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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Celgene Corporation
Sponsor:
Information provided by (Responsible Party):
Celgene Corporation
ClinicalTrials.gov Identifier:
NCT01571635
First received: April 3, 2012
Last updated: September 9, 2014
Last verified: September 2014
  Purpose

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


Condition Intervention Phase
Beta Thalassemia Major
Beta Thalassemia Intermedia
Drug: Dose level 1a
Drug: Dose level 1b
Drug: Dose level 2
Drug: dose level 3
Drug: dose level 4
Drug: dose level 5
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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 (β)-Thalassemia

Resource links provided by NLM:


Further study details as provided by Celgene Corporation:

Primary Outcome Measures:
  • Potential Recommended Dose (PRD) [ Time Frame: Up to 27 months ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Up to 27 months ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 27 months ] [ Designated as safety issue: No ]
    Assess the reduction of transfusion burden in transfusion dependent Beta-Thalassemia major and Intermedia subjects.

  • Number of Participants with Adverse Events [ Time Frame: Up to 27 months ] [ Designated as safety issue: Yes ]
    Number of participants with adverse events

  • PK-Observed Maximum Concentration (Cmax) [ Time Frame: Up to 16 samples over 27 months ] [ Designated as safety issue: No ]
    PK-observed maximum concentration (Cmax)

  • PK-Time to Maximum Concentration (Tmax) [ Time Frame: Up to 16 samples over 27 months ] [ Designated as safety issue: No ]
    PK-Time to maximum concentration (Tmax)

  • PK-Area Under the Concentration-Time Curve (AUC) [ Time Frame: Up to 16 samples over 27 months ] [ Designated as safety issue: No ]
    PK-Area under the concentration-time curve (AUC)

  • PK-Concentration of Anti-Sotatercept Antibody in Serum [ Time Frame: Up to 16 samples over 27 months ] [ Designated as safety issue: No ]
    PK-Concentration of anti-sotatercept antibody in serum

  • Hgb Level Increase [ Time Frame: Up to 27 months ] [ Designated as safety issue: No ]
    To assess the Hgb level increase from baseline in non-transfusion dependent Beta Thalassemia intermedia subjects.

  • SF 36 Quality of Life questionaire [ Time Frame: Up to 27 months ] [ Designated as safety issue: No ]
    The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Norm-based scores were used in analyses, higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from Baseline score indicates an improvement. (User's manual for the SF-36v2 health survey, 3rd edition, Maruish, 2011).

  • Fact-Anemia Questionnaire [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
    The Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire (Yellen, 1997) was used to assess health-related quality of life (HRQoL). In addition to general HRQoL, the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning. Patients with higher hemoglobin levels and better performance status reported significantly higher scores on these instruments (including the newly created subscales) than did those with lower hemoglobin levels and poorer performance status (Yellen, 1997)


Estimated Enrollment: 85
Study Start Date: March 2012
Estimated Study Completion Date: April 2016
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Starting Dose - Dose Level 1a
Experimental 0.1 mg/kg (dose level 1a) - Starting dose 0.1 mg/kg to 1.5 mg/kg. Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period
Drug: Dose level 1a
Experimental: Starting Dose - Dose level 1b
Experimental 0.3 mg/kg (dose level 1b) - Starting dose 0.1 mg/kg to 1.5 mg/kg. Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period
Drug: Dose level 1b
Experimental: Escalation dose - dose level 2
Experimental 0.5 mg/kg (dose level 2) - Escalation dose 0.1 mg/kg to 1.5 mg/kg. Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period
Drug: Dose level 2
Experimental: Escalation dose - dose level 3
Experimental 0.75 mg/kg (dose level 3) - Escalation dose 0.1 mg/kg to 1.5 mg/kg. Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period
Drug: dose level 3
Experimental: Escalation dose - dose level 4
Experimental 1.0 mg/kg (dose level 4) - Escalation dose 0.1 mg/kg to 1.5 mg/kg. Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period
Drug: dose level 4
Experimental: Escalation dose - dose level 5
Experimental 1.5 mg/kg (dose level 5) - Escalation dose 0.1 mg/kg to 1.5 mg/kg. Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period
Drug: dose level 5

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  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 per 30 days of pRBCs (Gale, 2011) confirmed for a minimum of 168 days (six months) immediately preceding enrollment (study 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, occurring within 168 days immediately preceding enrollment due to concurrent illness [e.g. infection], [Guidelines Clin Management of Thalassaemia, 2008]).
  4. Performance status: Eastern Cooperative Oncology Group (ECOG) score of 0 to 1.
  5. No concurrent severe hepatic disease:

    • Aspartate aminotransferase (AST) or alanine aminotransferase (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 (β-HCG) pregnancy test within 3 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 of childbearing potential 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 (ie, 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 FCBPs 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.

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

  1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from 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 hydroxyurea treatment for which the dose was changed in the last one year prior to subject enrollment.
  9. Subjects on long-term anticoagulant therapy, such as heparin or warfarin.
  10. Subjects who started bisphosphonates within the last three months prior to 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 > 3 x 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 (Appendix C).
  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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01571635

Contacts
Contact: Pierre Caron +33 (0)6 22 64 76 42 pcaron@celgene.com

Locations
France
Groupe Hospitalier Henri Mondor Recruiting
Créteil, France
Contact: Prof. Frederic Galacteros, MD    +33.(0)1.49.81.24.40    frederic.galacteros@hmn.aphp.fr   
Hôpital Necker-Enfants Malades Recruiting
Paris, France
Contact: Prof. Olivier Hermine, MD    +33.(0)1.44.49.52.82    olivier.hermine@nck.aphp.fr   
Greece
Laiko General Hospital Recruiting
Athens, Greece, GR11526
Italy
Universita Degli Studi Di Cagliari Recruiting
Cagliari, Italy, 09121
Ente Ospedaliero Ospedali Galliera Recruiting
Genova, Italy, 16128
Fondazione IRCCS Ospedale Maggiore Recruiting
Milano, Italy, 20122
Lebanon
American University of Beirut Medical Not yet recruiting
Beirut, Lebanon, 11-0236
United Kingdom
UCL Cancer Institue Recruiting
London, United Kingdom, WC1E6BT
Sponsors and Collaborators
Celgene Corporation
Investigators
Study Director: Abderrahmanne Laadem, CRP Celgene Corporation
  More Information

No publications provided

Responsible Party: Celgene Corporation
ClinicalTrials.gov Identifier: NCT01571635     History of Changes
Other Study ID Numbers: ACE-011-B-THAL-001, 2011-005659-15
Study First Received: April 3, 2012
Last Updated: September 9, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Italy: Ethics Committee
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Greece: National Organization of Medicines
France: Agence Nationale de Sécurité du Médicament et des produits de santé

Keywords provided by Celgene Corporation:
Beta-Thalassaemia

Additional relevant MeSH terms:
Beta-Thalassemia
Thalassemia
Anemia
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Hematologic Diseases
Hemoglobinopathies

ClinicalTrials.gov processed this record on October 20, 2014