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

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

Official Title
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A Phase 2A, Open-label Dose Finding Study to Determine the Safety and Tolerability of Sotatercept (ACE-011) in Adults With BETA(b)-THALASSEMIA.

Conditions
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Beta Thalassemia Major, Beta Thalassemia Intermedia

Intervention / Treatment
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* Drug: SOTATERCEPT (ACE-011)


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 | 
| 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) | 
| 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 | 
| 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) | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Beta-Thalassaemia