A Phase 2A, Open-label Dose Finding Study to Determine the Safety and Tolerability of Sotatercept (ACE-011) in Adults With BETA(b)-THALASSEMIA.
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- Celgene
- 入组人数
- 46
- 试验地点
- 18
- 主要终点
- Potential Recommended Dose as Determined by Number of Participants Experiencing Dose-Limiting Toxicities and Recommended Dose
研究概览
简要总结
Dose finding study to determine the safety and tolerability of Sotatercept (ACE-011) in adults with Beta (β)-Thalassemia
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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).
研究组 & 干预措施
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
干预措施: SOTATERCEPT (ACE-011) (Drug)
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
干预措施: SOTATERCEPT (ACE-011) (Drug)
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
干预措施: SOTATERCEPT (ACE-011) (Drug)
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
干预措施: SOTATERCEPT (ACE-011) (Drug)
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
干预措施: SOTATERCEPT (ACE-011) (Drug)
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
干预措施: SOTATERCEPT (ACE-011) (Drug)
结局指标
主要结局
Potential Recommended Dose as Determined by Number of Participants Experiencing Dose-Limiting Toxicities and Recommended Dose
时间窗: From first dose up to 28 days post the first 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.
次要结局
- Number of Participants With Red Blood Cell Transfusion Burden Reduction From Baseline During Treatment(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(Measurements were taken in 9 and 12-week intervals, from baseline up to approximately 112 months)
- Number of Participants Experiencing Adverse Events (AEs)(From first dose up to 112 days after the last dose of study treatment (up to 115 months))
- Concentrations of Sotatercept in Serum(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 Experiencing Quality of Life (QOL) Change From Baseline(From pre-dose up to Dose 8 (168 days/6months) and Dose 16 (336 days/12months) only)
- Number of Participants With Anti-Drug Antibody (ADA)(From first dose up to 4 months after last dose (up to approximately 116 months))