A Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS) Participants Who Require Red Blood Cell Transfusions and Are ESA Naïve

Study Overview
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Brief Summary
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The purpose of this study is to determine the effectiveness of luspatercept (ACE-536) compared to epoetin alfa on red blood cell (RBC) transfusion independence (for at least 12 weeks) with a concurrent hemoglobin increase of at least 1.5 g/dL in participants with anemia due to revised international prognostic scoring system (IPSS-R) very low, low, or intermediate risk myelodysplastic syndromes (MDS) who require RBC transfusions and have never been exposed to erythropoiesis stimulating agent (ESA).

Official Title
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A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Epoetin Alpha for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Due to Myelodysplastic Syndrome (MDS) ESA in Native Subjects Who Require Red Blood Cell Transfusions

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Luspatercept
* Drug: Epoetin alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of Myelodysplastic syndromes (MDS) according to WHO 2016 classification that meets revised international prognostic scoring system (IPSS-R) classification of very low, low, or intermediate risk disease, and have < 5% blasts in bone marrow Endogenous serum erythropoietin (sEPO) level of < 500 U/L Requires Red blood cell (RBC) transfusions, as documented by the criteria: Average transfusion requirement of 2 - 6 units/8 weeks of packed red blood cells (pRBCs) confirmed for a minimum of 8 weeks immediately preceding randomization Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 Exclusion Criteria: Clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any type of known clinically significant bleeding or sequestration or drug induced anemia Known history of diagnosis of Acute myeloid leukemia (AML) Uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment Other protocol-defined inclusion/exclusion criteria apply

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Luspatercept<br> | Drug: Luspatercept<br>* Specified dose on specified days<br>* Other names: ACE-536;|
| Active Comparator: Epoetin alfa<br> | Drug: Epoetin alfa<br>* Specified dose on specified days<br>* Other names: PROCRIT®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Red blood cell transfusion independence (RBC-TI) for 12 weeks (84 days) with a mean hemoglobin increase ≥ 1.5 g/dL |  | Week 1 through Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RBC-TI for 24 weeks |  | Week 1 through Week 24 | 
| Mean hemoglobin change over 24 weeks |  | Week 1 through Week 24 | 
| Hematologic improvement - erythroid response (HI-E) per International Working Group (IWG) |  | Week 1 through Week 24 | 
| Time to HI-E |  | Week 1 through Week 24 | 
| RBC-TI for ≥ 12 weeks (84 days) |  | Week 1 through Week 24 | 
| Duration of RBC-TI ≥ 12 weeks (84 days) |  | Week 1 through End of Treatment (EOT), up to approximately 60 months | 
| Time to RBC-TI ≥ 12 weeks (84 days) |  | Week 1 through Week 24 | 
| Time to first red blood cell (RBC) transfusion |  | Week 1 through EOT, up to approximately 60 months | 
| RBC transfusion burden on treatment |  | Week 1 through Week 24 | 
| RBC-TI for ≥ 56 days (8 weeks) |  | Week 1 through Week 24 | 
| RBC-TI for a consecutive 24-week period |  | Week 1 through Week 48 | 
| The European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30) |  | Screening through Week 24 | 
| The Functional Assessment of Cancer Therapy-Anemia Version 4 (FACT-An) questionnaire |  | Screening through Week 24 | 
| Number of participants with Adverse Events (AEs) |  | Week 1 through 42 days post last dose | 
| Pharmacokinetic - area under the concentration-time curve (AUC) |  | Randomization through 1-year post first dose | 
| Pharmacokinetic - maximum plasma concentration of drug (Cmax) |  | Randomization through 1-year post first dose | 
| Frequency of antidrug antibodies (ADA) |  | Randomization through 1-year post first dose | 
| Number of participants progressing to acute myeloid leukemia (AML) |  | Randomization through up to 60 months | 
| Percentage of participants progressing to AML |  | Randomization through up to 60 months | 
| Time to AML progression |  | Randomization through up to 60 months | 
| Overall survival |  | Randomization through up to 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Luspatercept, ACE-536, Anemia, Myelodysplastic Syndromes, Blood Transfusion, RBC Transfusion, Erythropoiesis-stimulating agents, Erythropoietin, Myelodysplasia