Anemia, Chronic Myelomonocytic Leukemia, Chronic Myelomonocytic Leukemia (CMML), Low to Intermediate-1 MDS, Myelodysplastic Syndromes, Myelodysplastic Syndromes (MDS)
Conditions
Keywords
ACE-011, anemia, dose-ranging, intermediate-1 risk myelodysplastic syndromes, low risk myelodysplastic syndromes (MDS), multicenter, open-label, parallel, phase 2, randomized, Sotatercept, Non-proliferative chronic myelomonocytic leukemia (CMML), hemoglobin, transfusions
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).
Interventions
DRUGSotatercept
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.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
| 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 |
| 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 |
Countries
France, United States
Participant flow
Recruitment details
Participants were stratified by concentration of serum erythropoietin (EPO) (\<500 versus ≥500 IU/L), by number of transfusions within 56 days of study enrollment (\<4 versus ≥4 units of red blood cells) and assigned randomly to 0.1 mg/kg and 0.3 mg/kg arms.
Pre-assignment details
Enrollment in the other arms (sotatercept 0.5, 1.0 and 2.0 mg/kg arms) commenced after the Steering Committee approved the higher doses based on the safety of preceding doses.
Participants by arm
| Arm | Count |
|---|---|
| Sotatercept 0.1 mg/kg Sotatercept 0.1 mg/kg administered via subcutaneous injection every third week (Q3W). Participants were randomized to either the 0.1 mg/kg arm or the 0.3 mg/kg arm. Efficacy and safety data were assessed by a Steering Committee. Based upon the occurrence of dose-limiting toxicity (DLT) in ≤ 1/5 subjects in Cycle 1 in the 0.1 mg/kg and 0.3 mg/kg treatment groups, the 0.5 mg/kg treatment group began inclusion in the randomization scheme. | 7 |
| Sotatercept 0.3 mg/kg Sotatercept 0.3 mg/kg administered via subcutaneous injection every third week (Q3W). Participants were randomized to either the 0.1 mg/kg arm or the 0.3 mg/kg arm. Efficacy and safety data were assessed by a Steering Committee. Based upon the occurrence of dose-limiting toxicity (DLT) in ≤ 1/5 subjects in Cycle 1 in the 0.1 mg/kg and 0.3 mg/kg treatment groups, the 0.5 mg/kg treatment group began inclusion in the randomization scheme. | 6 |
| Sotatercept 0.5 mg/kg Sotatercept 0.5 mg/kg administered via subcutaneous injection every third week (Q3W). Participants were randomized to one of the active treatment arms. Efficacy and safety data were assessed by a Steering Committee. Based upon the occurrence of dose-limiting toxicity (DLT) in ≤ 1/6 subjects in Cycle 1 in the 0.5 mg/kg treatment group, the 1.0 mg/kg treatment group began inclusion in the randomization scheme. | 21 |
| Sotatercept 1.0 mg/kg Sotatercept 1.0 mg/kg administered via subcutaneous injection every third week (Q3W). Participants were randomized to one of the active treatment arms. Efficacy and safety data were assessed by a Steering Committee. Based upon the occurrence of dose-limiting toxicity (DLT) in ≤ 1/6 subjects in Cycle 1 in the 1.0 mg/kg treatment group, the 2.0 mg/kg treatment group began inclusion in the randomization scheme. Following evaluation of all treatment group data by the Steering Committee, enrollment continued only in the 1.0 mg/kg arm because the arm had the greatest frequency of erythroid hematological improvement (HI-E). | 35 |
| Sotatercept 2.0 mg/kg Sotatercept 2.0 mg/kg administered via subcutaneous injection every third week (Q3W). Participants were randomized to one of the active treatment arms. Efficacy and safety data were assessed by a Steering Committee. The 2.0 mg/kg sotatercept dose was reduced to 1.5 mg/kg for ongoing and newly enrolled participants by protocol amendment. | 5 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 2 | 3 | 2 |
