* Pharmaceutical form: Tablets Route of administration: Oral<br>Drug: Ranitidine or equivalent<br>* Pharmaceutical form: Solution Route of administration: Intravenous<br>Drug: Diphenhydramine or equivalent<br>* Pharmaceutical form: Solution Route of administration: Intravenous<br>Drug: Methylprednisolone or equivalent<br>* Pharmaceutical form: Solution Route of administration: Intravenous<br>Drug: Montelukast or equivalent<br>* Pharmaceutical form: Tablets Route of administration: Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs) | An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had to have a causal relationship with the treatment. Serious adverse events (SAEs) were any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (defined as the time from the first dose of study drug until study cut-off date). | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Number of Participants With Hematological Abnormalities | Abnormal hematological parameters assessed were anemia, platelet count decreased, neutrophil count decreased, lymphocyte count decreased and monocytes. The hematological abnormality grades were based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. Monocytes were assessed as per potentially clinically significant abnormality (PCSA) criteria defined as: greater than (>) 0.7*10^9/L. | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Number of Participants With Renal Function Abnormalities | Abnormal renal parameters assessed were creatinine increased and estimated Glomerular Filtration Rate (eGFR). The renal function abnormality grades were based on NCI-CTCAE, Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. eGFR was assessed as per PCSA criteria: 60 (less than equal to) <= to less than (<) 90 milliliter/minute/1.73 meter square (mL/min/1.73m^2) (Mild), 30<= to <60 mL/min/1.73m^2 (Moderate), 15<=to <30 mL/min/1.73m^2 (Severe), <15 mL/min/1.73m^2 (End Stage Renal Disease). | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Number of Participants With Abnormal Electrolytes Parameters | Abnormal electrolyte parameters assessed were hypernatremia, hyponatremia, hyperkalemia, hypokalemia, hypercalcemia, hypocalcemia, blood bicarbonate decreased, hypermagnesemia, hypomagnesemia and chloride. The abnormal grades were based on NCI-CTCAE, Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. Chloride was estimated as per PCSA criteria: <80 millimoles per liter (mmol/L) and >115 mmol/L. | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Number of Participants With Abnormal Metabolism Parameters | Abnormal metabolism parameters assessed were hypoglycemia, hypoalbuminemia and glycated Hemoglobin (HbA1c). The abnormal grades were based on NCI-CTCAE, Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. HbA1c was estimated as per PCSA criteria: >8%. | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Number of Participants With Liver Function Abnormalities | Abnormal liver function parameters assessed were Alanine aminotransferase (ALT) increased, Aspartate aminotransferase (AST) increased, Alkaline phosphatase (ALP) increased, and Total bilirubin (TB) increased. The abnormal grades were based on NCI-CTCAE, Version 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Percentage of Participants With Response | Response was defined as the percentage of participants meeting at least one of the predefined desensitization efficacy criteria as measured by single antigen bead (SAB) assay as follows: reduction in cPRA resulting in at least 100% increase of likelihood of finding a compatible donor; reduction in antibody titer (>=75% reduction from Baseline) to achieve target cPRA; elimination of >=1 human leukocyte antigen (HLA) antibody (i.e., mean fluorescence intensity [MFI] reduced to <2000) as measured by a SAB assay, for antibodies with Baseline MFI >=3000. | From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) Parameters: Concentration Observed at the End of First Intravenous Infusion (Ceoi) of Isatuximab | Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab. | At End of infusion on Cycle 1 Day 1 | 
| PK Parameters: Maximum Concentration Observed (Cmax) After the First Infusion of Isatuximab | Cmax was defined as the maximum concentration observed after the first administration calculated using the noncompartmental analysis after the intravenous infusion of isatuximab. | At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1 | 
| PK Parameters: Time Taken to Reach Cmax (Tmax) After the First Infusion of Isatuximab | Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion of isatuximab. | At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1 | 
| PK Parameters: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab | Clast was defined as the last concentration of isatuximab observed above the lower limit of quantification calculated using non-compartmental analysis after the first infusion of isatuximab. | At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1 | 
| PK Parameters: Time of Clast (Tlast) After First Infusion of Isatuximab | 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 isatuximab. | At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1 | 
| PK Parameters: Trough Plasma Concentrations (Ctrough) of Isatuximab | Ctrough was the plasma concentration of isatuximab observed just before (pre-dose) treatment administration. | Cycle 2 Day 1 | 
