Study to Evaluate the Effects of ACE-536 in Patients With Beta-thalassemia

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effects of ACE-536 in patients with beta-thalassemia.

Detailed Description
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To evaluate the proportion of β-thalassemia patients who have an erythroid response, defined as: a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of red blood cell [RBC] transfusions) in non-transfusion dependent patients, or ≥ 20% reduction in RBC transfusion burden compared to pretreatment in transfusion dependent patients.

Official Title
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A Phase 2, Open-Label, Ascending Dose Study to Evaluate the Effects of ACE-536 in Patients With Beta-Thalassemia Intermedia

Conditions
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B-Thalassemia

Intervention / Treatment
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* Drug: ACE-536


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Men or women >=18 years of age For the dose escalation phase of the study: documented diagnosis of β-thalassemia intermedia (transfusion dependent patients must not have begun regular transfusions at age < 4.0 years). For the expansion cohort: documented diagnosis of β-thalassemia (including β-thalassemia major or β-thalassemia intermedia). Prior splenectomy or spleen size < 18 cm in the longest diameter by abdominal ultrasound (dose escalation cohorts only). Anemia, defined as: (i) mean hemoglobin concentration < 10.0 g/dL of 2 measurements (one performed within one day prior to Cycle 1 Day 1 and the other performed during the screening period [Day -28 to Day -1]) in non-transfusion dependent patients, defined as having received < 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1, or (ii) transfusion dependent, defined as requiring ≥ 4 units of RBCs every 8 weeks (confirmed over 6 months prior to Cycle 1 Day 1). Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN). Serum creatinine ≤ 1.5 x ULN. Adequate pregnancy avoidance measures. Patients are able to adhere to the study visit schedule, understand and comply with all protocol requirements. Understand and able to provide written informed consent. Key Exclusion Criteria: Any clinically significant pulmonary (including pulmonary hypertension), cardiovascular, endocrine, neurologic, hepatic, gastrointestinal, infectious, immunological (including clinically significant allo- or auto-immunization) or genitourinary disease considered by the investigator as not adequately controlled prior to Cycle 1 Day 1. Folate deficiency. Symptomatic splenomegaly. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B (HBV) or active infectious hepatitis C (HCV). Known history of thromboembolic events ≥ grade 3 according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.0 (current active minor version). Ejection fraction < 50% by echocardiogram, MUGA or cardiac MRI. Uncontrolled hypertension defined as systolic blood pressure (BP) ≥ 150 mm Hg or diastolic BP ≥ 95 mm Hg. Heart failure class 3 or higher (New York Heart Association, NYHA). QTc > 450 msec on screening ECG. Platelet count < 100 x10(9)/L or > 1,000 x10(9)/L. Proteinuria ≥ Grade 2. Any active infection requiring parenteral antibiotic therapy within 28 days prior to Cycle 1 Day 1 or oral antibiotics within 14 days of Cycle 1 Day 1. Treatment with another investigational drug or device, or approved therapy for investigational use ≤ 28 days prior to Cycle 1 Day 1, or if the half-life of the previous investigational product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer. Transfusion event within 7 days prior to Cycle 1 Day 1. Patients receiving or planning to receive hydroxyurea treatment. Patients must not have had hydroxyurea within 90 days of Cycle 1 Day 1. Splenectomy within 56 days prior to Cycle 1 Day 1. Major surgery (except splenectomy) within 28 days prior to Cycle 1 Day 1. Patients must have completely recovered from any previous surgery prior to Cycle 1 Day 1. Iron chelation therapy initiated within 56 days prior to Cycle 1 Day 1. Cytotoxic agents, systemic corticosteroids, immunosuppressants, or anticoagulant therapy such as warfarin or heparin within 28 days prior to Cycle 1 Day 1 (prophylactic aspirin up to 100 mg/d is permitted). Pregnant of lactating females. History of severe allergic or anaphylactic reactions of hypersensitivity to recombinant proteins or excipients in the investigational drug. Prior treatment with sotatercept (ACE-011) or ACE-536.

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: ACE 536<br>ACE-536 - 1 of 7 possible dose levels. | Drug: ACE-536<br>* Subjects receive ACE-536 administered subcutaneously (SC) every 3 weeks for up to 5 cycles.<br>* Other names: luspatercept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who have an erythroid response. | Proportion of patients who have an erythroid response, defined as a 1) a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of red blood cell [RBC] transfusions) in non-transfusion dependent patients, or 2) ≥ 20% reduction in RBC transfusion burden compared to pretreatment in transfusion dependent patients. | Assessed at approximately 24 weeks from patient screening. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events. |  | From treatment initiation to End-of-Study visit (approximately 24 weeks later). | 
| Change in hemoglobin level in non-transfusion dependent patients. |  | Baseline to approximately 24 weeks. | 
| Changes in biomarkers of erythropoiesis, hemolysis, iron metabolism and bone metabolism. |  | Baseline to approximately 24 weeks. | 
| ACE-536 pharmacokinetics. |  | Measured at multiple time points over the course of treatment, from study day 1 to approximately 24 weeks. |