| Overall Study | Disease Relapse | 0 | 0 | 2 | 1 | 0 |
| Overall Study | Lack of Therapeutic Effect | 7 | 4 | 13 | 20 | 1 |
| Overall Study | Other | 0 | 0 | 1 | 9 | 1 |
| Overall Study | Progressive Disease | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 3 | 1 | 1 |
Baseline characteristics
| Characteristic | Sotatercept 0.1 mg/kg | Sotatercept 0.3 mg/kg | Sotatercept 0.5 mg/kg | Sotatercept 1.0 mg/kg | Sotatercept 2.0 mg/kg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 67 years STANDARD_DEVIATION 8.3 | 75 years STANDARD_DEVIATION 6.9 | 69 years STANDARD_DEVIATION 8 | 71 years STANDARD_DEVIATION 8.2 | 69 years STANDARD_DEVIATION 13 | 70 years STANDARD_DEVIATION 8.4 |
| Age, Customized >=65 - <75 years | 2 Participants | 3 Participants | 8 Participants | 17 Participants | 2 Participants | 32 Participants |
| Age, Customized <65 years | 3 Participants | 0 Participants | 7 Participants | 6 Participants | 1 Participants | 17 Participants |
| Age, Customized >=75 years | 2 Participants | 3 Participants | 6 Participants | 12 Participants | 2 Participants | 25 Participants |
| Erythropoietin level <=200 mIU/mL | 2 Participants | 3 Participants | 6 Participants | 16 Participants | 2 Participants | 29 Participants |
| Erythropoietin level >200 to <=500 mIU/mL | 2 Participants | 1 Participants | 6 Participants | 6 Participants | 0 Participants | 15 Participants |
| Erythropoietin level >500 mIU/mL | 3 Participants | 2 Participants | 9 Participants | 9 Participants | 2 Participants | 25 Participants |
| Erythropoietin level Missing | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 1 Participants | 5 Participants |
| Erythropoietin Level <=200 mIU/mL | 2 Participants | 3 Participants | 6 Participants | 16 Participants | 2 Participants | 29 Participants |
| Erythropoietin Level >200 to <=500 mIU/mL | 2 Participants | 1 Participants | 6 Participants | 6 Participants | 0 Participants | 15 Participants |
| Erythropoietin Level >500 mIU/mL | 3 Participants | 2 Participants | 9 Participants | 9 Participants | 2 Participants | 25 Participants |
| Erythropoietin Level Missing | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 6 Participants | 13 Participants | 19 Participants | 4 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 6 Participants | 16 Participants | 1 Participants | 23 Participants |
| Height | 1.70 meters STANDARD_DEVIATION 0.11 | 1.75 meters STANDARD_DEVIATION 0.054 | 1.70 meters STANDARD_DEVIATION 0.093 | 1.68 meters STANDARD_DEVIATION 0.089 | 1.56 meters STANDARD_DEVIATION 0.043 | 1.68 meters STANDARD_DEVIATION 0.095 |
| International Prognostic Scoring System (IPSS) Risk Category High: >= 2.5 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| International Prognostic Scoring System (IPSS) Risk Category Intermediate- 1: 0.5 to 1 | 3 Participants | 2 Participants | 16 Participants | 24 Participants | 5 Participants | 50 Participants |
| International Prognostic Scoring System (IPSS) Risk Category Intermediate- 2: 1.5 to 2 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| International Prognostic Scoring System (IPSS) Risk Category Low - 0 | 4 Participants | 4 Participants | 5 Participants | 11 Participants | 0 Participants | 24 Participants |
| Number of Previous Erythropoiesis-Stimulating Agents (ESA) Therapies for Myelodysplastic Syndromes 0 ESA therapies | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Number of Previous Erythropoiesis-Stimulating Agents (ESA) Therapies for Myelodysplastic Syndromes 1 ESA therapy | 6 Participants | 2 Participants | 11 Participants | 23 Participants | 3 Participants | 45 Participants |
