Study of Sotatercept for the Treatment of Anemia in low-or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) or Non-proliferative Chronic Myelomonocytic Leukemia (CMML)
- Conditions
- AnemiaMyelodysplastic SyndromesMyelodysplastic Syndromes (MDS)Chronic Myelomonocytic LeukemiaLow to Intermediate-1 MDSChronic Myelomonocytic Leukemia (CMML)
- Interventions
- Registration Number
- NCT01736683
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief Summary
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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 74
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Sotatercept 1.0 mg/kg Sotatercept Sotatercept 1.0 mg/kg Sotatercept 0.3 mg/kg Sotatercept Sotatercept 0.3 mg/kg Sotatercept 0.5 mg/kg Sotatercept Sotatercept 0.5 mg/kg Sotatercept 1.5 mg/kg Sotatercept Sotatercept 1.5 mg/kg Sotatercept 0.1 mg/kg Sotatercept Sotatercept 0.1 mg/kg Sotatercept 2.0 mg/kg Sotatercept Sotatercept 2.0 mg/kg
- Primary Outcome Measures
Name Time Method Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) Day 2 to Day 142 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.
- Secondary Outcome Measures
Name Time Method Kaplan-Meier Estimates for Overall Survival (OS) Day 1 to 257.3 weeks 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.
Time to Erythroid Hematological Improvement (HI-E) Response Day 1 to Day 87 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.
Duration of Erythroid Hematological Improvement (HI-E) Day 1 to 183.7 weeks 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.
Time to Progression to Acute Myeloid Leukemia (AML) for Participants Who Had Progression Day 1 to 183.7 weeks 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.
Kaplan-Meier Estimates for Progression-free Survival Day 1 to 257.3 weeks 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
Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints Cycle 1 Day 8 and !5 up to Cycle 2 Day 1 Maximum observed serum concentration, obtained directly from the observed concentration versus time data.
Participants With Treatment-Emergent Adverse Events (TEAE) Day 1 up to 59.2 months 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.
Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval Day 2 to Day 142 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
Time to Progression to Events of Higher Risk Myelodysplastic Syndromes (MDS) Using the International Prognostic Scoring System (IPSS) For Participants Who Had Progression Day 1 to 257.3 weeks 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.
Dose Limiting Toxicities (DLTs) Day 1 to 59.2 months 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
Trial Locations
- Locations (20)
Institute Paoli-Calmettes Service Haematology
🇫🇷Bp 156,, France
CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang
🇫🇷Lille, France
CHRU Nantes
🇫🇷Nantes, France
Centre Henri Becquerel
🇫🇷Rouen, France
Rocky Mountain Cancer Center-Midtown
🇺🇸Denver, Colorado, United States
Johns Hopkins
🇺🇸Baltimore, Maryland, United States
Columbia University Medical Center/New York-Presbyterian Hospital
🇺🇸New York, New York, United States
Dana-Farber / Harvard Cancer Institute
🇺🇸Boston, Massachusetts, United States
Texas Oncology Round Rock Cancer Center - Round Rock
🇺🇸Round Rock, Texas, United States
H. Lee Moffitt Cancer Center and Research Institute
🇺🇸Tampa, Florida, United States
Monter Cancer Center, North Shore LIJ Health Systems
🇺🇸Lake Success, New York, United States
Sarah Cannon Research Inst
🇺🇸Nashville, Tennessee, United States
Texas Oncology, P.A. - Tyler
🇺🇸Tyler, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Yakima Valley Memorial Hospital/ North Star Lodge
🇺🇸Yakima, Washington, United States
Centre Hospitalier Universitaire d'Avicennes
🇫🇷Bobigny Cedex, France
Hopital Cochin Hematologie
🇫🇷Paris Cedex 14, France
CHU Purpan
🇫🇷Toulouse, France
The Cleveland Clinic Foundation Hematology and Medical Oncology Rm 35
🇺🇸Cleveland, Ohio, United States
Virginia Oncology Associates
🇺🇸Norfolk, Virginia, United States