ACE-536 Extension Study - Myelodysplastic Syndromes

Study Overview
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Brief Summary
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Study A536-05 is an open-label extension study for patients previously enrolled in study A536-03 (ClinicalTrials.gov Identifier NCT01749514), to evaluate the long-term safety and tolerability of ACE-536 in patients with low or intermediate-1 risk MDS.

Detailed Description
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Study A536-05 is an open-label extension study to evaluate the safety, tolerability, and pharmacodynamic effects of up to 24 months of ACE-536 treatment in patients with low or intermediate-1 risk myelodysplastic syndromes previously treated with ACE-536 for up to 3 months in study A536-03 (ClinicalTrials.gov Identifier NCT01749514). The starting dose level in study A536-05 will be 1.0 mg/kg by subcutaneous (SC) injection 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 for the Treatment of Anemia in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) Previously Enrolled in Study A536-03

Conditions
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Myelodysplastic Syndromes

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 A536-03 (ClinicalTrials.gov Identifier: NCT01749514) Adequate birth control measures 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. In addition, patients with treatment interruption (defined as patients who complete their end-of-study visit in A536-03 and cannot directly roll over to A536-05) must also meet the following criteria: Documented diagnosis of idiopathic/de novo MDS or non-proliferative chronic myelomonocytic leukemia (CMML) according to the World Health Organization (WHO) criteria 2 (white blood count (WBC) < 13,000/μL) that meets International Prognostic Scoring System (IPSS) classification (Appendix 2) of low or intermediate-1 risk disease as determined by microscopic and standard cytogenetic analyses of the bone marrow and peripheral complete blood count (CBC) obtained during screening; Anemia defined as: 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 7-28 days prior to Cycle 1 Day 1), for non-transfusion dependent (NTD) patients (defined as having received ˂ 4 units of red blood cells (RBCs) within 8 weeks prior to Cycle 1 Day 1), OR Transfusion Dependent (TD), defined as having received ≥ 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1. Platelet count ≥ 30 x 109/L Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (if related to anemia) Adequate renal (creatinine ≤ 2.0 x upper limit of normal [ULN]) and hepatic (total bilirubin < 2 x ULN and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN) function Exclusion Criteria: Discontinuation/withdrawal from the base study A536-03 (due to patient request, patient unwillingness or inability to comply with the protocol, pregnancy, use of prohibited medication [e.g. azacitidine], medical reason or adverse event (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 Prior treatment with azacitidine or decitabine Treatment within 28 days prior to Cycle 1 Day 1 with: an erythropoiesis-stimulating agent (ESA), Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF), Lenalidomide Iron chelation therapy if initiated within 56 days prior to Cycle 1 Day 1 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 Major surgery within 28 days prior to Cycle 1 Day 1. Patients must have completely recovered from any previous surgery prior to 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 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<br>ACE-536 1.0 mg/kg once every 3 weeks by subcutaneous injection. | Drug: ACE-536<br>* ACE-536 1.0 mg/kg once every 3 weeks by subcutaneous injection<br>* Other names: luspatercept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the long-term safety and tolerability of ACE-536 in patients with low or intermediate-1 risk MDS who were previously enrolled in study A536-03 |  | From first dose (Study Day1) to end of treatment (Study Day 730) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Erythroid response in non-transfusion dependent (NTD) patients | Proportion of patients with a mean hemoglobin (Hgb) increase ≥ 1.5 g/dL over an 8-week period as compared to baseline, not influenced by red blood cell (RBC) transfusion | From first dose (Study Day1) to end of treatment (Study Day 730) | 
| Rates of erythroid, neutrophil and platelet (HI-E, HI-N and HI-P) responses. |  | Measured during any 8 week period on study, up to 28 weeks from patient screening, compared with the 8-week period prior to study day 1. | 
| Erythroid response in transfusion dependent (TD) patients | Proportion of patients with a decrease of ≥ 4 units or ≥ 50% of units of red blood cells (RBCs) transfused over a period of 8 weeks, relative to the 8 weeks immediately prior to Day 1 | From first dose (Study Day1) to end of treatment (Study Day 730) | 
| Proportion of TD patients who become transfusion independent | Defined as patients requiring no RBC transfusion for a period of ≥ 8 weeks | From first dose (Study Day1) to end of treatment (Study Day 730) | 
| Time to, and duration of, erythroid response in NTD and TD patients |  | From first dose (Study Day1) to end of treatment (Study Day 730) | 
| Mean mean change in RBC transfusion burden (#RBC units/8 weeks) in TD patients |  | From first dose (Study Day1) to end of treatment (Study Day 730) | 
| Mean change in hemoglobin levels in NTD patients |  | From first dose (Study Day1) to end of treatment (Study Day 730) | 
| ACE-536 pharmacokinetic profile (Tmax, Cmax and AUC) |  | From first dose (Study Day1) to end of treatment (Study Day 730) | 
| Change from baseline in markers of erythropoiesis |  | From first dose (Study Day1) to end of treatment (Study Day 730) | 
| Change from baseline in markers of iron metabolism |  | From first dose (Study Day1) to end of treatment (Study Day 730) |