| Number of Previous Erythropoiesis-Stimulating Agents (ESA) Therapies for Myelodysplastic Syndromes 2 ESA therapies | 0 Participants | 4 Participants | 8 Participants | 10 Participants | 2 Participants | 24 Participants |
| Number of Previous Erythropoiesis-Stimulating Agents (ESA) Therapies for Myelodysplastic Syndromes 3 ESA therapies | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Number of Previous Non-ESA Agents for Myelodysplastic Syndromes (MDS) 0 non-ESA agents | 0 Participants | 0 Participants | 2 Participants | 7 Participants | 2 Participants | 11 Participants |
| Number of Previous Non-ESA Agents for Myelodysplastic Syndromes (MDS) 1 non-ESA agent | 1 Participants | 0 Participants | 7 Participants | 16 Participants | 1 Participants | 25 Participants |
| Number of Previous Non-ESA Agents for Myelodysplastic Syndromes (MDS) 2 non-ESA agents | 2 Participants | 1 Participants | 6 Participants | 7 Participants | 1 Participants | 17 Participants |
| Number of Previous Non-ESA Agents for Myelodysplastic Syndromes (MDS) 3 non-ESA agents | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 8 Participants |
| Number of Previous Non-ESA Agents for Myelodysplastic Syndromes (MDS) 4 non-ESA agents | 0 Participants | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 6 Participants |
| Number of Previous Non-ESA Agents for Myelodysplastic Syndromes (MDS) >5 non-ESA agents | 1 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 5 Participants |
| Number of Previous Non-ESA Agents for Myelodysplastic Syndromes (MDS) 5 non-ESA agents | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | NA Participants | NA Participants | NA Participants | NA Participants | NA Participants | NA Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 7 Participants | 16 Participants | 1 Participants | 24 Participants |
| Race (NIH/OMB) White | 7 Participants | 6 Participants | 14 Participants | 18 Participants | 3 Participants | 48 Participants |
| Red Blood Cell (RBC) Transfusion Burden Categories >= 4 units (High Transfusion Burden) | 7 Participants | 6 Participants | 18 Participants | 27 Participants | 4 Participants | 62 Participants |
| Red Blood Cell (RBC) Transfusion Burden Categories < 4 units (Low Transfusion Burden) | 0 Participants | 0 Participants | 3 Participants | 8 Participants | 1 Participants | 12 Participants |
| Region of Enrollment France | 0 Participants | 0 Participants | 6 Participants | 17 Participants | 1 Participants | 24 Participants |
| Region of Enrollment United States | 7 Participants | 6 Participants | 15 Participants | 18 Participants | 4 Participants | 50 Participants |
| Sex: Female, Male Female | 3 Participants | 0 Participants | 4 Participants | 17 Participants | 4 Participants | 28 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 17 Participants | 18 Participants | 1 Participants | 46 Participants |
| Weight | 85.3 kg STANDARD_DEVIATION 21.79 | 79.5 kg STANDARD_DEVIATION 13.9 | 77.9 kg STANDARD_DEVIATION 13.97 | 73.5 kg STANDARD_DEVIATION 15.55 | 56.4 kg STANDARD_DEVIATION 7.25 | 75.2 kg STANDARD_DEVIATION 16.14 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 7 | 1 / 6 | 6 / 21 | 6 / 35 | 1 / 5 |
| other Total, other adverse events | 6 / 7 | 4 / 6 | 18 / 21 | 32 / 35 | 5 / 5 |
| serious Total, serious adverse events | 1 / 7 | 2 / 6 | 6 / 21 | 10 / 35 | 2 / 5 |
Outcome results
Primary
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.
