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

Sponsor

Celgene (Industry)

Overall Status

Completed

CT.gov ID

NCT01571635

Collaborator

(none)

Enrollment

Locations

Arms

115.4

Actual Duration (Months)

3.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Beta Thalassemia Major Beta Thalassemia Intermedia	Drug: SOTATERCEPT (ACE-011)	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

46 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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.

Actual Study Start Date :

Oct 10, 2012

Actual Primary Completion Date :

Jul 2, 2015

Actual Study Completion Date :

May 24, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sotatercept dose level 0.1mg/kg 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) 0.1 mg/kg to 1.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period. Other Names: (ACE-011)
Experimental: Sotatercept dose level 0.3mg/ kg 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) 0.1 mg/kg to 1.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period. Other Names: (ACE-011)
Experimental: Sotatercept dose level 0.5mg/kg 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) 0.1 mg/kg to 1.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period. Other Names: (ACE-011)
Experimental: Sotatercept dose level 0.75mg/kg 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) 0.1 mg/kg to 1.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period. Other Names: (ACE-011)
Experimental: Sotatercept dose level 1.0mg/kg 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) 0.1 mg/kg to 1.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period. Other Names: (ACE-011)
Experimental: Sotatercept dose level 1.5mg/kg 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) 0.1 mg/kg to 1.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period. Other Names: (ACE-011)

Outcome Measures

Primary Outcome Measures

Potential Recommended Dose (PRD) [Up to 27 months]
The potential recommended dose (PRD) will be determined following the assessment of efficacy and safety parameters based on the first three doses of Sotatercept administered, up to at least 21 days following the first dose, for all doses evaluated. The PRD of Sotatercept will be defined as the highest dose level at which no more than one out of six subjects experiences a dose-limiting toxicity (DLT). The recommended dose of Sotatercept will be defined based on the review of the efficacy and safety parameters as well as dose modification data. The efficacy parameter is defined as: - for transfusion dependent B-Thalassemia major and intermedia : the reduction of transfusion burden by ≥ 20% compared to the calculated baseline transfusion burden to each subject ; - for non-transfusion dependent B-Thalassemia intermedia subjects : increase in Hgb level by ≥ 1 g/dl compared to the baseline Hgb, sustained for 12 weeks.
Actual Recommended Dose (RD) [Up to 27 months]
The RD of Sotatercept will be defined based on the review of the efficacy and safety parameters as well as dose modification data. The efficacy parameter is defined as: - for transfusion dependent B-Thalassemia major and intermedia : the reduction of transfusion burden by ≥ 20% compared to the calculated baseline transfusion burden to each subject ; - for non-transfusion dependent B-Thalassemia intermedia subjects : increase in Hgb level by ≥ 1 g/dl compared to the baseline Hgb, sustained for 12 weeks.

Secondary Outcome Measures

Reduction of Transfusion Burden [Up to 27 months]
Assess the reduction of transfusion burden in transfusion dependent Beta-Thalassemia major and Intermedia subjects.
Number of Participants with Adverse Events [Up to 27 months]
Number of participants with adverse events
PK-Observed Maximum Concentration (Cmax) [Up to 16 samples over 27 months]
PK-observed maximum concentration (Cmax)
PK-Time to Maximum Concentration (Tmax) [Up to 16 samples over 27 months]
PK-Time to maximum concentration (Tmax)
PK-Area Under the Concentration-Time Curve (AUC) [Up to 16 samples over 27 months]
PK-Area under the concentration-time curve (AUC)
PK-Concentration of Anti-Sotatercept Antibody in Serum [Up to 16 samples over 27 months]
PK-Concentration of anti-sotatercept antibody in serum
Hgb Level Increase [Up to 27 months]
Hgb level increase during the study treatment compared to the baseline Hgb level in non-transfusion dependent Beta Thalassemia intermedia subjects.
RBC Transfusion Burden [Up to 27 months]
Reduction of transfusion burden by ≥ 20% compared to the calculated baseline transfusion burden for transfusion dependent Beta Thalassemia major and Beta Thalassemia Intermedia subjects.
PK-Serum Concentration of Sotatercept [Up to 16 samples over 27 months]
PK-Serum concentration of sotatercept

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Hopital Henri Mondor	Créteil	France	94010
2	Groupe Hospitalier Henri Mondor	Créteil	France
3	Hospital of Necker	Paris	France	75015
4	Hôpital Necker-Enfants Malades	Paris	France
5	Local Institution - 300	Ampelokipi - Athens	Greece	115 26
6	Laiko General Hospital	Ampelokipi - Athens	Greece	11526
7	Universita degli Studi di Cagliari - ASL8	Cagliari	Italy	09121
8	Universita Degli Studi Di Cagliari	Cagliari	Italy	09121
9	Ospedale Galliera	Genoa	Italy	16128
10	Ente Ospedaliero Ospedali Galliera	Genova	Italy	16128
11	Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Milano	Italy	20122
12	Fondazione IRCCS Ospedale Maggiore	Milano	Italy	20122
13	Local Institution - 100	London	United Kingdom	WC1E 6BT
14	UCL Cancer Institute	London	United Kingdom	WC1E 6BT
15	UCL Cancer Institue	London	United Kingdom	WC1E6BT

Sponsors and Collaborators

Celgene

Investigators

Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Celgene

ClinicalTrials.gov Identifier:

NCT01571635

Other Study ID Numbers:

ACE-011-B-THAL-001
2011-005659-15

First Posted:

Apr 5, 2012

Last Update Posted:

Aug 22, 2022

Last Verified:

Aug 1, 2022

Keywords provided by Celgene

Beta-Thalassaemia

Additional relevant MeSH terms:

Thalassemia

beta-Thalassemia

Study Results

No Results Posted as of Aug 22, 2022