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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)

Primary Purpose

Anemia, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Sotatercept

About this trial

This is an interventional treatment trial for Anemia focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Rocky Mountain Cancer Center-Midtown
H. Lee Moffitt Cancer Center and Research Institute
Johns Hopkins
Dana-Farber / Harvard Cancer Institute
Monter Cancer Center, North Shore LIJ Health Systems
Columbia University Medical Center/New York-Presbyterian Hospital
The Cleveland Clinic Foundation Hematology and Medical Oncology Rm 35
Sarah Cannon Research Inst
Texas Oncology Round Rock Cancer Center - Round Rock
University of Texas Health Science Center at San Antonio
Texas Oncology, P.A. - Tyler
Virginia Oncology Associates
Yakima Valley Memorial Hospital/ North Star Lodge
Centre Hospitalier Universitaire d'Avicennes
Institute Paoli-Calmettes Service Haematology
CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang
CHRU Nantes
Hopital Cochin Hematologie
Centre Henri Becquerel
CHU Purpan

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Arm Label

Sotatercept 0.1 mg/kg

Sotatercept 0.3 mg/kg

Sotatercept 0.5 mg/kg

Sotatercept 1.0 mg/kg

Sotatercept 1.5 mg/kg

Sotatercept 2.0 mg/kg

Arm Description

Sotatercept 0.1 mg/kg

Sotatercept 0.3 mg/kg

Sotatercept 0.5 mg/kg

Sotatercept 1.0 mg/kg

Sotatercept 1.5 mg/kg

Sotatercept 2.0 mg/kg

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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 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 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.

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

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.

Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints

Maximum observed serum concentration, obtained directly from the observed concentration versus time data.

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.

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

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

Full Information

NCT ID

NCT01736683

First Posted

November 27, 2012

Last Updated

October 20, 2022

Sponsor

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT01736683

Brief Title

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

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)

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Completed

Study Start Date

November 28, 2012 (Actual)

Primary Completion Date

April 30, 2018 (Actual)

Study Completion Date

April 30, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Merck Sharp & Dohme LLC

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

74 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sotatercept 0.1 mg/kg

Arm Type

Experimental

Arm Description

Sotatercept 0.1 mg/kg

Arm Title

Sotatercept 0.3 mg/kg

Arm Type

Experimental

Arm Description

Sotatercept 0.3 mg/kg

Arm Title

Sotatercept 0.5 mg/kg

Arm Type

Experimental

Arm Description

Sotatercept 0.5 mg/kg

Arm Title

Sotatercept 1.0 mg/kg

Arm Type

Experimental

Arm Description

Sotatercept 1.0 mg/kg

Arm Title

Sotatercept 1.5 mg/kg

Arm Type

Experimental

Arm Description

Sotatercept 1.5 mg/kg

Arm Title

Sotatercept 2.0 mg/kg

Arm Type

Experimental

Arm Description

Sotatercept 2.0 mg/kg

Intervention Type

Drug

Intervention Name(s)

Sotatercept

Other Intervention Name(s)

ACE-011, ActRIIA-IgG1Fc

Intervention Description

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.

Primary Outcome Measure Information:

Title

Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate)

Description

Time Frame

Day 2 to Day 142

Secondary Outcome Measure Information:

Title

Time to Erythroid Hematological Improvement (HI-E) Response

Description

Time Frame

Day 1 to Day 87

Title

Duration of Erythroid Hematological Improvement (HI-E)

Description

Time Frame

Day 1 to 183.7 weeks

Title

Time to Progression to Acute Myeloid Leukemia (AML) for Participants Who Had Progression

Description

Time Frame

Day 1 to 183.7 weeks

Title

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

Description

Time Frame

Day 1 to 257.3 weeks

Title

Kaplan-Meier Estimates for Progression-free Survival

Description

Time Frame

Day 1 to 257.3 weeks

Title

Kaplan-Meier Estimates for Overall Survival (OS)

Description

Time Frame

Day 1 to 257.3 weeks

Title

Pharmacokinetic Parameters of Sotatercept: Serum Concentration at Various Study Timepoints

Description

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

Title

Participants With Treatment-Emergent Adverse Events (TEAE)

Description

Time Frame

Day 1 up to 59.2 months

Title

Dose Limiting Toxicities (DLTs)

Description

Time Frame

Day 1 to 59.2 months

Title

Number of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval

Description

Time Frame

Day 2 to Day 142

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Rodrigo Ito, MD

Organizational Affiliation

Celgene Corporation

Official's Role

Study Director

Facility Information:

Facility Name

Rocky Mountain Cancer Center-Midtown

City

Denver

State/Province

Colorado

ZIP/Postal Code

80218

Country

United States

Facility Name

H. Lee Moffitt Cancer Center and Research Institute

City

Tampa

State/Province

Florida

ZIP/Postal Code

33612

Country

United States

Facility Name

Johns Hopkins

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21231

Country

United States

Facility Name

Dana-Farber / Harvard Cancer Institute

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

Monter Cancer Center, North Shore LIJ Health Systems

City

Lake Success

State/Province

New York

ZIP/Postal Code

11042

Country

United States

Facility Name

Columbia University Medical Center/New York-Presbyterian Hospital

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Facility Name

The Cleveland Clinic Foundation Hematology and Medical Oncology Rm 35

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44195

Country

United States

Facility Name

Sarah Cannon Research Inst

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37203

Country

United States

Facility Name

Texas Oncology Round Rock Cancer Center - Round Rock

City

Round Rock

State/Province

Texas

ZIP/Postal Code

78681

Country

United States

Facility Name

University of Texas Health Science Center at San Antonio

City

San Antonio

State/Province

Texas

ZIP/Postal Code

78229

Country

United States

Facility Name

Texas Oncology, P.A. - Tyler

City

Tyler

State/Province

Texas

ZIP/Postal Code

75702

Country

United States

Facility Name

Virginia Oncology Associates

City

Norfolk

State/Province

Virginia

ZIP/Postal Code

23502

Country

United States

Facility Name

Yakima Valley Memorial Hospital/ North Star Lodge

City

Yakima

State/Province

Washington

ZIP/Postal Code

98902

Country

United States

Facility Name

Centre Hospitalier Universitaire d'Avicennes

City

Bobigny Cedex

ZIP/Postal Code

93009

Country

France

Facility Name

Institute Paoli-Calmettes Service Haematology

City

Bp 156,

ZIP/Postal Code

13273

Country

France

Facility Name

CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang

City

Lille

ZIP/Postal Code

59037

Country

France

Facility Name

CHRU Nantes

City

Nantes

ZIP/Postal Code

44093

Country

France

Facility Name

Hopital Cochin Hematologie

City

Paris Cedex 14

ZIP/Postal Code

75679

Country

France

Facility Name

Centre Henri Becquerel

City

Rouen

ZIP/Postal Code

79038

Country

France

Facility Name

CHU Purpan

City

Toulouse

ZIP/Postal Code

31059

Country

France

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

IPD Sharing URL

http://engagezone.msd.com/ds_documentation.php

Citations:

PubMed Identifier

29331635

Citation

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.

Results Reference

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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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