Time frame: Day 2 to Day 142
Population: Efficacy Evaluable Population: all participants who take at least one dose of study medication and have baseline and at least one post-baseline assessment of efficacy without major deviation from protocol.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sotatercept 0.1 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | All participants | 0 percentage of participants |
| Sotatercept 0.1 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | TDE subpopulation | 0 percentage of participants |
| Sotatercept 0.3 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | All participants | 66.7 percentage of participants |
| Sotatercept 0.3 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | TDE subpopulation | 66.7 percentage of participants |
| Sotatercept 0.5 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | TDE subpopulation | 44.4 percentage of participants |
| Sotatercept 0.5 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | NTDE subpopulation | 33.3 percentage of participants |
| Sotatercept 0.5 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | All participants | 42.9 percentage of participants |
| Sotatercept 1.0 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | NTDE subpopulation | 62.5 percentage of participants |
| Sotatercept 1.0 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | All participants | 60.0 percentage of participants |
| Sotatercept 1.0 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | TDE subpopulation | 59.3 percentage of participants |
| Sotatercept 2.0 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | All participants | 40.0 percentage of participants |
| Sotatercept 2.0 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | TDE subpopulation | 25.0 percentage of participants |
| Sotatercept 2.0 mg/kg | Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) | NTDE subpopulation | 100 percentage of participants |
Secondary
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
Time frame: Day 1 to 59.2 months
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sotatercept 0.1 mg/kg | Dose Limiting Toxicities (DLTs) | 1. Increase to >= 140 mmHg systolic | 1 Participants |
| Sotatercept 0.1 mg/kg | Dose Limiting Toxicities (DLTs) | 4. >=90 mmHg diastolic and increase > 20 mmHg base | 0 Participants |
| Sotatercept 0.1 mg/kg | Dose Limiting Toxicities (DLTs) | 3. =140 systolic and increase > 20 mmHg base | 0 Participants |
| Sotatercept 0.1 mg/kg | Dose Limiting Toxicities (DLTs) | 6. Incre in dose of baseline anti-hypertension med | 0 Participants |
| Sotatercept 0.1 mg/kg | Dose Limiting Toxicities (DLTs) | 5. Introduction of new anti-hypertension med | 0 Participants |
| Sotatercept 0.1 mg/kg | Dose Limiting Toxicities (DLTs) | 2. Increase to >=90 mmHg diastolic | 0 Participants |
| Sotatercept 0.1 mg/kg | Dose Limiting Toxicities (DLTs) | 7.>= Grade 2 hypertension TEAE | 0 Participants |
| Sotatercept 0.3 mg/kg | Dose Limiting Toxicities (DLTs) | 4. >=90 mmHg diastolic and increase > 20 mmHg base | 0 Participants |
| Sotatercept 0.3 mg/kg | Dose Limiting Toxicities (DLTs) | 1. Increase to >= 140 mmHg systolic | 1 Participants |
| Sotatercept 0.3 mg/kg | Dose Limiting Toxicities (DLTs) | 2. Increase to >=90 mmHg diastolic | 0 Participants |
| Sotatercept 0.3 mg/kg | Dose Limiting Toxicities (DLTs) | 3. =140 systolic and increase > 20 mmHg base | 1 Participants |
| Sotatercept 0.3 mg/kg | Dose Limiting Toxicities (DLTs) | 7.>= Grade 2 hypertension TEAE | 1 Participants |
| Sotatercept 0.3 mg/kg | Dose Limiting Toxicities (DLTs) | 5. Introduction of new anti-hypertension med | 0 Participants |
| Sotatercept 0.3 mg/kg | Dose Limiting Toxicities (DLTs) | 6. Incre in dose of baseline anti-hypertension med | 0 Participants |
| Sotatercept 0.5 mg/kg | Dose Limiting Toxicities (DLTs) | 1. Increase to >= 140 mmHg systolic | 8 Participants |
