Dose finding study to determine the safety and tolerability of sotatercept (ACE-011) in adults with beta-thalassemia (ß-thalassemia)

Phase 1

• Conditions: Subjects with red blood cell (RBC) transfusion dependent ß-thalassemia major and ß thalassemia intermedia, as well as non-transfusion dependent ß-thalassemia intermedia will take part in this study.; MedDRA version: 20.1Level: LLTClassification code 10062923Term: Thalassemia intermediaSystem Organ Class: 100000004850; MedDRA version: 20.1Level: LLTClassification code 10054661Term: Thalassemia majorSystem Organ Class: 100000004850; MedDRA version: 20.1Level: LLTClassification code 10054660Term: Thalassemia betaSystem Organ Class: 100000004850; Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2011-005659-15-GR
• Lead Sponsor: Celgene Corporation

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2012-12-06
• Last Update Posted: 29 November 2021

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 85

Inclusion Criteria

1.Men and women = 18 years of age at the time of signing the informed consent document with a diagnosis of ß-thalassemia major (including all subtypes) or ß-thalassemia intermedia.

2.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 (Day 1);
•No transfusion-free period of more than 45 consecutive days during the 168 days immediately preceding enrollment;
• Mean prior transfusion Hgb level is = 10.5 g/dL for 168 days immediately preceding enrollment (study Day 1) and the last pre-transfusion Hgb immediately preceding enrollment (study Day 1) is = 10.5 g/dL.
3.For non-transfusion dependent subjects: non-transfusion dependency is defined as transfusion free, with the exception of = one episode of transfusion in the period of a minimum of 168 days immediately preceding enrollment (One episode of transfusion is defined as = 4 transfusion units administered, occurred within 168 days immediately preceding enrollment due to concurrent illness [e.g. infection], [Guidelines Clin Management of Thalassaemia, 2008])

4.Performance status: ECOG score of 0 to 1.

5.No concurrent severe hepatic disease:
•AST or ALT no greater than 3 x upper limit of normal (ULN);
•Albumin = 3 g/dL.

6.Serum creatinine = 1.5 x ULN and creatinine clearance >60 ml/min

7.Females of childbearing potential (FCBP) 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 (ß-HCG) pregnancy test within three days of sotatercept dosing (Study 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).

8.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.

9.Agreement to adhere to the study visit schedule, understand and comply with all protocol requirements.

10. Understand and provide written informed consent.

* For subjects with a weight less than 50 kg, a conversion factor as per Gale, 2012, is allowed to be used.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 83
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 3

Exclusion Criteria

1.Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing participating in the study.

2.Evidence of active hepatitis C (HCV) infection, or active infectious hepatitis B, or known positive for human immunodeficiency virus (HIV).

3.Known history of thromboembolic events = Grade 3 according to NCI CTCAE version 4.0 (current active minor version)

4. Subjects with insulin dependent diabetes

5. Subjects with major cardiac problems such as:
• Major risk of heart failure.
• Cardiac arrhythmia which requires treatment (i.e atrial fibrillation)

6. Treatment with another investigational drug or device < 28 days prior to study entry as well as any prior exposure to sotatercept.

7.Use of an erythropoiesis stimulating agent (ESA) within the 28 days prior to enrollment (study Day 1).

8.Subjects on hydroxyria treatment for which the dose was changed in the last one year prior subject enrollment

9. Subjects on long-term anticoagulant therapy, such as heparin or warfarin.

10. Subjects who started bisphosphonates within the last 3 months prior subject enrollment

11.Pregnant or lactating females.

12.Uncontrolled hypertension. Controlled hypertension for this protocol is considered = Grade 1 according to NCI CTCAE version 4.0 (current active minor version).

13.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 confirmed by a specialist.

14.Adrenal insufficiency.

15.Heart failure as classified by the New York Heart Association (NYHA) classification of 3 or higher.

16.Major surgery within 30 days prior to study Day 1 (subjects must have completely recovered from any previous surgery prior to study Day 1).

17. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see Investigator Brochure)

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified