Study to Determine the Safety and Tolerability of Sotatercept (ACE-011) in Adults With Beta( β)- Thalassemia.

NCT01571635 | Terminated Phase 2 Results

• 2 other identifiers: ACE-011-B-THAL-0012011-005659-15
• Study Type: interventional
• Target: 46
• Locations: 4 countries
• Sites: 18

Brief Summary

Dose finding study to determine the safety and tolerability of Sotatercept (ACE-011) in adults with Beta (β)-Thalassemia

Conditions

Beta Thalassemia Major; Beta Thalassemia Intermedia

Keywords

Beta-Thalassaemia

Outcome Measures

Primary Outcomes (1)

• Potential Recommended Dose as Determined by Number of Participants Experiencing Dose-Limiting Toxicities and Recommended Dose

  Number of participants with dose-limiting toxicities (DLT) are used to determine the potential recommended dose (PRD). PRD is defined as the highest dose with up to 1 out of 6 patients experiencing a DLT. DLT is defined as any side effects of the study treatment serious enough to prevent an increase in dose or level of treatment, including at least one of the following: Hypertension ≥ Grade 3 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0; Hgb \> 14 g/dL sustained for four weeks; any NCI CTCAE toxicity ≥ Grade 3. Grade 3 is defined as severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily life. PRD was identified as 1 mg/kg. Due to study termination, no patients were enrolled after 1 mg/kg cohort or in the Expansion Cohort. Thus, primary analyses to determine recommended dose (RD) were not conducted.

  From first dose up to 28 days post the first dose

Secondary Outcomes (6)

• Number of Participants With Red Blood Cell Transfusion Burden Reduction From Baseline During Treatment

  From baseline to the last dose of study treatment (up to approximately 112 months)

• Number of Participants With Hemoglobin Level Increase From Baseline in Non-Transfusion Dependent B-Thalassemia Intermedia Participants

  Measurements were taken in 9 and 12-week intervals, from baseline up to approximately 112 months

• Number of Participants Experiencing Adverse Events (AEs)

  From first dose up to 112 days after the last dose of study treatment (up to 115 months)

• Concentrations of Sotatercept in Serum

  Dose 1, Day 8; Dose 1, Day 15; Dose 2, Day 1; Dose 2, Day 8; Dose 3, Day 1; Dose 3, Day 8; Dose 4, Day 1; Dose 5, Day 1; Dose 6, Day 1

• Number of Participants With Anti-Drug Antibody (ADA)

  From first dose up to 4 months after last dose (up to approximately 116 months)

Study Arms (6)

Sotatercept dose level 0.1mg/kg

EXPERIMENTAL

Experimental 0.1 mg/kg -Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period

Drug: SOTATERCEPT (ACE-011)

Sotatercept dose level 0.3mg/ kg

EXPERIMENTAL

Experimental 0.3 mg/kg - Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period

Drug: SOTATERCEPT (ACE-011)

Sotatercept dose level 0.5mg/kg

EXPERIMENTAL

Experimental 0.5 mg/kg -Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period

Drug: SOTATERCEPT (ACE-011)

Sotatercept dose level 0.75mg/kg

EXPERIMENTAL

Experimental 0.75 mg/kg - Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period

Drug: SOTATERCEPT (ACE-011)

Sotatercept dose level 1.0mg/kg

EXPERIMENTAL

Experimental 1.0 mg/kg -Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period

Drug: SOTATERCEPT (ACE-011)

Sotatercept dose level 1.5mg/kg

EXPERIMENTAL

Experimental 1.5 mg/kg -Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period

Drug: SOTATERCEPT (ACE-011)

Interventions

SOTATERCEPT (ACE-011) DRUG

0.1 mg/kg to 1.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period.

Also known as: (ACE-011)

Sotatercept dose level 0.1mg/kg; Sotatercept dose level 0.3mg/ kg; Sotatercept dose level 0.5mg/kg; Sotatercept dose level 0.75mg/kg; Sotatercept dose level 1.0mg/kg; Sotatercept dose level 1.5mg/kg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women 18 years of age at the time of signing the informed consent document with a diagnosis of β-thalassemia major (including all subtypes) or β-thalassemia intermedia.
• For transfusion dependent subjects: permanent transfusion dependency is defined as requiring packed red blood cells (pRBCs) and iron chelation therapy:
• Average transfusion requirement of at least 2 units/30 days of pRBCs (Gale, 2011) confirmed for a minimum of 168 days (six months) immediately preceding enrollment (study Day 1, first Dose);
• No transfusion-free period of more than 45 consecutive days during the 168 days immediately preceding enrollment (study Day 1, first Dose);
• Prior transfusion hemoglobin levels ≤ 10.5 g/dL.
• Performance status: Eastern Cooperative Oncology Group (ECOG) score of 0 to 1
• No concurrent severe hepatic disease:
• Aspartate Aminotransferase (AST) or Alanine Transaminase (ALT) no greater than 3 x upper limit of normal (ULN);
• Albumin ≥ 3 g/dL.
• Serum creatinine ≤ 1.5 x ULN.
• Females of childbearing potential participating in the study are to use highly effective methods of birth control during study participation and for 112 days (approximately five times the mean terminal half-life of sotatercept \[23 days\] based on multiple-dose PK data) following the last dose of sotatercept. FCBP must have a negative serum beta Human Chorionic Gonadotropin (β-HCG) pregnancy test within three days of Sotatercept dosing (Day 1). Subjects must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of sotatercept. A FCBP is a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy or who has not been postmenopausal for at least 24 consecutive months (i.e., who has had menses at some time in the preceding 24 months).
• Males must agree to use a latex condom during any sexual contact with FCBSs while participating in the study and for 112 days following the last dose of Sotatercept, even if he has undergone a successful vasectomy. Subjects must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of sotatercept.
• Agreement to adhere to the study visit schedule, understand and comply with all protocol requirements.
• Understand and provide written informed consent.

You may not qualify if:

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing participating in the study.
• Evidence of active Hepatitis C antibody (HCV), Hepatitis B surface antigen (HBsAg and HB core Ab), or Human Immunodeficiency Virus (HIV) antibody.
• Known history of thromboembolic events ≥ Grade 3 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 (current active minor version).
• Subjects with insulin dependent diabetes.
• Subjects with major cardiac problems such as:
• Major risk of heart failure, confirmed with myocardiac T2\* ≤ 10 ms. Myocardiac T2\* performed in the last one and a half years prior to subject enrollment (study Day 1, first Dose) will be considered valid.
• Cardiac arrhythmia which requires treatment (i.e. atrial fibrillation).
• Treatment with another investigational drug or device \< 28 days prior to study entry.
• Use of an Erythropoiesis Stimulating Agent (ESA) within the 28 days prior to enrollment (study Day 1, first Dose).
• Subjects on hydroxyurea treatment for which the dose was changed in the last one year prior to subject enrollment (study Day 1, first Dose).
• Subjects on anticoagulant therapy, such as warfarin.
• Subjects who started bisphosphonates within the last three months prior to subject enrollment (study Day 1, first Dose).
• Pregnant or lactating females.
• Uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ Grade 1 according to NCI CTCAE version 4.0 (current active minor version) (Appendix B).
• A history of major organ damage including:

Sponsors & Collaborators

• Celgene: lead

Study Sites (18)

Hopital Henri Mondor

Créteil, 94010, France

Location

Groupe Hospitalier Henri Mondor

Créteil, France

Location

Hospital of Necker

Paris, 75015, France

Location

Local Institution - 001

Paris, 75015, France

Location

Hôpital Necker-Enfants Malades

Paris, France

Location

Local Institution - 300

Ampelokipi - Athens, 115 26, Greece

Location

Laiko General Hospital

Ampelokipi - Athens, 11526, Greece

Location

Universita degli Studi di Cagliari - ASL8

Cagliari, 09121, Italy

Location

Universita Degli Studi Di Cagliari

Cagliari, 09121, Italy

Location

Local Institution - 200

Genoa, 16128, Italy

Location

Ospedale Galliera

Genoa, 16128, Italy

Location

Ente Ospedaliero Ospedali Galliera

Genova, 16128, Italy

Location

Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

Fondazione IRCCS Ospedale Maggiore

Milan, 20122, Italy

Location

Local Institution - 201

Milan, 20122, Italy

Location

Local Institution - 100

London, WC1E 6BT, United Kingdom

Location

UCL Cancer Institute

London, WC1E 6BT, United Kingdom

Location

UCL Cancer Institue

London, WC1E6BT, United Kingdom

Location

Related Publications (3)

• Cappellini MD, Porter J, Origa R, Forni GL, Voskaridou E, Galacteros F, Taher AT, Arlet JB, Ribeil JA, Garbowski M, Graziadei G, Brouzes C, Semeraro M, Laadem A, Miteva D, Zou J, Sung V, Zinger T, Attie KM, Hermine O. Sotatercept, a novel transforming growth factor beta ligand trap, improves anemia in beta-thalassemia: a phase II, open-label, dose-finding study. Haematologica. 2019 Mar;104(3):477-484. doi: 10.3324/haematol.2018.198887. Epub 2018 Oct 18.

  PMID: 30337358 BACKGROUND

• Cappellini M, et al. A Phase 2a, Open-Label, Dose-Finding Study to Determine the Safety and Tolerability of Sotatercept (ACE-011) in Adults With Beta ( )-Thalassemia: Interim Results. Presented at the 55th Annual Meeting of the American Society of Hematology (ASH), December 7-10, 2013, New Orleans, LA. Abstract No. 3448

  BACKGROUND

• "Porter J, et al. Interim Results From a Phase 2A, Open-Label, Dose-Finding Study To Determine The Safety, Efficacy, And Tolerability of Sotatercept (ACE-001) In Adults with Beta-Thalassemia. Presented at the 19thCongress of the European Hematology Association, June 12-15, 2015, Milan, Italy. Abstract No. S622 "

  BACKGROUND

Related Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

MeSH Terms

Conditions

beta-Thalassemia

Interventions

ACE-011

Condition Hierarchy (Ancestors)

Thalassemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Limitations and Caveats

Sotatercept development in β-thalassemia indication was stopped and no further patients were enrolled after 1 mg/kg cohort was completed. Due to the early termination of the study and no enrollment of the Expansion Cohort, the primary analyses to determine the recommended dose (RD) and the secondary analysis of QoL change from baseline were not conducted.

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Please Email

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 3, 2012
• First Posted: April 5, 2012
• Study Start: October 10, 2012
• Primary Completion: July 2, 2015
• Study Completion: May 24, 2022
• Last Updated: June 18, 2023
• Results First Posted: June 18, 2023

Record last verified: 2023-05

Locations

GR (2); FR (5); IT (8); GB (3)