| Sotatercept 0.5 mg/kg | Dose Limiting Toxicities (DLTs) | 2. Increase to >=90 mmHg diastolic | 2 Participants |
| Sotatercept 0.5 mg/kg | Dose Limiting Toxicities (DLTs) | 5. Introduction of new anti-hypertension med | 4 Participants |
| Sotatercept 0.5 mg/kg | Dose Limiting Toxicities (DLTs) | 4. >=90 mmHg diastolic and increase > 20 mmHg base | 2 Participants |
| Sotatercept 0.5 mg/kg | Dose Limiting Toxicities (DLTs) | 6. Incre in dose of baseline anti-hypertension med | 0 Participants |
| Sotatercept 0.5 mg/kg | Dose Limiting Toxicities (DLTs) | 7.>= Grade 2 hypertension TEAE | 2 Participants |
| Sotatercept 0.5 mg/kg | Dose Limiting Toxicities (DLTs) | 3. =140 systolic and increase > 20 mmHg base | 5 Participants |
| Sotatercept 1.0 mg/kg | Dose Limiting Toxicities (DLTs) | 5. Introduction of new anti-hypertension med | 3 Participants |
| Sotatercept 1.0 mg/kg | Dose Limiting Toxicities (DLTs) | 2. Increase to >=90 mmHg diastolic | 2 Participants |
| Sotatercept 1.0 mg/kg | Dose Limiting Toxicities (DLTs) | 4. >=90 mmHg diastolic and increase > 20 mmHg base | 2 Participants |
| Sotatercept 1.0 mg/kg | Dose Limiting Toxicities (DLTs) | 7.>= Grade 2 hypertension TEAE | 4 Participants |
| Sotatercept 1.0 mg/kg | Dose Limiting Toxicities (DLTs) | 3. =140 systolic and increase > 20 mmHg base | 10 Participants |
| Sotatercept 1.0 mg/kg | Dose Limiting Toxicities (DLTs) | 1. Increase to >= 140 mmHg systolic | 19 Participants |
| Sotatercept 1.0 mg/kg | Dose Limiting Toxicities (DLTs) | 6. Incre in dose of baseline anti-hypertension med | 0 Participants |
| Sotatercept 2.0 mg/kg | Dose Limiting Toxicities (DLTs) | 5. Introduction of new anti-hypertension med | 1 Participants |
| Sotatercept 2.0 mg/kg | Dose Limiting Toxicities (DLTs) | 3. =140 systolic and increase > 20 mmHg base | 2 Participants |
| Sotatercept 2.0 mg/kg | Dose Limiting Toxicities (DLTs) | 6. Incre in dose of baseline anti-hypertension med | 0 Participants |
| Sotatercept 2.0 mg/kg | Dose Limiting Toxicities (DLTs) | 2. Increase to >=90 mmHg diastolic | 1 Participants |
| Sotatercept 2.0 mg/kg | Dose Limiting Toxicities (DLTs) | 1. Increase to >= 140 mmHg systolic | 2 Participants |
| Sotatercept 2.0 mg/kg | Dose Limiting Toxicities (DLTs) | 4. >=90 mmHg diastolic and increase > 20 mmHg base | 1 Participants |
| Sotatercept 2.0 mg/kg | Dose Limiting Toxicities (DLTs) | 7.>= Grade 2 hypertension TEAE | 1 Participants |
Secondary
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.
Time frame: Day 1 to 183.7 weeks
Population: Efficacy Evaluable Population of participants who responded
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sotatercept 0.3 mg/kg | Duration of Erythroid Hematological Improvement (HI-E) | TDE subpopulation | 62.5 days |
| Sotatercept 0.3 mg/kg | Duration of Erythroid Hematological Improvement (HI-E) | All participants | 62.5 days |
| Sotatercept 0.5 mg/kg | Duration of Erythroid Hematological Improvement (HI-E) | NTDE subpopulation | 79.0 days |
| Sotatercept 0.5 mg/kg | Duration of Erythroid Hematological Improvement (HI-E) | All participants | 104.0 days |
| Sotatercept 0.5 mg/kg | Duration of Erythroid Hematological Improvement (HI-E) | TDE subpopulation | 105.5 days |
| Sotatercept 1.0 mg/kg | Duration of Erythroid Hematological Improvement (HI-E) | NTDE subpopulation | 1043.0 days |
| Sotatercept 1.0 mg/kg | Duration of Erythroid Hematological Improvement (HI-E) | All participants | 133.0 days |
| Sotatercept 1.0 mg/kg | Duration of Erythroid Hematological Improvement (HI-E) | TDE subpopulation | 96.5 days |
| Sotatercept 2.0 mg/kg | Duration of Erythroid Hematological Improvement (HI-E) | All participants | 96.0 days |
| Sotatercept 2.0 mg/kg | Duration of Erythroid Hematological Improvement (HI-E) | TDE subpopulation | 58.0 days |
| Sotatercept 2.0 mg/kg | Duration of Erythroid Hematological Improvement (HI-E) | NTDE subpopulation | 134.0 days |
Secondary
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.
