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

Study Overview
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Brief Summary
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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

Detailed Description
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28 weeks (including screening)

Official Title
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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

Conditions
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Warm Autoimmune Hemolytic Anemia (wAIHA)

Intervention / Treatment
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* Drug: Isatuximab SAR650984


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

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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(wAIHA)