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

Immune System Disorder Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04294459
• Other study ID #: TED16414
• Secondary ID: 2019-004154-28U1
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: June 18, 2020
• Est. completion date: May 2, 2022

Study information

• Verified date: May 2023
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 23
• Est. completion date: May 2, 2022
• Est. primary completion date: May 2, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Immune System Diseases
• Immune System Disorder

Intervention

Drug:
• Isatuximab SAR650984
Pharmaceutical form: Solution for infusion Route of administration: Intravenous
• Acetaminophen (paracetamol) or equivalent
Pharmaceutical form: Tablets Route of administration: Oral
• Ranitidine or equivalent
Pharmaceutical form: Solution Route of administration: Intravenous
• Diphenhydramine or equivalent
Pharmaceutical form: Solution Route of administration: Intravenous
• Methylprednisolone or equivalent
Pharmaceutical form: Solution Route of administration: Intravenous
• Montelukast or equivalent
Pharmaceutical form: Tablets Route of administration: Oral

Locations

Country	Name	City	State
Spain	Investigational Site Number :7240002	Barcelona	Barcelona [Barcelona]
Spain	Investigational Site Number :7240001	Hospitalet de Llobregat	Catalunya [Cataluña]
United States	Investigational Site Number :8400004	Houston	Texas
United States	Investigational Site Number :8400002	New York	New York
United States	Investigational Site Number :8400001	Rochester	Minnesota
United States	Investigational Site Number :8400003	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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