Time frame: Day 1 to 257.3 weeks
Population: Efficacy Evaluable Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sotatercept 0.1 mg/kg | Kaplan-Meier Estimates for Overall Survival (OS) | 82.7 weeks |
| Sotatercept 0.3 mg/kg | Kaplan-Meier Estimates for Overall Survival (OS) | NA weeks |
| Sotatercept 0.5 mg/kg | Kaplan-Meier Estimates for Overall Survival (OS) | NA weeks |
| Sotatercept 1.0 mg/kg | Kaplan-Meier Estimates for Overall Survival (OS) | NA weeks |
| Sotatercept 2.0 mg/kg | Kaplan-Meier Estimates for Overall Survival (OS) | NA weeks |
Secondary
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
Time frame: Day 1 to 257.3 weeks
Population: Efficacy Evaluable Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sotatercept 0.1 mg/kg | Kaplan-Meier Estimates for Progression-free Survival | 82.7 weeks |
| Sotatercept 0.3 mg/kg | Kaplan-Meier Estimates for Progression-free Survival | NA weeks |
| Sotatercept 0.5 mg/kg | Kaplan-Meier Estimates for Progression-free Survival | NA weeks |
| Sotatercept 1.0 mg/kg | Kaplan-Meier Estimates for Progression-free Survival | NA weeks |
| Sotatercept 2.0 mg/kg | Kaplan-Meier Estimates for Progression-free Survival | NA weeks |
Secondary
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
Time frame: Day 2 to Day 142
Population: Efficacy Evaluable Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sotatercept 0.1 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | All participants | 0 Participants |
| Sotatercept 0.1 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | TDE subpopulation | 0 Participants |
| Sotatercept 0.3 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | All participants | 1 Participants |
| Sotatercept 0.3 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | TDE subpopulation | 1 Participants |
| Sotatercept 0.5 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | TDE subpopulation | 2 Participants |
| Sotatercept 0.5 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | NTDE subpopulation | 1 Participants |
| Sotatercept 0.5 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | All participants | 3 Participants |
| Sotatercept 1.0 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | NTDE subpopulation | 6 Participants |
| Sotatercept 1.0 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | All participants | 15 Participants |
| Sotatercept 1.0 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | TDE subpopulation | 9 Participants |
| Sotatercept 2.0 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | All participants | 1 Participants |
| Sotatercept 2.0 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | TDE subpopulation | 0 Participants |
| Sotatercept 2.0 mg/kg | Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval | NTDE subpopulation | 1 Participants |
Secondary
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.
Time frame: Day 1 up to 59.2 months
Population: Safety population: all participants who receive at least one dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sotatercept 0.1 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Serious TEAE | 1 Participants |
| Sotatercept 0.1 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >= 1 Treatment-emergent adverse event (TEAE) | 6 Participants |
| Sotatercept 0.1 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Serious TEAE related to treatment | 0 Participants |
| Sotatercept 0.1 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >= 1 TEAE leading to drug discontinuation | 0 Participants |
| Sotatercept 0.1 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose interruption + reduction | 0 Participants |
| Sotatercept 0.1 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose interruption | 0 Participants |
| Sotatercept 0.1 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose reduction | 0 Participants |
| Sotatercept 0.1 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Treatment-related TEAE | 2 Participants |
| Sotatercept 0.1 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to death | 0 Participants |
| Sotatercept 0.1 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE severity grade 3/4 related to treatment | 0 Participants |
| Sotatercept 0.1 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE severity 3 or 4 | 1 Participants |
| Sotatercept 0.3 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Treatment-related TEAE | 3 Participants |
| Sotatercept 0.3 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >= 1 Treatment-emergent adverse event (TEAE) | 4 Participants |
| Sotatercept 0.3 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Serious TEAE | 2 Participants |
| Sotatercept 0.3 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Serious TEAE related to treatment | 0 Participants |
| Sotatercept 0.3 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE severity 3 or 4 | 2 Participants |
| Sotatercept 0.3 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE severity grade 3/4 related to treatment | 0 Participants |
| Sotatercept 0.3 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to death | 1 Participants |
| Sotatercept 0.3 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose reduction | 0 Participants |
| Sotatercept 0.3 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose interruption | 1 Participants |
| Sotatercept 0.3 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose interruption + reduction | 0 Participants |
| Sotatercept 0.3 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >= 1 TEAE leading to drug discontinuation | 2 Participants |
| Sotatercept 0.5 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to death | 0 Participants |
| Sotatercept 0.5 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE severity 3 or 4 | 9 Participants |
| Sotatercept 0.5 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >= 1 Treatment-emergent adverse event (TEAE) | 20 Participants |
| Sotatercept 0.5 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >= 1 TEAE leading to drug discontinuation | 2 Participants |
