A Non-randomized, Open Label, Multi-center, Phase II Study to Assess the Safety and Efficacy of Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin (r-ATG) and Cyclosporine A (CsA) in East-Asian Patients With Treatment Naive Severe Aplastic Anemia (REACTS)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 36
- 试验地点
- 12
- 主要终点
- Complete Response (CR) Rate at Week 26
研究概览
简要总结
This study was designed to evaluate the efficacy and safety of eltrombopag when added to r-ATG and CsA in treatment naive East-Asian adult and pediatric patients with severe aplastic anemia (SAA).
详细描述
This was a non-randomized, open label, single arm, multi-center, Phase II study to evaluate the efficacy and safety of eltrombopag in combination with immunosuppressive therapy (IST) regimen of r-ATG + CsA in East-Asian patients with severe aplatsic anemia who had not received prior IST.
Eligible participants were enrolled into the study and received eltrombopag (from Day 1 to Week 26) concomitantly with r-ATG (on Days 1-5) and CsA (from Day 1 to Week 26) in the core treatment part.
Participants who were assessed as responders (meeting complete (CR) or partial (PR) response criteria) at Week 26 were eligible for the extension part of the study and continued treatment with eltrombopag and CsA after Week 26 up to Week 52. During the extension part, eltrombopag treatment was provided up to Week 52. CsA was maintained or tapered at the investigator's discretion according to local practice, with a total duration of at least 2 years (18 months after Week 26). There was a 30 days after end of treatment safety follow-up at the end of the extension part.
All participants were offered to enter the long term follow-up after the discontinuation of eltrombopag, with yearly efficacy and clonal evolution assessments up to Year 3 (Week 156).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Years 至 100 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written study informed consent and (where applicable) assent from the subject, parent, or guardian must be obtained prior to participation in the study.
- •Subjects of East Asian ethnicity aged ≥ 6 years old at the time of written informed consent and assent form (if applicable).
- •SAA characterized by:
- •Bone marrow cellularity < 25%, or 25-50% with < 30% residual hematopoietic cells and pancytopenia, with at least two of the following parameters in peripheral blood:
- •Absolute neutrophil count < 0.5×109/L
- •Platelet count < 20×109/L
- •Absolute reticulocyte count < 20×109/L
- •HSCT not suitable or available as a treatment option (determined as per local practices or national guidelines), or has been refused by subject.
排除标准
- •Prior IST with any ATG/ALG , alemtuzumab, high dose cyclophosphamide (≥ 45 mg/kg/day), CsA within 6 months, or prior thrombopoietin receptor agonists.
- •Eastern Cooperative Oncology Group (ECOG) performance status (age ≥ 16 years) >2, or Lansky performance status (age < 16 years) <
- •Prior and/or active medical history of:
- •Known underlying congenital/inherited bone marrow failure or aplastic anemia (e.g.,such as but not limited to Fanconi anemia, congenital dyskeratosis, congenital amegakaryocytic thrombocytopenia, or Shwachman-Diamond Syndrome)
- •Symptomatic paroxysmal nocturnal hemoglobinuria (PNH) and/or PNH clones >50% of polymorphonuclear neutrophil (PMN) or RBC at time of enrollment
- •Myelodysplastic syndrome (MDS)
- •Any cytogenetic abnormalities on karyotyping or FISH within 30 days of study enrollment (an evaluable karyotyping with at least 10 metaphases is mandatory for eligibility)
- •Other known or suspected underlying primary immunodeficiency
- •Any concomitant malignancies that have not fully recovered from treatment or have not been disease-free for 5 years
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN).
- •Creatinine ≥ 2.5×local ULN
- •Past medical history of thromboembolism within 6 months, and/or prior or current antiphospholipid antibody syndrome (APS).
- •Presence of clinically active uncontrolled significant (of such severity that it would preclude the subject's ability to consent, be compliant with study procedures, tolerate protocol therapy) infection, including bacterial, fungal, mycobacterial, parasitic or viral infection, or any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the subject or compliance with the protocol
- •Any severe and/or uncontrolled medical conditions which could cause unacceptable safety risks or compromise compliance with the protocol, such as:
- •Known hepatocellular disease (e.g. active hepatitis or cirrhosis)
- •Impairment of gastrointestinal (GI) function or gastrointestinal disease that may significantly alter the absorption of study treatment (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
- •Active skin, mucosa, ocular or GI disorders of Grade > 1
- •Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening. A positive serology for Hepatitis B (HB) is considered as a positive test for HBsAg. In addition, if serology is negative for HBsAg but hepatitis B core antibody (HBcAb) is positive (regardless of hepatitis B surface antibody (HBsAb) status), a hepatitis B virus (HBV) DNA test will be performed and if positive the patient will be excluded.
