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

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).