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

NCT04294459 | Terminated Phase 1 Results FDA Drug

• 3 other identifiers: TED164142019-004154-28U1111-1238-9716
• Study Type: interventional
• Target: 23
• Locations: 2 countries
• Sites: 6

Brief 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.

Conditions

Immune System Disorder

Keywords

Anti-CD38 monoclonal antibody

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (18)

• Pharmacokinetics (PK) Parameters: Concentration Observed at the End of First Intravenous Infusion (Ceoi) of Isatuximab

  At End of infusion on Cycle 1 Day 1

• PK Parameters: Maximum Concentration Observed (Cmax) 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 Taken to Reach Cmax (Tmax) 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: Last Concentration Observed Above the Lower Limit of Quantification (Clast) 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

  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

Study Arms (2)

Cohort A: Participants with cPRA >=99.90%

EXPERIMENTAL

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; Drug: Acetaminophen (paracetamol) or equivalent; Drug: Ranitidine or equivalent; Drug: Diphenhydramine or equivalent; Drug: Methylprednisolone or equivalent; Drug: Montelukast or equivalent

Cohort B: Participants with cPRA 80.00% to 99.89%

EXPERIMENTAL

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; Drug: Acetaminophen (paracetamol) or equivalent; Drug: Ranitidine or equivalent; Drug: Diphenhydramine or equivalent; Drug: Methylprednisolone or equivalent; Drug: Montelukast or equivalent

Interventions

Isatuximab SAR650984 DRUG

Pharmaceutical form: Solution for infusion Route of administration: Intravenous

Also known as: Sarclisa

Cohort A: Participants with cPRA >=99.90%; Cohort B: Participants with cPRA 80.00% to 99.89%

Acetaminophen (paracetamol) or equivalent DRUG

Pharmaceutical form: Tablets Route of administration: Oral

Cohort A: Participants with cPRA >=99.90%; Cohort B: Participants with cPRA 80.00% to 99.89%

Ranitidine or equivalent DRUG

Pharmaceutical form: Solution Route of administration: Intravenous

Cohort A: Participants with cPRA >=99.90%; Cohort B: Participants with cPRA 80.00% to 99.89%

Diphenhydramine or equivalent DRUG

Pharmaceutical form: Solution Route of administration: Intravenous

Cohort A: Participants with cPRA >=99.90%; Cohort B: Participants with cPRA 80.00% to 99.89%

Methylprednisolone or equivalent DRUG

Pharmaceutical form: Solution Route of administration: Intravenous

Cohort A: Participants with cPRA >=99.90%; Cohort B: Participants with cPRA 80.00% to 99.89%

Montelukast or equivalent DRUG

Pharmaceutical form: Tablets Route of administration: Oral

Cohort A: Participants with cPRA >=99.90%; Cohort B: Participants with cPRA 80.00% to 99.89%

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sanofi: lead

Study Sites (6)

Investigational Site Number :8400003

San Francisco, California, 94143, United States

Location

Investigational Site Number :8400001

Rochester, Minnesota, 55905, United States

Location

Investigational Site Number :8400002

New York, New York, 10016, United States

Location

Investigational Site Number :8400004

Houston, Texas, 77030, United States

Location

Investigational Site Number :7240002

Barcelona, Barcelona [Barcelona], 08035, Spain

Location

Investigational Site Number :7240001

L'Hospitalet de Llobregat, Catalunya [Cataluña], 08907, Spain

Location

Related Publications (2)

• Mannon RB, Vincenti FG. Poised for Innovation: Considerations for End Points for New Drug Development in Kidney Transplantation. J Am Soc Nephrol. 2024 Nov 1;35(11):1603-1606. doi: 10.1681/ASN.0000000000000475. Epub 2024 Aug 5. No abstract available.

  PMID: 39102302 DERIVED

• Vincenti F, Bestard O, Brar A, Cruzado JM, Seron D, Gaber AO, Ali N, Tambur AR, Lee H, Abbadessa G, Paul JA, Dudek M, Siegel RJ, Torija A, Semiond D, Lepine L, Ternes N, Montgomery RA, Stegall M. Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant. J Am Soc Nephrol. 2024 Mar 1;35(3):347-360. doi: 10.1681/ASN.0000000000000287. Epub 2023 Dec 26.

  PMID: 38147137 DERIVED

Related Links

• TED16414 Plain Language Results Summary

MeSH Terms

Conditions

Immune System Diseases

Interventions

isatuximab; Acetaminophen; Ranitidine; Diphenhydramine; Methylprednisolone; montelukast

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Furans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Ethylamines; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Limitations and Caveats

Sponsor decided to terminate the study for non-safety reasons on 02 May 2022. Based on available clinical data at time of interim analysis, it was determined that enrollment of the remaining participants was unlikely to have any significant impact on the study results and hence the trial was stopped. All 23 participants enrolled in the study were followed-up per protocol until the planned study termination date.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi Aventis Recherche & Développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 19, 2020
• First Posted: March 4, 2020
• Study Start: June 18, 2020
• Primary Completion: May 2, 2022
• Study Completion: May 2, 2022
• Last Updated: September 17, 2025
• Results First Posted: May 30, 2023

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

ES (2); US (4)