| Sotatercept 0.5 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose reduction | 0 Participants |
| Sotatercept 0.5 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose interruption + reduction | 0 Participants |
| Sotatercept 0.5 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE severity grade 3/4 related to treatment | 1 Participants |
| Sotatercept 0.5 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Serious TEAE related to treatment | 0 Participants |
| Sotatercept 0.5 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Serious TEAE | 6 Participants |
| Sotatercept 0.5 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Treatment-related TEAE | 7 Participants |
| Sotatercept 0.5 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose interruption | 2 Participants |
| Sotatercept 1.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose interruption + reduction | 1 Participants |
| Sotatercept 1.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE severity 3 or 4 | 13 Participants |
| Sotatercept 1.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Treatment-related TEAE | 18 Participants |
| Sotatercept 1.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE severity grade 3/4 related to treatment | 0 Participants |
| Sotatercept 1.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to death | 0 Participants |
| Sotatercept 1.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose reduction | 0 Participants |
| Sotatercept 1.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >= 1 Treatment-emergent adverse event (TEAE) | 34 Participants |
| Sotatercept 1.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose interruption | 9 Participants |
| Sotatercept 1.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >= 1 TEAE leading to drug discontinuation | 3 Participants |
| Sotatercept 1.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Serious TEAE | 10 Participants |
| Sotatercept 1.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Serious TEAE related to treatment | 0 Participants |
| Sotatercept 2.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose interruption | 1 Participants |
| Sotatercept 2.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to death | 0 Participants |
| Sotatercept 2.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Treatment-related TEAE | 4 Participants |
| Sotatercept 2.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Serious TEAE related to treatment | 1 Participants |
| Sotatercept 2.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 Serious TEAE | 2 Participants |
| Sotatercept 2.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >= 1 TEAE leading to drug discontinuation | 2 Participants |
| Sotatercept 2.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE severity grade 3/4 related to treatment | 1 Participants |
| Sotatercept 2.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose reduction | 0 Participants |
| Sotatercept 2.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE leading to dose interruption + reduction | 0 Participants |
| Sotatercept 2.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >= 1 Treatment-emergent adverse event (TEAE) | 5 Participants |
| Sotatercept 2.0 mg/kg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE severity 3 or 4 | 2 Participants |
Secondary
Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints
Maximum observed serum concentration, obtained directly from the observed concentration versus time data.
Time frame: Cycle 1 Day 8 and !5 up to Cycle 2 Day 1
Population: Pharmacokinetic (PK) population includes participants with a sufficient amount of post-dose quantifiable PK sotatercept profile.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sotatercept 0.1 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 1 Day 15 | 240.31 ng/mL | Geometric Coefficient of Variation 75.32 |
| Sotatercept 0.1 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 1 Day 8 | 288.06 ng/mL | Geometric Coefficient of Variation 70.94 |
| Sotatercept 0.1 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 2 Day 1 | 252.20 ng/mL | Geometric Coefficient of Variation 28.43 |
| Sotatercept 0.3 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 1 Day 15 | 1207.68 ng/mL | Geometric Coefficient of Variation 16.14 |
| Sotatercept 0.3 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 1 Day 8 | 1426.00 ng/mL | Geometric Coefficient of Variation 27.76 |
| Sotatercept 0.3 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 2 Day 1 | 957.58 ng/mL | Geometric Coefficient of Variation 18.63 |
| Sotatercept 0.5 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 2 Day 1 | 1323.91 ng/mL | Geometric Coefficient of Variation 44.4 |
| Sotatercept 0.5 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 1 Day 8 | 2237.46 ng/mL | Geometric Coefficient of Variation 40.77 |
| Sotatercept 0.5 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 1 Day 15 | 1869.52 ng/mL | Geometric Coefficient of Variation 36.97 |
| Sotatercept 1.0 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 1 Day 15 | 5149.74 ng/mL | Geometric Coefficient of Variation 36.04 |
| Sotatercept 1.0 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 1 Day 8 | 6525.37 ng/mL | Geometric Coefficient of Variation 28.31 |
| Sotatercept 1.0 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 2 Day 1 | 3467.58 ng/mL | Geometric Coefficient of Variation 57.06 |
| Sotatercept 2.0 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 2 Day 1 | 5329.63 ng/mL | Geometric Coefficient of Variation 38.27 |
| Sotatercept 2.0 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 1 Day 15 | 8303.73 ng/mL | Geometric Coefficient of Variation 43.57 |
| Sotatercept 2.0 mg/kg | Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints | Cycle 1 Day 8 | 12886.14 ng/mL | Geometric Coefficient of Variation 30.47 |
Secondary
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.