- •Cardiac disorder (subjects with congestive heart disease of New York Heart Association (NYHA) functional classification Grade II/III/IV (for pediatric subjects, refer to the Grade II/III/IV of Modified ross heart failure classification for Children) should not be enrolled; subjects with NYHA Grade II due to cardiac disorder should not be enrolled but those with NYHA Grade II due to aplastic anemia (AA) may be enrolled.), arrhythmia with a risk of thrombosis (e.g. atrial fibrillation), pulmonary hypertension, or uncontrolled hypertension (>180/100 mmHg).
研究组 & 干预措施
eltrombopag
Participants received eltrombopag in combination with r-ATG and CsA.
- Eltrombopag was administered orally once daily with initial doses of 75mg/day for ≥ 12 years old and 37.5 mg/day for participants between ≥ 6 and < 12 years. Doses could be adjusted based on platelet count
- r-ATG was administered intravenously at a dose of 2.5 to 3.5 mg/kg/day on Days 1-5
- CsA was administered orally every 12 h at a starting dose of 3-6 mg/kg/day
干预措施: eltrombopag (Drug)
eltrombopag
Participants received eltrombopag in combination with r-ATG and CsA.
- Eltrombopag was administered orally once daily with initial doses of 75mg/day for ≥ 12 years old and 37.5 mg/day for participants between ≥ 6 and < 12 years. Doses could be adjusted based on platelet count
- r-ATG was administered intravenously at a dose of 2.5 to 3.5 mg/kg/day on Days 1-5
- CsA was administered orally every 12 h at a starting dose of 3-6 mg/kg/day
干预措施: rabbit anti-thymocyte globulin (r-ATG) (Drug)
eltrombopag
Participants received eltrombopag in combination with r-ATG and CsA.
- Eltrombopag was administered orally once daily with initial doses of 75mg/day for ≥ 12 years old and 37.5 mg/day for participants between ≥ 6 and < 12 years. Doses could be adjusted based on platelet count
- r-ATG was administered intravenously at a dose of 2.5 to 3.5 mg/kg/day on Days 1-5
- CsA was administered orally every 12 h at a starting dose of 3-6 mg/kg/day
干预措施: cyclosporine A (CsA) (Drug)
结局指标
主要结局
Complete Response (CR) Rate at Week 26
时间窗: Week 26 (6 months after starting study treatment)
Complete response rate was defined as percentage of patients achieving complete response (CR). Complete response was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart: * Absolute neutrophil count \> 1.0 ×10\^9/L * Platelet count \> 100 ×10\^9/L * Hemoglobin \> 100 g/L The participants who discontinued from the trial before Week 26 and those that received blood products prior to response assessment (7 days prior for platelet transfusions, 14 days for RBC transfusion and 21 days for growth factors) were treated as non-responders.
次要结局
- Complete Response (CR) Rate(Week 13 (3 months), Week 52 (12 months) and yearly after up to 3 years)
- Overall Response (ORR) Rate(Week 13 (3 months), 26 weeks (6 months), 52 weeks and yearly after up to 3 years)
- Duration of Complete Response(Up to aproximately 3 years)
- Duration of Overall Response(Up to aproximately 3 years)
- Overall Survival (OS)(Up to approximately 3 years)
- Overall Survival (OS) Rate(Week 26, Week 52 and yearly after up to 3 years)
- Red Blood Cells (RBC) and Platelet Transfusion-free Interval Before Week 13 and 26(Week 13, 26)
- Percentage of Participants Who Become RBC Transfusion Independent(From date of first dose to approximately 3 years)
- Percentage of Participants Who Become Platelet Transfusion Independent(From date of first dose to approximately 3 years)
- Time From the Date of First Dose of Investigational Treatment to the Date of First Occurrence of Any Clonal Evolution Events(From date of first dose to approximately 3 years)
- Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: AUClast(Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose)
- Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: AUCtau(Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose)
- Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Ctrough(Pre-dose on day 15 after initation of eltrombopag and and pre-dose on the 15th day after each new dose up to week 26)
- Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Cmax(Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose)
- Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: CLss/F(Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose)
- Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Tmax(Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose)