Study of Sotatercept for the Treatment of Anemia in low-or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) or Non-proliferative Chronic Myelomonocytic Leukemia (CMML)

Study Overview
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Brief Summary
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The primary objective of this study is to determine a safe, tolerable and effective dose of sotatercept that results in the greatest frequency of improvement of anemia in patients diagnosed with low- or intermediate-1 risk myelodysplastic syndromes (MDS) or non-proliferative chronic myelomonocytic leukemia (CMML).

Official Title
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An Open-label, Randomized, Phase 2, Parallel, Dose-Ranging, Multicenter Study of Sotatercept for the Treatment of Patients With Anemia and Low or Intermediate-1 Risk Myelodysplastic Syndromes or Non-proliferative Chronic Myelomonocytic Leukemia (CMML)

Conditions
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Anemia, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Low to Intermediate-1 MDS, Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML)

Intervention / Treatment
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* Drug: Sotatercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥ 18 years of age Documented diagnosis of myelodysplastic syndromes (MDS) or non-proliferative chronic myelomonocytic leukemia (CMML), white blood cells (WBC) ≤ 13,000 /mm^3, World Health Organization (WHO) that meets International Prognostic Scoring System (IPSS) criteria for low or intermediate-1 risk disease Anemia, Hemoglobin (Hgb) ≤ 9.0 g/dL or ≥ 2 units of Red Blood Cells (RBCs) within 84 days No response or loss of response to Erythropoiesis-Stimulating Agents (ESAs) or erythropoetin (EPO) > 500 mU/ml Eastern Cooperative Group (ECOG) score ≤2. Creatinine < 1.5 * Upper Limit of the Normal (ULN) Total bilirubin ≤3.0 mg/dL Aspartate aminotransferase (AST)/Serum glutamic oxaloacetic transaminase (SGOT) & Alanine Aminotransferase (ALT)/Serum Glutamic Pyruvic (SGPT) ≤3.0 * Upper Limit of Norma (ULN) Free of metastatic malignancy (other than MDS) for ≥2 years Highly effective methods of birth control for females and males Exclusion Criteria: Chromosome 5q deletion Pregnant or breast feeding women and males who do not agree to use condom during the sexual contact with females of childbearing potential Major surgery within 30 days Incomplete recovery or incomplete healing of wounds from previous surgery Heart failure ≥3 (New York Heart Association (NYHA)) Thromboembolic or myocardial infarction event within 6 months Concurrent anti-cancer cytotoxic chemotherapy History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant protein Known positive for Human Immunovirus (HIV) or infectious Hepatitis type C or active infectious Hepatitis type B Clinically significant anemia unrelated to MDS Thrombocytopenia (<30,000/uL) Uncontrolled hypertension Treatment with another investigational drug or device within 28 days prior to Day 1 Prior exposure to sotatercept (ACE-011) Any serious medical condition, lab abnormality or psychiatric illness