| PK Parameters: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 168 Hours Over the Dosing Interval (AUC0-168 Hours) After First Infusion of Isatuximab | AUC0-168 hours was defined as the area under the plasma concentration versus time curve from time 0 to 168 hours post dose calculated using trapezoidal method after first infusion of isatuximab. | At Start of infusion (SOI), End of infusion (EOI), EOI+4H (initial protocol) EOI+1H (amended protocol), 72H and 168H on Day 1 of Cycle 1 | 
| Number of Participants With Anti-drug Antibodies (ADA) Against Isatuximab | ADA responses were categorized as treatment boosted ADA and treatment-induced ADA. Treatment boosted ADA was defined as pre-existing ADAs with a significant increase in the ADA titer during the study compared to the Baseline titer. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in participants without pre-existing ADA. | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Duration of Response (DOR) | Duration of response (DOR) was defined as time (in weeks) from laboratory sample collection date used in determining a participant to be a responder (defined as participants meeting at least one of the predefined desensitization efficacy criteria: reduction in cPRA resulting in at least 100% increase of likelihood of finding a compatible donor; reduction in antibody titer [>=75% reduction from Baseline] to achieve target cPRA; elimination of >=1 anti-HLA antibody i.e. MFI reduced to <2000 as measured by a SAB assay, for antibodies with Baseline MFI >=3000) up to the laboratory sample collection date when participant was confirmed as no longer meeting any response criterion (i.e., non-responder) or the date of death due to any cause, whichever occurs first. DOR was analyzed using Kaplan-Meier method. | From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks) | 
| Number of Participants Achieving Target cPRA | Target calculated panel reactive antibodies (cPRA) was defined as the reduction of cPRA required to achieve at least 100% increase of likelihood of compatible donor (LCD). Number of participants who achieved target cPRA was assessed using the Organ Procurement and Transplantation Network (OPTN) calculator during the specified timepoint were reported in this outcome measure. Participants who retained their target cPRA values were censored at the date of the last available laboratory assessment achieving their target cPRA. | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Duration for Achieving Target cPRA | Duration of achieving target cPRA was defined as the time (in weeks) from laboratory sample collection date of achieving target cPRA (defined as the reduction of cPRA required to achieve at least 100% increase of LCD) the first time up to the laboratory sample collection date when no longer achieving target cPRA calculated using OPTN calculator or the date of death due to any cause, whichever occurs first. The duration of achieving target cPRA was assessed using the Kaplan-Meier method. | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Number of Participants With Anti-Human Leukocyte Antigen (HLA)-Antibody Reduction | Number of participants with anti-HLA-antibody (Baseline MFI >=3000) reduced to <2000 as measured using a SAB assay per central laboratory assessment was reported in this outcome measure. Participants were categorized in various categories of number of antibodies which were reduced as: none, 1-5, >5-10, >10-15, and >15. If multiple visits had the same number of total anti-HLA antibody reduction, the last visit data was summarized. | From first dose of study drug until end of follow-up period (maximum duration: up to 39.1 weeks) | 
| Time to First Transplant Offer | Time to first transplant offer was defined as time (in days) from date of first study treatment dose up to date of first kidney transplant offer. Data on transplant status were collected and followed up until study cut-off date. | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Time to Transplant | Time to transplant was defined as time (in days) from date of first study treatment dose up to date of kidney transplant. Data on transplant status were collected and followed up until study cut-off date. | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Number of Kidney Transplant Offers | Number of kidney transplants offers received for each participant was reported in the outcome measure. Data on transplant offers were collected and followed up until study cut-off date. | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Time to First Antibody Mediated Rejection (AMR) Episode | Time to first AMR was defined as time from date of first study treatment dose up to date of biopsy with first AMR (defined as the graft rejection due to generation of antibodies against the graft). Transplanted participants without any AMR were censored at the participant's last assessment or contact date collected in the study or at the analysis cut-off date, whichever was earlier. | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Percentage of Participants Who Experienced Any Antibody Mediated Rejection (AMR) | Antibody mediated rejection was defined as the graft rejection due to generation of antibodies against the graft. The number of participants with AMR field checked as 'yes' based on the graft rejection biopsy in the electronic case report form was considered. | From first dose of study drug until study cut-off date (maximum duration: up to 97.7 weeks) | 
| Number of Participants With Graft Survival at 6 Months Post-Transplant | Number of participants with graft survival status as functioning at 6-months post-transplant was reported in this outcome measure. | At 6 Months post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-CD38 monoclonal antibody