Safety, Pharmacokinetics, and Efficacy of Subcutaneous Isatuximab in Adults With Warm Autoimmune Hemolytic Anemia (wAIHA)

A Multicenter, Open-label, Non-randomized, Phase 1b/2 Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Subcutaneous Isatuximab in Adults With Warm Autoimmune Hemolytic Anemia

Primary Objectives:

• Part A: To evaluate the safety and tolerability of subcutaneous injections of isatuximab in adults with wAIHA
• Part B: To evaluate the efficacy of the selected dose in adults with wAIHA

Secondary Objectives:

• Part A (Cohorts 2 and 3 only)
• To evaluate the efficacy of isatuximab in adults with wAIHA
• To evaluate the durability of response to isatuximab and time to response
• To evaluate the impact of isatuximab treatment on fatigue

Part B

• To evaluate the safety and tolerability of isatuximab in adults with wAIHA
• To evaluate the durability of response to isatuximab and time to response
• To evaluate the impact of isatuximab treatment on fatigue

Parts A (all Cohorts) and B

• To evaluate the effect of isatuximab on markers of hemolysis
• To characterize the pharmacokinetic profile of isatuximab in adults with wAIHA
• To evaluate the immunogenicity of isatuximab

Study Overview

• Status: Terminated
• Conditions: Warm Autoimmune Hemolytic Anemia (wAIHA)
• Intervention / Treatment: Drug: Isatuximab SAR650984

Detailed Description

28 weeks (including screening)

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Investigational Site Number :0560001
• France
  • Creteil Cedex, France, 94010
    • Investigational Site Number :2500001
  • Pessac, France, 33600
    • Investigational Site Number :2500002
• Germany
  • Essen, Germany, 45147
    • Investigational Site Number :2760001 Universitätsklinikum Essen Klinik für Hämatologie und Stammzellentransplantation
• Hungary
  • Budapest, Hungary, 1083
    • Investigational Site Number :3480001 Egyetem ÁOK, Belgyógyászati és Onkológiai Klinika, Klinikai Farmakológiai Részleg
• Italy
  • Milano, Italy, 20122
    • Investigational Site Number :3800001 Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via F. Sforza 35
• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Investigational Site Number :5280001
• United Kingdom
  • London, City Of
    • London, London, City Of, United Kingdom, NW1 2PG
      • Investigational Site Number :8260001
• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California-Site Number:8400001
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center-Site Number:8400004

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria :

• Participant must be ≥18 to years of age, inclusive, at the time of signing the informed consent.

  - Males and females with a confirmed diagnosis of primary w AIHA or systemic lupus erythematosus (SLE)-associated w AIHA (without other SLE-related manifestations apart from cutaneous and musculoskeletal manifestations) who meet the following criteria:

  1. Hemoglobin level <10 g/dL at screening.
  2. Hemolysis (haptoglobin ≤40 mg/dL and total or indirect/unconjugated bilirubin above the upper limit of normal).

  3. Positive direct antiglobulin test (DAT) (IgG or IgG + complement C3d pattern or IgM warm autoantibodies (positive dual DAT)).

     • Participants who have previously failed to maintain a sustained response after treatment with corticosteroids (corticosteroid-refractory or corticosteroid-dependent primary wAIHA).
     • Part A only: Participants who have previously failed to maintain a sustained response after treatment with rituximab (or other anti-CD20 monoclonal antibodies). The last dose of the anti-CD20 antibody must have been administered at least 12 weeks before enrollment.
     • Part B: Participants who have had an insufficient response to at least 1 prior therapy in addition to corticosteroids (splenectomy is regarded as a prior therapy).
     • Contraceptive use by men and women

     Exclusion criteria:

• Clinically significant medical history or ongoing chronic illness that would jeopardize the safety of the participant or compromise the quality of the data derived from his or her participation in the study as determined by the Investigator.

  • Serious infection that required hospitalization within 3 months prior to enrollment.
  • Secondary wAIHA from any cause including drugs, lymphoproliferative disorders, infectious or autoimmune disease (SLE without other SLE-related manifestations apart from cutaneous and musculoskeletal manifestations is allowed), or active hematologic malignancies. Participants with positive antinuclear antibodies but without a definitive diagnosis of an autoimmune disease are allowed.
  • History of coagulation or bleeding disorders (Evans Syndrome is allowed).
  • Uncontrolled or active HBV or HCV infection
  • HIV infection.
  • Serum gammaglobulin levels <3 g/L.
  • Females who are pregnant, lactating, or considered unreliable with respect to contraceptive practice.
  • Concurrent treatment with corticosteroids, unless the participant has been on a stable daily dose for ≥ 15 days prior to enrollment.
  • Treatment with cyclophosphamide within 4 weeks prior to enrollment.
  • Treatment with cytotoxic drugs (other than cyclophosphamide) within 12 weeks prior to enrollment.
  • Treatment with non-cytotoxic, immunomodulatory drugs (including but not limited to Cyclosporine, Sirolimus, Tacrolimus, Idelalisib, Ibrutinib), excluding biologic agents, within 4 weeks prior to enrollment.
  • Treatment with any biologic agent within 12 weeks prior to enrollment.