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: Sotatercept 0.1 mg/kg<br>Sotatercept 0.1 mg/kg | Drug: Sotatercept<br>* Sotatercept is supplied as a lyophilized powder that is reconstituted using Water for Injection (WFI) and administered as a subcutaneous injection (SC) injection by the study staff at the clinical site.<br>* Other names: ActRIIA-IgG1Fc;|
| Experimental: Sotatercept 0.3 mg/kg<br>Sotatercept 0.3 mg/kg | Drug: Sotatercept<br>* Sotatercept is supplied as a lyophilized powder that is reconstituted using Water for Injection (WFI) and administered as a subcutaneous injection (SC) injection by the study staff at the clinical site.<br>* Other names: ActRIIA-IgG1Fc;|
| Experimental: Sotatercept 0.5 mg/kg<br>Sotatercept 0.5 mg/kg | Drug: Sotatercept<br>* Sotatercept is supplied as a lyophilized powder that is reconstituted using Water for Injection (WFI) and administered as a subcutaneous injection (SC) injection by the study staff at the clinical site.<br>* Other names: ActRIIA-IgG1Fc;|
| Experimental: Sotatercept 1.0 mg/kg<br>Sotatercept 1.0 mg/kg | Drug: Sotatercept<br>* Sotatercept is supplied as a lyophilized powder that is reconstituted using Water for Injection (WFI) and administered as a subcutaneous injection (SC) injection by the study staff at the clinical site.<br>* Other names: ActRIIA-IgG1Fc;|
| Experimental: Sotatercept 1.5 mg/kg<br>Sotatercept 1.5 mg/kg | Drug: Sotatercept<br>* Sotatercept is supplied as a lyophilized powder that is reconstituted using Water for Injection (WFI) and administered as a subcutaneous injection (SC) injection by the study staff at the clinical site.<br>* Other names: ActRIIA-IgG1Fc;|
| Experimental: Sotatercept 2.0 mg/kg<br>Sotatercept 2.0 mg/kg | Drug: Sotatercept<br>* Sotatercept is supplied as a lyophilized powder that is reconstituted using Water for Injection (WFI) and administered as a subcutaneous injection (SC) injection by the study staff at the clinical site.<br>* Other names: ActRIIA-IgG1Fc;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | The responder rate includes non-transfusion dependent efficacy (NTDE) participants and transfusion dependent efficacy (TDE) participants. For non-transfusion dependence efficacy (NTDE) participants who required < 4 units of RBCs in the 8 weeks prior to start of therapy, HI-E was defined as an increase of >=1.5 g/dL hemoglobin sustained for 56 days over a period of >=8 weeks. For transfusion dependence efficacy (TDE) participants who required >=4 units of RBCs in the 8 weeks prior to start of therapy, HI-E was defined as a decrease of >= 4 units of RBCs transfused sustained for 56 days over a period of 8 weeks. | Day 2 to Day 142 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Erythroid Hematological Improvement (HI-E) Response | Time to first response = start date of first response (HI-E) - first dose date + 1 day. For NTDE participants (who required < 4 units of RBCs in the 8 weeks prior to start of therapy), HI-E was defined as an increase of >=1.5 g/dL hemoglobin sustained for 56 days over a period of >=8 weeks. For TDE participants (who required >=4 units of RBCs in the 8 weeks prior to start of therapy), HI-E was defined as a decrease of >= 4 units of RBCs transfused sustained for 56 days over a period of 8 weeks. | Day 1 to Day 87 | 
| Duration of Erythroid Hematological Improvement (HI-E) | The duration of HI-E response for participants who responded was (the last date of the consecutive hemoglobin [Hgb] measurements of the first >=56 day interval) - (the first date of the consecutive Hgb measurements of the first >=56 day interval) + 1 day. | Day 1 to 183.7 weeks | 
| Time to Progression to Acute Myeloid Leukemia (AML) for Participants Who Had Progression | Progression to AML used criteria by the International Working Group (IWG) Response Criteria in Myelodysplasia (Cheson, 2006). Progression is considered if any of the following are met: - >=50% increase in blasts - >=50% decrement from maximum remission/response levels in granulocytes or platelets - Reduction in Hgb concentration by >=2 g/dL - Transfusion dependence This outcome was defined as a Kaplan-Meier estimate however few participants progressed so a Kaplan-Meier analysis could not be performed. Disclosed are time to progression values only for participants who did progress to AML. | Day 1 to 183.7 weeks | 
| Time to Progression to Events of Higher Risk Myelodysplastic Syndromes (MDS) Using the International Prognostic Scoring System (IPSS) For Participants Who Had Progression | Progression to events of higher risk MDS used criteria from the International Prognostic Scoring System for MDS (IPSS) which assigns a prognostic score (0=good and increasing in risk by half-grades with the top score outlined below) for three prognostic variables: - Marrow blasts (score 0-2.0) - Karyotype (score 0-1.0) - Cytopenias: neutrophil, platelets, and Hg counts (score 0-0.5) The three individual scores are summed resulting in a full range of 0- 3.5 and placed into risk categories 0 = low risk 0.5-1.0 = intermediate-1 risk 1.5-2.0 = intermediate-2 risk >=2.5 = high risk This outcome was defined as a Kaplan-Meier estimate however few participants progressed so a Kaplan-Meier analysis could not be performed. Data reported represent event times (weeks) for participants who did progress to higher risk MDS categories. | Day 1 to 257.3 weeks | 
| Kaplan-Meier Estimates for Progression-free Survival | Participants who had disease progression were considered to have events. Participants who died without acute myeloid leukemia (AML) were also considered to have events with the event date as the date of death. Those who did not have disease progression and who were lost to follow-up were censored at the last known disease progression assessment date. Participants without disease progression at the last follow-up contact were censored at the date of the last follow-up contact date. Disease Progression to AML used criteria by the International Working Group (IWG) Response Criteria in Myelodysplasia (Cheson, 2006). Progression is considered if any of the following are met: - >=50% increase in blasts - >=50% decrement from maximum remission/response levels in granulocytes or platelets - Reduction in hemoglobin (Hgb) concentration by >=2 g/dL - Transfusion dependence | Day 1 to 257.3 weeks | 
| Kaplan-Meier Estimates for Overall Survival (OS) | OS was defined as the time between start of treatment and the death/censored date. Participants who died (regardless of the cause of death) were considered to have an event. Participants who were alive at the end of the study, and participants who were lost to follow-up, were censored at the last date when subjects were known to be alive. | Day 1 to 257.3 weeks | 
| Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Maximum observed serum concentration, obtained directly from the observed concentration versus time data. | Cycle 1 Day 8 and !5 up to Cycle 2 Day 1 | 
| Participants With Treatment-Emergent Adverse Events (TEAE) | An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on or after the first treatment of the study medication and within 42 days after the last dose. The severity of AEs was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0 and the scale: Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life threatening Grade 5 = Death. Relation to study drug was determined by the investigator. A treatment-related TEAE is defined as TEAE which was considered to be related to the study drug and reported as 'Suspected' on the CRF. AEs with a missing relationship were treated as 'treatment-related' in data summaries. | Day 1 up to 59.2 months | 
| Dose Limiting Toxicities (DLTs) | The following were DLTs if the investigator suspected they were treatment related: 1. Increase to >= 140 mmHg systolic blood pressure 2. Increase to >=90 mmHg diastolic blood pressure 3. Increase to >=140 systolic and increase > 20 mmHg compared to baseline systolic 4. Increase to >=90 mmHg diastolic and increase > 20 mmHg compared to baseline diastolic 5. Introduction of new anti-hypertension medication during treatment 6. Increase in dose of baseline anti-hypertension medication during treatment 7. >= Grade 2 (moderate severity or worse) hypertension as an adverse event | Day 1 to 59.2 months | 
| Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | Number of participants who achieved RBC-independence was defined as participants who required no RBC-transfusions during a 56-day interval of erythroid hematological improvement (HI-E). NTDE = non-transfusion dependence efficacy participants who required < 4 units of RBCs in the 8 weeks prior to start of therapy TDE = transfusion dependence efficacy participants who required >=4 units of RBCs in the 8 weeks prior to start of therapy | Day 2 to Day 142 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multicenter, ACE-011, anemia, dose-ranging, intermediate-1 risk myelodysplastic syndromes, low risk myelodysplastic syndromes (MDS), open-label, parallel, phase 2, randomized, Sotatercept, Non-proliferative chronic myelomonocytic leukemia (CMML), hemoglobin, transfusions