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

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)

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).

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Anemia; Chronic Myelomonocytic Leukemia; Myelodysplastic Syndromes (MDS); Chronic Myelomonocytic Leukemia (CMML); Low to Intermediate-1 MDS
• Intervention / Treatment: Drug: Sotatercept

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bobigny Cedex, France, 93009
    • Centre Hospitalier Universitaire d'Avicennes
  • Bp 156,, France, 13273
    • Institute Paoli-Calmettes Service Haematology
  • Lille, France, 59037
    • CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang
  • Nantes, France, 44093
    • CHRU Nantes
  • Paris Cedex 14, France, 75679
    • Hopital Cochin Hematologie
  • Rouen, France, 79038
    • Centre Henri Becquerel
  • Toulouse, France, 31059
    • CHU Purpan
• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Center-Midtown
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center and Research Institute
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber / Harvard Cancer Institute
  • New York
    • Lake Success, New York, United States, 11042
      • Monter Cancer Center, North Shore LIJ Health Systems
    • New York, New York, United States, 10032
      • Columbia University Medical Center/New York-Presbyterian Hospital
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation Hematology and Medical Oncology Rm 35
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Inst
  • Texas
    • Round Rock, Texas, United States, 78681
      • Texas Oncology Round Rock Cancer Center - Round Rock
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
    • Tyler, Texas, United States, 75702
      • Texas Oncology, P.A. - Tyler
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates
  • Washington
    • Yakima, Washington, United States, 98902
      • Yakima Valley Memorial Hospital/ North Star Lodge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sotatercept 0.1 mg/kg	Drug: Sotatercept; 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.; Other Names: ACE-011; ActRIIA-IgG1Fc
Experimental: Sotatercept 0.3 mg/kg	Drug: Sotatercept; 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.; Other Names: ACE-011; ActRIIA-IgG1Fc
Experimental: Sotatercept 0.5 mg/kg	Drug: Sotatercept; 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.; Other Names: ACE-011; ActRIIA-IgG1Fc
Experimental: Sotatercept 1.0 mg/kg	Drug: Sotatercept; 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.; Other Names: ACE-011; ActRIIA-IgG1Fc
Experimental: Sotatercept 1.5 mg/kg	Drug: Sotatercept; 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.; Other Names: ACE-011; ActRIIA-IgG1Fc
Experimental: Sotatercept 2.0 mg/kg	Drug: Sotatercept; 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.; Other Names: ACE-011; ActRIIA-IgG1Fc

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Rodrigo Ito, MD, Celgene Corporation

Publications and helpful links

General Publications

• Komrokji R, Garcia-Manero G, Ades L, Prebet T, Steensma DP, Jurcic JG, Sekeres MA, Berdeja J, Savona MR, Beyne-Rauzy O, Stamatoullas A, DeZern AE, Delaunay J, Borthakur G, Rifkin R, Boyd TE, Laadem A, Vo B, Zhang J, Puccio-Pick M, Attie KM, Fenaux P, List AF. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol. 2018 Feb;5(2):e63-e72. doi: 10.1016/S2352-3026(18)30002-4. Epub 2018 Jan 10.

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2012
• Primary Completion (Actual): April 30, 2018
• Study Completion (Actual): April 30, 2018

Study Registration Dates

• First Submitted: November 27, 2012
• First Submitted That Met QC Criteria: November 27, 2012
• First Posted (Estimate): November 29, 2012

Study Record Updates

• Last Update Posted (Actual): October 24, 2022
• Last Update Submitted That Met QC Criteria: October 20, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: hemoglobin; anemia; open-label; transfusions; Sotatercept; multicenter; randomized; phase 2; parallel; ACE-011; dose-ranging; intermediate-1 risk myelodysplastic syndromes; low risk myelodysplastic syndromes (MDS); Non-proliferative chronic myelomonocytic leukemia (CMML)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid; Syndrome; Myelodysplastic Syndromes; Leukemia; Preleukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Anemia
• Other Study ID Numbers: 7962-017; ACE-011-MDS-001 (Other Identifier: Celgene); 2012-002601-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf