Clinical trial NCT01571635: Study to Determine the Safety and Tolerability of Sotatercept (ACE-011) in Adults With Beta( β)- Thalassemia.
Official title: A Phase 2A, Open-label Dose Finding Study to Determine the Safety and Tolerability of Sotatercept (ACE-011) in Adults With BETA(b)-THALASSEMIA.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Beta Thalassemia Major
Beta Thalassemia Intermedia
Keywords: Beta-Thalassaemia
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2012-04-05
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: Inclusion Criteria:

* 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.
* For non-transfusion dependent subjects: non-transfusion dependency is defined as a transfusion free for a minimum of 168 days immediately preceding enrollment (study Day 1, first Dose), with the exception of ≤ to one episode of transfusion in the period of a minimum of 168 days immediately preceding enrollment (study Day 1, first Dose) (One episode of transfusion is defined as ≤ 4 transfusion units administered, occurred within 42 days \[first transfusion is counted as day 1\] due to concurrent illness \[e.g. infection\], \[Guidelines Clin Management of Thalassaemia, 2008\]). (This inclusion criteria is not valid for France).
* 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.

Exclusion Criteria:

* 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:

  * Liver disease with ALT \> 3x ULN or histopathological evidence of liver cirrhosis on liver biopsy;
  * Heart disease with ejection fraction ≥ Grade 2 according to NCI CTCAE version 4.0 (current active minor version);
  * Kidney disease with a calculated creatinine clearance \< 40 mL/min (Cockcroft-Gault formula);
  * Pulmonary fibrosis or pulmonary hypertension as confirmed by a specialist.
* Adrenal insufficiency.
* Heart failure as classified by the New York Heart Association (NYHA) classification of 3 or higher (Appendix C).
* Major surgery within 30 days prior to study Day 1 (subjects must have completely recovered from any previous surgery prior to study Day 1).
* History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the Investigational Product (see Investigator Brochure).

Primary outcomes:
measure: Potential Recommended Dose as Determined by Number of Participants Experiencing Dose-Limiting Toxicities and Recommended Dose
timeFrame: From first dose up to 28 days post the first dose
Secondary outcomes:
measure: Number of Participants With Red Blood Cell Transfusion Burden Reduction From Baseline During Treatment
timeFrame: From baseline to the last dose of study treatment (up to approximately 112 months)
measure: Number of Participants With Hemoglobin Level Increase From Baseline in Non-Transfusion Dependent B-Thalassemia Intermedia Participants
timeFrame: Measurements were taken in 9 and 12-week intervals, from baseline up to approximately 112 months
measure: Number of Participants Experiencing Adverse Events (AEs)
timeFrame: From first dose up to 112 days after the last dose of study treatment (up to 115 months)
measure: Concentrations of Sotatercept in Serum
timeFrame: 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
measure: Number of Participants With Anti-Drug Antibody (ADA)
timeFrame: From first dose up to 4 months after last dose (up to approximately 116 months)
measure: Number of Participants Experiencing Quality of Life (QOL) Change From Baseline
timeFrame: From pre-dose up to Dose 8 (168 days/6months) and Dose 16 (336 days/12months) only
Other outcomes:
Locations:
city: Créteil
country: France
facility: Hopital Henri Mondor
city: Créteil
country: France
facility: Groupe Hospitalier Henri Mondor
city: Paris
country: France
facility: Hospital of Necker
city: Paris
country: France
facility: Local Institution - 001
city: Paris
country: France
facility: Hôpital Necker-Enfants Malades
city: Ampelokipi - Athens
country: Greece
facility: Local Institution - 300
city: Ampelokipi - Athens
country: Greece
facility: Laiko General Hospital
city: Cagliari
country: Italy
facility: Universita degli Studi di Cagliari - ASL8
city: Cagliari
country: Italy
facility: Universita Degli Studi Di Cagliari
city: Genoa
country: Italy
facility: Local Institution - 200
city: Genoa
country: Italy
facility: Ospedale Galliera
city: Genova
country: Italy
facility: Ente Ospedaliero Ospedali Galliera
city: Milano
country: Italy
facility: Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: Fondazione IRCCS Ospedale Maggiore
city: Milano
country: Italy
facility: Local Institution - 201
city: London
country: United Kingdom
facility: Local Institution - 100
city: London
country: United Kingdom
facility: UCL Cancer Institute
city: London
country: United Kingdom
facility: UCL Cancer Institue
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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
citation: "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 "