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

• ClinicalTrials.gov Identifier: NCT04661033
• Recruitment Status: Recruiting
• First Posted: December 9, 2020
• Last Update Posted: October 5, 2022
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Warm Autoimmune Hemolytic Anemia (wAIHA)	Drug: Isatuximab SAR650984	Phase 1; Phase 2

Detailed Description:

28 weeks (including screening)

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 23 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: September 9, 2021
• Estimated Primary Completion Date: July 22, 2024
• Estimated Study Completion Date: July 22, 2024

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Part A To assess safety and tolerability [ Time Frame: Through Day 169 ]
   Standard clinical and laboratory parameters and adverse events.
2. Part B -To evaluate overall response rate (R) or complete response (CR) at Day 85 [ Time Frame: Through 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

Secondary Outcome Measures :

1. Part A (Cohorts 2 and 3 Only) -To evaluate overall response rate (R) or complete response (CR) at Day 85 [ Time Frame: Through 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.

2. Part A (Cohorts 2 and 3 Only) and Part B -Proportion of participants with durable hemoglobin response by Day 169 [ Time Frame: Through 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.
3. Part A (Cohorts 2 and 3 Only) and Part B -Overall response rate at Day 169 [ Time Frame: Through 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
4. Part A (Cohorts 2 and 3 Only) and Part B -FACIT-fatigue scale score [ Time Frame: Through Day 169 ]
   -FACIT-fatigue scale score
5. Part B -To assess safety and tolerability [ Time Frame: Through Day 169 ]
   Standard clinical and laboratory parameters and adverse events.
6. Part A (All Cohorts) and B -Change from baseline in LDH [ Time Frame: Through Day 169 ]
7. Part A (All Cohorts) and B -Change from baseline in haptoglobin [ Time Frame: Through Day 169 ]
8. Part A (All Cohorts) and B -Change from baseline in reticulocytes [ Time Frame: Through Day 169 ]
9. Part A (All Cohorts) and B -Change from baseline in total bilirubin [ Time Frame: Through Day 169 ]
10. Part A (All Cohorts) and B -PK parameters after subcutaneous administrations (Cmax) [ Time Frame: Through Day 169 ]
    Maximum concentration received after injection (Cmax)
11. Part A (All Cohorts) and B -PK parameters after subcutaneous administrations (AUC0-2week) [ Time Frame: Through Day 169 ]
    Area under the plasma concentration versus time curve calculated over the dosing interval T (336 h) (AUC0-2week)
12. Part A (All Cohorts) and B Incidence of anti-isatuximab antibodies [ Time Frame: Through Day 169 ]
13. Part A (All Cohorts) and B Titer (if relevant) of anti-isatuximab antibodies [ Time Frame: Through Day 169 ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Trial Transparency email recommended (Toll free number for US & Canada); 800-633-1610 ext option 6; Contact-US@sanofi.com

Locations

United States, California

University of Southern California-Site Number:8400001; Recruiting

Los Angeles, California, United States, 90033

United States, Pennsylvania

Fox Chase Cancer Center-Site Number:8400004; Recruiting

Philadelphia, Pennsylvania, United States, 19111

Belgium

Investigational Site Number :0560001; Recruiting

Leuven, Belgium, 3000

France

Investigational Site Number :2500001; Recruiting

Creteil Cedex, France, 94010

Investigational Site Number :2500002; Recruiting

Pessac, France, 33600

Germany

Investigational Site Number :2760001 Universitätsklinikum Essen Klinik für Hämatologie und Stammzellentransplantation; Recruiting

Essen, Germany, 45147

Contact: Nicole PREISING nicole.preising@uk-essen.de

Principal Investigator: Prof. Dr. Alexander Röth

Hungary

Investigational Site Number :3480001 Egyetem ÁOK, Belgyógyászati és Onkológiai Klinika, Klinikai Farmakológiai Részleg; Recruiting

Budapest, Hungary, 1083

Contact: György NAGY +36 20 943 6465 gyorgypalnagy@gmail.com

Principal Investigator: Prof. Dr. István Takacs Semmelweis

Italy

Investigational Site Number :3800001 Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via F. Sforza 35; Recruiting

Milano, Italy, 20122

Contact: Dr. Milesi Giulia giulia.milesi@policlinico.mi.it

Principal Investigator: Dr. Wilma Barcellini

Netherlands

Investigational Site Number :5280001; Recruiting

Leiden, Netherlands, 2333 ZA

United Kingdom

Investigational Site Number :8260001; Recruiting

London, London, City Of, United Kingdom, NW1 2PG

Sponsors and Collaborators

Sanofi

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

More Information

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT04661033
• Other Study ID Numbers: ACT16832; 2020-003880-24 ( EudraCT Number ); U1111-1255-5350 ( Other Identifier: UTN )
• First Posted: December 9, 2020
• Last Update Posted: October 5, 2022
• Last Verified: October 4, 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sanofi:

(wAIHA)

Additional relevant MeSH terms:

Anemia; Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune; Hemolysis; Hematologic Diseases; Pathologic Processes; Autoimmune Diseases; Immune System Diseases