Time frame: Day 1 to Day 87
Population: Efficacy Evaluable Population of participants who responded
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sotatercept 0.3 mg/kg | Time to Erythroid Hematological Improvement (HI-E) Response | All participants | 24.0 days |
| Sotatercept 0.3 mg/kg | Time to Erythroid Hematological Improvement (HI-E) Response | TDE subpopulation | 24.0 days |
| Sotatercept 0.5 mg/kg | Time to Erythroid Hematological Improvement (HI-E) Response | All participants | 1.0 days |
| Sotatercept 0.5 mg/kg | Time to Erythroid Hematological Improvement (HI-E) Response | TDE subpopulation | 1.5 days |
| Sotatercept 0.5 mg/kg | Time to Erythroid Hematological Improvement (HI-E) Response | NTDE subpopulation | 1.0 days |
| Sotatercept 1.0 mg/kg | Time to Erythroid Hematological Improvement (HI-E) Response | NTDE subpopulation | 1.0 days |
| Sotatercept 1.0 mg/kg | Time to Erythroid Hematological Improvement (HI-E) Response | All participants | 1.0 days |
| Sotatercept 1.0 mg/kg | Time to Erythroid Hematological Improvement (HI-E) Response | TDE subpopulation | 1.5 days |
| Sotatercept 2.0 mg/kg | Time to Erythroid Hematological Improvement (HI-E) Response | All participants | 48 days |
| Sotatercept 2.0 mg/kg | Time to Erythroid Hematological Improvement (HI-E) Response | TDE subpopulation | 87 days |
| Sotatercept 2.0 mg/kg | Time to Erythroid Hematological Improvement (HI-E) Response | NTDE subpopulation | 9.0 days |
Secondary
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.
Time frame: Day 1 to 183.7 weeks
Population: Efficacy Evaluable Population of participants who progressed to AML
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotatercept 0.5 mg/kg | Time to Progression to Acute Myeloid Leukemia (AML) for Participants Who Had Progression | 45.6 weeks |
| Sotatercept 1.0 mg/kg | Time to Progression to Acute Myeloid Leukemia (AML) for Participants Who Had Progression | 78.0 weeks |
Secondary
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.
Time frame: Day 1 to 257.3 weeks
Population: Efficacy Evaluable Population of participants who progressed to high risk MDS categories
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotatercept 0.1 mg/kg | Time to Progression to Events of Higher Risk Myelodysplastic Syndromes (MDS) Using the International Prognostic Scoring System (IPSS) For Participants Who Had Progression | 15.1 weeks |
| Sotatercept 0.5 mg/kg | Time to Progression to Events of Higher Risk Myelodysplastic Syndromes (MDS) Using the International Prognostic Scoring System (IPSS) For Participants Who Had Progression | 24.7 weeks |
| Sotatercept 1.0 mg/kg | Time to Progression to Events of Higher Risk Myelodysplastic Syndromes (MDS) Using the International Prognostic Scoring System (IPSS) For Participants Who Had Progression | 67.4 weeks |