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Isatuximab Part A/Cohort 1; Isatuximab dose subcutaneous (SC) every 2 weeks x 2 doses	Drug: Isatuximab SAR650984; Pharmaceutical form:Solution for injection Route of administration: Subcutaneous
Experimental: Isatuximab Part A/Cohort 2; Isatuximab dose subcutaneous (SC) every 2 weeks x 6 doses	Drug: Isatuximab SAR650984; Pharmaceutical form:Solution for injection Route of administration: Subcutaneous
Experimental: Isatuximab Part A/Cohort 3 (optional); Isatuximab dose subcutaneous (SC) every 2 weeks x 2 doses	Drug: Isatuximab SAR650984; Pharmaceutical form:Solution for injection Route of administration: Subcutaneous
Experimental: Isatuximab Part B; Isatuximab dose subcutaneous (SC) every 2 weeks x 6 doses	Drug: Isatuximab SAR650984; Pharmaceutical form:Solution for injection Route of administration: Subcutaneous

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A To assess safety and tolerability	Standard clinical and laboratory parameters and adverse events.	Through Day 169
Part B -To evaluate overall response rate (R) or complete response (CR) at Day 85	R is defined as an increase in hemoglobin by ≥2 g/dL from baseline and an absence of transfusion in the last 7 days and absence of rescue medications in the past 4 weeks. Biochemical evidence of hemolysis may still be present. CR is defined as hemoglobin ≥11 g/dL (women) or ≥12 g/dL (men), no evidence of hemolysis (normal bilirubin, LDH, haptoglobin, and reticulocytes), absence of transfusion in the last 7 days and absence of rescue medication in the past 4 weeks	Through Day 85

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A (Cohorts 2 and 3 Only) -To evaluate overall response rate (R) or complete response (CR) at Day 85	R is defined as an increase in hemoglobin by ≥2 g/dL from baseline and an absence of transfusion in the last 7 days and absence of rescue medications in the past 4 weeks. Biochemical evidence of hemolysis may still be present. CR is defined as hemoglobin ≥11 g/dL (women) or ≥12 g/dL(men), no evidence of hemolysis (normal bilirubin, LDH, haptoglobin, and reticulocytes), and absence of transfusion in the last 7 days and absence of rescue medication in the past 4 weeks.	Through Day 85
Part A (Cohorts 2 and 3 Only) and Part B -Proportion of participants with durable hemoglobin response by Day 169	Durable response is defined as Hb level ≥10 g/dL with an increase from baseline of ≥2 g/dL on three consecutive evaluable visits during the study period; with absence of transfusion and no rescue medication during the period of 3 consecutive visits and for at least 7 days (transfusions) and 4 weeks (rescue medication) prior to the first consecutive visit.	Through Day 169
Part A (Cohorts 2 and 3 Only) and Part B -Overall response rate at Day 169	Overall response rate at Day 169, median time to R or CR, median time to loss of R or CR (loss of R defined as hemoglobin <10 g/dL at two consecutive visits at least 7 days apart and initiation of new treatment for anemia or increase in steroid dose; loss of CR is defined as hemoglobin <11 g/dL (women) or <12 g/dL (men) at two consecutive visits at least 7 days apart), proportion of participants requiring rescue therapy (any wAIHAdirected therapy other than prednisone or transfusion) or splenectomy	Through Day 169
Part A (Cohorts 2 and 3 Only) and Part B -FACIT-fatigue scale score	-FACIT-fatigue scale score	Through Day 169
Part B -To assess safety and tolerability	Standard clinical and laboratory parameters and adverse events.	Through Day 169
Part A (All Cohorts) and B -Change from baseline in LDH		Through Day 169
Part A (All Cohorts) and B -Change from baseline in haptoglobin		Through Day 169
Part A (All Cohorts) and B -Change from baseline in reticulocytes		Through Day 169
Part A (All Cohorts) and B -Change from baseline in total bilirubin		Through Day 169
Part A (All Cohorts) and B -PK parameters after subcutaneous administrations (Cmax)	Maximum concentration received after injection (Cmax)	Through Day 169
Part A (All Cohorts) and B -PK parameters after subcutaneous administrations (AUC0-2week)	Area under the plasma concentration versus time curve calculated over the dosing interval T (336 h) (AUC0-2week)	Through Day 169
Part A (All Cohorts) and B Incidence of anti-isatuximab antibodies		Through Day 169
Part A (All Cohorts) and B Titer (if relevant) of anti-isatuximab antibodies		Through Day 169

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Study Director: Clinical Sciences & Operations, Sanofi

Study record dates

Study Major Dates

• Study Start (Actual): September 9, 2021
• Primary Completion (Actual): June 26, 2023
• Study Completion (Actual): June 26, 2023

Study Registration Dates

• First Submitted: December 1, 2020
• First Submitted That Met QC Criteria: December 8, 2020
• First Posted (Actual): December 9, 2020

Study Record Updates

• Last Update Posted (Actual): July 6, 2023
• Last Update Submitted That Met QC Criteria: July 3, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: (wAIHA)
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Hematologic Diseases; Anemia; Hemolysis; Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune
• Other Study ID Numbers: ACT16832; 2020-003880-24 (EudraCT Number); U1111-1255-5350 (Other Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No