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

Beta Thalassemia Major Clinical Trial

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.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01571635
• Other study ID #: ACE-011-B-THAL-001
• Secondary ID: 2011-005659-15
• Status: Terminated
• Phase: Phase 2
• Start date: October 10, 2012
• Est. completion date: May 24, 2022

Study information

• Verified date: May 2023
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 46
• Est. completion date: May 24, 2022
• Est. primary completion date: July 2, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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.
• 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 (ß-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).

Related Conditions & MeSH terms

• Beta Thalassemia Intermedia
• Beta Thalassemia Major
• beta-Thalassemia
• Thalassemia

Intervention

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.

Locations

Country	Name	City	State
France	Groupe Hospitalier Henri Mondor	Créteil
France	Hopital Henri Mondor	Créteil
France	Hôpital Necker-Enfants Malades	Paris
France	Hospital of Necker	Paris
France	Local Institution - 001	Paris
Greece	Laiko General Hospital	Ampelokipi - Athens
Greece	Local Institution - 300	Ampelokipi - Athens
Italy	Universita Degli Studi Di Cagliari	Cagliari
Italy	Universita degli Studi di Cagliari - ASL8	Cagliari
Italy	Local Institution - 200	Genoa
Italy	Ospedale Galliera	Genoa
Italy	Ente Ospedaliero Ospedali Galliera	Genova
Italy	Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Milano
Italy	Fondazione IRCCS Ospedale Maggiore	Milano
Italy	Local Institution - 201	Milano
United Kingdom	Local Institution - 100	London
United Kingdom	UCL Cancer Institue	London
United Kingdom	UCL Cancer Institute	London

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

France,  Greece,  Italy,  United Kingdom, 

References & Publications (3)

"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 "

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

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Potential Recommended Dose as Determined by Number of Participants Experiencing Dose-Limiting Toxicities and Recommended Dose	Number of participants with dose-limiting toxicities (DLT) are used to determine the potential recommended dose (PRD). PRD is defined as the highest dose with up to 1 out of 6 patients experiencing a DLT. DLT is defined as any side effects of the study treatment serious enough to prevent an increase in dose or level of treatment, including at least one of the following: Hypertension = Grade 3 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0; Hgb > 14 g/dL sustained for four weeks; any NCI CTCAE toxicity = Grade 3. Grade 3 is defined as severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily life.; PRD was identified as 1 mg/kg. Due to study termination, no patients were enrolled after 1 mg/kg cohort or in the Expansion Cohort. Thus, primary analyses to determine recommended dose (RD) were not conducted.	From first dose up to 28 days post the first dose
Secondary	Number of Participants With Red Blood Cell Transfusion Burden Reduction From Baseline During Treatment	Transfusion burden at baseline is defined as the total number of units of RBC transfusions that participants received within 168 days (24 weeks) prior to the first dose of study therapy. Transfusion burden during treatment is defined as the total number of RBC transfusion units that each participant received during the treatment divided by the treatment duration and multiplied by 168 days. The result is a 168-day transfusion burden average. Baseline measurement includes RBC transfusion history for transfusion dependent and non-transfusion dependent participants, starting at 168 days prior to enrollment.	From baseline to the last dose of study treatment (up to approximately 112 months)
Secondary	Number of Participants With Hemoglobin Level Increase From Baseline in Non-Transfusion Dependent B-Thalassemia Intermedia Participants	The Number of participants with a change in Hemoglobin levels will be listed for non-RBC transfusion dependent participants. Baseline assessments are the average of the last two measurements prior to the start of therapy.	Measurements were taken in 9 and 12-week intervals, from baseline up to approximately 112 months
Secondary	Number of Participants Experiencing Adverse Events (AEs)	An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal. Treatment emergent adverse events (TEAE) are defined as an AE that began after the start of trial medication treatment; or if the event was continuous from baseline and was serious, trial medication-related, or resulted in death, discontinuation, or interruption or reduction of trial therapy.	From first dose up to 112 days after the last dose of study treatment (up to 115 months)
Secondary	Concentrations of Sotatercept in Serum	Sotatercept was administered as a subcutaneous injection every 21 days during the Treatment Period. Pharmacokinetic (PK) samples were collected at the pre-specified timepoints.	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
Secondary	Number of Participants With Anti-Drug Antibody (ADA)	The number of participants with Anti-Sotatercept Antibody is a summary of antidrug antibody (ADA) status for ADA-evaluated participants. A participant is counted as 'positive' if there is any positive result captured during the study, a participant is counted as 'negative' if there is no positive result captured during the study. ADA data was collected Day 1 in dose schedules 1 through 6. Starting from Dose 7, ADA was measured at Day 1 every 3 Doses, then finally at the post-treatment follow-up visit at Month 2 and Month 4.	From first dose up to 4 months after last dose (up to approximately 116 months)
Secondary	Number of Participants Experiencing Quality of Life (QOL) Change From Baseline	The number of participants in the expansion cohort experiencing changes from baseline in Quality of Life. QOL was planned to be assessed at Day 168 (6 months) and Day 336 (12 months), after Dose 1 Day 1, independent of Dose Delay for participants enrolled in the Expansion Cohort only. QOL was planned to be calculated using the SF-36 and the FACT Anemia. The SF-36 is a Medical Outcomes Study (MOS) consisting of 36 questions developed to determine health status. The SF-36 measures eight scales: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The FACT Anemia measures fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) Measurement System.; Due to early study termination, no participants were enrolled in the expansion cohort and QOL was not assessed.	From pre-dose up to Dose 8 (168 days/6months) and Dose 16 (336 days/12months) only

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