Efficacy, Safety and Pharmacokinetics of Rilzabrutinib in Patients With Warm Autoimmune Hemolytic Anemia (wAIHA)

Study Overview
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Brief Summary
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This is a single group treatment, Phase 2, open-label, study to evaluate the efficacy, safety and pharmacokinetics of rilzabrutinib in adult patients with wAIHA. All participants will receive rilzabrutinib orally. The screening period is up to 28 days, followed by a treatment period of 24 weeks for Part A. Participants who complete Part A and are deemed eligible for Part B will continue to receive the study medication for 52 weeks following the Last Patient In (LPI-Part B). There will be a 7-day safety follow-up period after receiving the last dose of study drug either in Part A (for those not eligible for Part B or early terminated) or Part B. The estimated total duration of the study is approximately 137 weeks (Parts A and B), including the follow-up period. For participants deemed ineligible for Part B, the total length of the study will be 29 weeks (Part A only), including screening and the follow-up period. In Part B, participants who temporarily stop rilzabrutinib treatment and maintain a durable response from W50 to W74, will have their EOS visit at Week 75. In this case, participation will be for 79 weeks including the screening period.

Official Title
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A Multicenter, Open-label, Phase IIb Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Rilzabrutinib in Patients With Warm Autoimmune Hemolytic Anemia

Conditions
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Warm Autoimmune Hemolytic Anemia (wAIHA)

Intervention / Treatment
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* Drug: rilzabrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients with a confirmed diagnosis of primary wAIHA or systemic lupus erythematosus (SLE)-associated wAIHA (without other SLE-related manifestations apart from cutaneous and musculoskeletal manifestations) Participants who have previously failed to maintain a sustained response after treatment with corticosteroids. Eastern Cooperative Oncology Group (ECOG) performance status grade 2 or lower. Up-to-date vaccination status as per local guidelines. Body mass index (BMI) >17.5 and <40 kg/m2 All contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Part B only Evidence of treatment efficacy to rilzabrutinib as defined by achieving overall response during Part A. Completion of Part A treatment period (24 weeks). 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. Participants with medical history of lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for the past 3 years. Secondary wAIHA from any cause including drugs, lymphoproliferative disorders (low-count monoclonal B-cell lymphocytosis is allowed), infectious or autoimmune disease, or active hematologic malignancies. Participants with positive antinuclear antibodies but without a definitive diagnosis of an autoimmune disease are allowed. Myelodysplastic syndrome. Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA. HIV infection. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days or 5 half-lives, whichever is greater, prior to treatment start. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. Part B only Participants who receive any therapy during Part A known to be active in wAIHA. Presence of unacceptable side effect(s) or toxicity associated with rilzabrutinib such that there is an unfavorable risk-benefit assessment for continued treatment with rilzabrutinib in the opinion of the Investigator and/or Sponsor. 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rilzabrutinib<br>Oral rilzabrutinib 400 mg BID | Drug: rilzabrutinib<br>* Pharmaceutical form: Tablet Route of administration: Oral<br>* Other names: PRN1008/SAR444671;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Proportion of participants with overall hemoglobin response | Response is defined as an increase in hemoglobin (Hb) by ≥2 g/dL from baseline and an absence of transfusion in the last 7 days, without biochemical resolution of hemolysis at the time response is achieved and an absence of rescue medications during the last 4 weeks. Complete Response is defined as hemoglobin ≥11 g/dL (women) or ≥12 g/dL (men), no evidence of hemolysis (normal bilirubin, lactate dehydrogenase (LDH) , haptoglobin, and reticulocytes), and absence of transfusion in the last 7 days and an absence of rescue medications during the last 4 weeks. | By Week 24 in Part A | 
| Part B: Proportion of participants who maintain durable response achieved during Part A or achieve a durable response during Part B and have a hemoglobin response | Durable response (Part B) is defined as Hb level ≥10 g/dL with an increase from baseline (Part A) of ≥2 g/dL on three consecutive scheduled visits during Week 24 to Week 50; 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. | At Week 50 in Part B | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with durable hemoglobin response | Durable response (Part A) is defined as Hb level ≥10 g/dL with an increase from baseline of ≥2 g/dL on three consecutive evaluable visits during the 24-week treatment 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. | By Week 24 in Part A | 
| Median time from baseline to first hemoglobin response |  | From Day 1 to Week 24 in Part A | 
| Frequency of rescue therapy (any wAIHA-directed therapy other than predniso[lo]ne or transfusion) received |  | After Week 1 of treatment to Week 24 in Part A and Week 75 in Part B | 
| Change from baseline in FACIT-Fatigue scale score | The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale is a 13-item questionnaire used to assesses self-reported fatigue and its impact on daily activities and function. | Until Week 24 in Part A and Week 75 in Part B | 
| Incidence of treatment emergent adverse events (TEAEs), serious TEAEs, adverse events of special interest (AESIs) | Safety assessment including clinical laboratory evaluations, vital sign measurements and ECG | Until Week 24 in Part A and Week 75 in Part B |