ACE-536 Extension Study - Beta Thalassemia

Study Overview
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Brief Summary
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Study A536-06 is an open-label extension study for patients previously enrolled in study A536-04 (ClinicalTrials.gov Identifier NCT01749540), to evaluate the long-term safety and tolerability of ACE-536 in adult patients with beta-thalassemia.

Detailed Description
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Study A536-06 is an open-label extension study for patients previously enrolled in study A536-04 (ClinicalTrials.gov Identifier NCT01749540), to evaluate the safety,tolerability and pharmacodynamic effects of up to 24 months of ACE-536 treatment in adult patients with beta-thalassemia previously treated with ACE-536 for up to 3 months in study A536-04. The starting dose level in A536-06 will be 0.8 mg/kg by subcutaneous (SC) injection once every 3 weeks. Dose titration/modification rules will be followed for individual patients and will be based upon safety and efficacy data collected during the course of treatment.

Official Title
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An Open-Label Extension Study to Evaluate the Long-Term Effects of ACE-536 in Patients With β-Thalassemia Previously Enrolled in Study A536-04

Conditions
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Beta-Thalassemia

Intervention / Treatment
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* Drug: ACE-536


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Completion of the treatment period in the base study A536-04. Females of child bearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥ 24 consecutive months) must have negative urine or blood pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation and for 12 weeks following the last dose of ACE-536. Males must agree to use a latex condom during any sexual contact with females of child-bearing potential during study participation and for 12 weeks following the last dose of ACE-536, even if he has undergone a successful vasectomy. Patients must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of ACE-536. Patient is able to adhere to the study visit schedule, understand and comply with all protocol requirements. Patient understands and is able to provide written informed consent Patients with treatment interruption (defined as patients who complete the EOS visit for study A536-04 and are ≥ 28 days post EOS visit) must also meet the following criteria Mean hemoglobin concentration < 10.0 g/dL of 2 measurements (not influenced by RBC transfusion) (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 NTD patients. Adequate folate levels or on folate therapy. Platelet count ≥ 100 x 10(9) /L and ≤ 1,000 x 10(9) /L. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN). Serum creatinine ≤ 1.5 x ULN. Ejection fraction ≥ 50% by Echocardiogram (ECHO) or Multi gated acquisition scan (MUGA). Exclusion Criteria: Discontinuation/withdrawal from study A536-04 due to patient request, patient unwillingness or inability to comply with the protocol, pregnancy, use of prohibited medication (e.g., hydroxyurea), medical reason or AE, hypersensitivity reaction to the study drug, at the discretion of the sponsor, or loss to follow-up prior to completion of the treatment period. 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. Symptomatic splenomegaly. 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. Patients receiving or planning to receive hydroxyurea treatment. Patients must not have had hydroxyurea within 90 days of Cycle 1 Day 1. For patients with treatment interruption: Iron chelation therapy if 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/day and low molecular weight (LMW) heparin for superficial vein thrombosis (SVT) is permitted). Treatment with another investigational drug (including sotatercept [ACE-011]) 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 at any time between the end of treatment of the base study A536-04 and Cycle 1 Day 1. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B (HBV) or active infectious hepatitis C (HCV). Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 150 mm Hg or diastolic blood pressure (DBP) ≥ 100 mm Hg. 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). Pregnant or lactating females. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug. Any other condition not specifically noted above which, in the judgment of the investigator, would preclude the patient from participating in the study.

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 0.8 mg/kg once every 3 weeks SC<br>ACE-536 0.8 mg/kg once every 3 weeks by SC injection | Drug: ACE-536<br>* ACE-536 0.8 mg/kg once every 3 weeks by SC injection<br>* Other names: luspatercept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long-term safety and tolerability of ACE-536 in patients with β thalassemia who were previously enrolled in study A536-04 | safety and tolerability will be assessed by recording and classification of all adverse events (clinical and laboratory) reported by study investigators in all subjects who received at least one dose of study drug | From first dose (Study Day 1) to end of treatment (Study Day 730) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Erythroid response (8-week) in non-transfusion dependent (NTD) patients | Proportion of patients with a mean hemoglobin increase ≥ 1.5 g/dL over continuous 8-week interval compared to baseline, not influenced by red blood cell (RBC) transfusion | From first dose (Study Day 1) to end of treatment (Study Day 730) | 
| Erythroid response (12-week) in non-transfusion dependent (NTD) patients | Proportion of patients with a mean hemoglobin increase ≥ 1.5 g/dL over continuous 12-week interval compared to baseline, not influenced by red blood cell (RBC) transfusion | From first dose (Study Day 1) to end of treatment (Study Day 730) | 
| Erythroid response (8-week) in transfusion dependent (TD) patients | Proportion of patients with a reduction in RBC transfusion burden by ≥ 20% over a continuous 8-week interval compared to the 8 weeks prior to the start of treatment | From first dose (Study Day 1) to end of treatment (Study Day 730) | 
| Erythroid response (12-week) in transfusion dependent (TD) patients | Proportion of patients with a reduction in RBC transfusion burden by ≥ 50% over a continuous 12-week interval compared to the 12 weeks prior to the start of treatment | From first dose (Study Day 1) to end of treatment (Study Day 730) | 
| Time to, and duration of, erythroid response | Length of time required to achieve erythroid response, and total duration of that response | From first dose (Study Day 1) to end of treatment (Study Day 730) | 
| Mean change from baseline in hemoglobin levels in NTD patients | Mean change in hemoglobin, not influenced by RBC transfusion | From first dose (Study Day 1) to end of treatment (Study Day 730 | 
| Mean % change from baseline in transfusion burden in TD patients | Mean change in transfusion burden from baseline burden | From first dose (Study Day 1) to end of treatment (Study Day 730) | 
| Mean change in pre-transfusion hemoglobin levels in TD patients | Mean change in pre-transfusion hemoglobin | From first dose (Study Day 1) to end of treatment (Study Day 730) | 
| Changes in markers of erythropoiesis | Assessment of erythropoietin levels, reticulocyte count, nucleated RBC count and solubel transferrin receptor | From first dose (Study Day 1) to end of treatment (Study Day 730) | 
| Changes in markers of iron metabolism | Assessment of serum iron, TIBC, serum ferritin, transferrin saturation, hepcidin and NTBI | From first dose (Study Day 1) to end of treatment (Study Day 730) | 
| ACE-536 pharmacokinetic profileversus time curve (AUC) | Assessment of Cmax, Tmax and area under the plasma concentration | From first dose (Study Day 1) to end of treatment (Study Day 730) | 
| Quality of Life assessments (exploratory) | FACT-An and SF-36 health surveys | From first dose (Study Day 1) to end of treatment (Study Day 730) |