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

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ClinicalTrials.gov Identifier: NCT01736683
Recruitment Status : Completed
First Posted : November 29, 2012
Results First Posted : June 13, 2019
Last Update Posted : June 25, 2019
Sponsor:
Information provided by (Responsible Party):
Celgene

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).

Condition or disease Intervention/treatment Phase
Anemia Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia Low to Intermediate-1 MDS Myelodysplastic Syndromes (MDS) Chronic Myelomonocytic Leukemia (CMML) Drug: Sotatercept Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 74 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : November 28, 2012
Actual Primary Completion Date : April 30, 2018
Actual Study Completion Date : April 30, 2018


Arm Intervention/treatment
Experimental: Sotatercept 0.1 mg/kg
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
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
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
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
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
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




Primary Outcome Measures :
  1. Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) [ Time Frame: 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 :
  1. Time to Erythroid Hematological Improvement (HI-E) Response [ Time Frame: 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.

  2. Duration of Erythroid Hematological Improvement (HI-E) [ Time Frame: 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.

  3. Time to Progression to Acute Myeloid Leukemia (AML) for Participants Who Had Progression [ Time Frame: 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.

  4. Time to Progression to Events of Higher Risk Myelodysplastic Syndromes (MDS) Using the International Prognostic Scoring System (IPSS) For Participants Who Had Progression [ Time Frame: 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.

  5. Kaplan-Meier Estimates for Progression-free Survival [ Time Frame: 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

  6. Kaplan-Meier Estimates for Overall Survival (OS) [ Time Frame: 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.

  7. Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints [ Time Frame: 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.

  8. Participants With Treatment-Emergent Adverse Events (TEAE) [ Time Frame: 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.

  9. Dose Limiting Toxicities (DLTs) [ Time Frame: 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

  10. Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval [ Time Frame: 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01736683


Locations
Show Show 20 study locations
Sponsors and Collaborators
Celgene
Investigators
Layout table for investigator information
Study Director: Rodrigo Ito, MD Celgene Corporation
  Study Documents (Full-Text)

Documents provided by Celgene:
Study Protocol  [PDF] August 4, 2015
Statistical Analysis Plan  [PDF] May 1, 2018

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT01736683    
Other Study ID Numbers: ACE-011-MDS-001
2012-002601-22 ( EudraCT Number )
First Posted: November 29, 2012    Key Record Dates
Results First Posted: June 13, 2019
Last Update Posted: June 25, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Upon request
URL: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/
Keywords provided by Celgene:
ACE-011
Sotatercept
anemia
dose-ranging
intermediate-1 risk myelodysplastic syndromes
low risk myelodysplastic syndromes (MDS)
multicenter
open-label
parallel
phase 2
randomized
Non-proliferative chronic myelomonocytic leukemia (CMML)
hemoglobin
transfusions
Additional relevant MeSH terms:
Layout table for MeSH terms
Leukemia
Preleukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Anemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Bone Marrow Diseases
Precancerous Conditions
Leukemia, Myeloid
Myelodysplastic-Myeloproliferative Diseases