A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia (Part 1: Open-label, Part 2: Randomized, Double-blind, Part 3: Extension)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 162
- 试验地点
- 1
- 主要终点
- Number of Participants With Platelet Response up to Week 8 During Part 1
研究概览
简要总结
This was a worldwide, three-part (Part 1: open-label, Part 2: randomized, double-blind, Part 3: extension), multi-center study to evaluate the effect of eltrombopag in subjects with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have thrombocytopenia due to bone marrow insufficiency from their underlying disease or prior chemotherapy. This objective was assessed by a composite primary endpoint that consists of the following: the proportion of ≥Grade 3 hemorrhagic adverse events, or platelet counts <10 Gi/L, or platelet transfusions. Patients with MDS or AML and Grade 4 thrombocytopenia due to bone marrow insufficiency from their underlying disease or prior chemotherapy were enrolled in the study. No low or intermediate-1 risk MDS subjects were enrolled in the study. Subjects must have had at least one of the following during the 4 weeks prior to enrolment: platelet count <10 Gi/L, platelet transfusion, or symptomatic hemorrhagic event. Supportive standard of care (SOC), including hydroxyurea, was allowed as indicated by local practice throughout the study. The study had 3 sequential parts. Subjects who were enrolled in Part 1 (open-label) cannot be enrolled in Part 2 of the study (randomized, double-blind); however, subjects who completed the treatment period for Part 1 or Part 2 (8 and 12 weeks, respectively) continued in Part 3 (extension) if the investigator determined that the subject was receiving clinical benefit on treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Supportive Care
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 110 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult subjects (18 years of age or older) with MDS or AML (bone marrow blasts ≤50%) with thrombocytopenia due to bone marrow insufficiency from the disease or prior treatment. Subjects with transient thrombocytopenia due to active treatment with disease modifying agents or chemotherapy (except for hydroxyurea) are excluded.
- •Subjects must have Grade 4 thrombocytopenia (platelet counts <25 Gi/L) due to bone marrow insufficiency (or Grade 4 thrombocytopenia, but platelet count greater than or equal to 25 Gi/L due to platelet transfusion). In addition, subjects must have had at least one of the following during the 4 week screening period: platelet transfusion, or symptomatic bleeding or platelet count <10 Gi/L. Subjects whose thrombocytopenia below 10 Gi/L is due to causes other than bone marrow insufficiency (e.g., fever, infection, autoimmune disease) are not eligible.
- •Subjects must have platelet count, bleeding and platelet transfusion data available over a period of at least 4 weeks prior to randomization.
- •Prior systemic treatment for malignancy, with the exception of hydroxyurea, must have been discontinued prior to entry into the study: at least 4 weeks before Day 1 for the following: chemotherapy, demethylating agents (azacitidine or decitabine), lenalidomide, thalidomide, clofarabine and IL-11(oprelvekin); at least 8 weeks before Day 1 for antithymocyte/antilymphocyte globulin.
- •Subjects with a prior stem cell transplant (SCT) must have relapsed after the SCT.
- •Subjects must be stable and, in the opinion of the investigator, be expected to complete a 12 week treatment period.
- •ECOG Status 0-
- •Subject must be able to understand and comply with protocol requirements and instructions.
- •Subject has signed and dated an informed consent form.
- •Adequate baseline organ function defined by the criteria below: total bilirubin ≤ 1.5xULN except for Gilbert's syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect (hemolytic) bilirubin in the absence of ALT abnormality), ALT ≤ 3xULN, creatinine ≤ 2.5xULN
- •Women must be either of non-child bearing potential or women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the first dose of study treatment.
- •In France, a subject eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
排除标准
- •Subjects with MDS and an IPSS of low or intermediate-1 risk at screening.
- •Subjects with a diagnosis of acute promyelocytic or megakaryocytic leukemia or AML secondary to a myeloproliferative neoplasm.
- •History of treatment with romiplostim or other TPO-R agonists.
- •Subjects with a QTc >480 msec (QTc >510 msec for subjects with Bundle Branch Block).
- •Leukocytosis ≥25,000/uL on Day 1 of treatment with study medication.
- •Subjects with known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator.
- •Female subjects who are nursing or pregnant (positive serum or urine β-human chorionic gonadotropin [β-hCG] pregnancy test) at screening or pre-dose on Day
- •Current alcohol or drug abuse.
- •Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
- •Active and uncontrolled infections (e.g. sepsis, hepatitis B, hepatitis C).
- •Subjects infected with Human Immunodeficiency Virus (HIV).
- •Subjects with liver cirrhosis (as determined by the investigator).
- •Subjects receiving or planned to receive any prohibited medication.
- •Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or excipient (microcrystalline cellulose, mannitol, polyvinylpyrrolidone, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol 400 and polysorbate 80) that contraindicates the subjects' participation.
- •In France, subjects who have participated in any study using an investigational drug during the previous 30 days.
研究组 & 干预措施
Part 1, Open Label
100 mg daily (50 mg for subjects of East Asian heritage), intrasubject dose escalations to a maximum dose 300 mg (150 mg for subjects of East Asian heritage) are allowed.
干预措施: eltrombopag (Drug)
Part 2, eltrombopag arm
100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)
干预措施: eltrombopag (Drug)
Part 2, placebo arm
100 mg matching placebo daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg matching placebo (150 mg for subjects of East Asian heritage)
干预措施: placebo (Drug)
part 3 extension
100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)
干预措施: eltrombopag (Drug)
结局指标
主要结局
Number of Participants With Platelet Response up to Week 8 During Part 1
时间窗: From Baseline up to Week 8 during Part 1
A participant was considered as a responder if he/she met the following response criteria: a Baseline platelet count \<20 Giga cells per liter (Gi/L) and a post-Baseline increased to \>20 Gi/L and at least 2 times the Baseline value; or a Baseline platelet count \>=20 Gi/L and a post-Baseline absolute platelet count increased to \>=50 Gi/L and at least 2 times the Baseline value. The response criteria was evaluated at each visit. Increase in platelet count observed up to 3 days after a platelet transfusion was not considered as a platelet response. The Part 1 Population was comprised of all participants enrolled into Part 1.
Clinically Relevant Thrombocytopenic Events (CRTE) From Week 5 up to Week 12 During Part 2
时间窗: From Week 5 up to Week 12 during Part 2
A participant was considered to have a CRTE at a given assessment if he/she had platelet counts \<10 Gi/L, or platelet transfusions, or \>=Grade 3 hemorrhagic adverse events. CRTEs during Weeks 5 to 12 were compared between treatments using a generalized linear mixed model. Average of weekly proportion of subjects with CRTE during Week 5 to 12 was estimated for each treatment. Intent to Treat (ITT) Population was comprised of all randomized participants during Part 2.
次要结局
- Summary of Health Outcomes(week 12)
- EQ-5D Utility Score Analysis(Change from baseline, up to week 12)
- Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 1 Subjects)(Day 1 to week 8)
- Change in Mean Platelet Count(Baseline to Week 12)
- Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 2 Subjects)(Day 1 to week 12)
- Hematologic Improvement(Weeks 5 to 12)
- Number of Participants With Maximum Bleeding Grade According to World Health Organization on Bleeding Scale(Weeks 5 to 12)
- Functional Assessment of Cancer Therapy (FACT)(Change from baseline, up to week 12)
- Maximum Duration of Platelet Transfusion Independence(Weeks 5 to 12)
- Mean Number of Platelet Transfusions(Weeks 5 to 12)
- Independent Reviewer-Assessed Best Response(up to week 12)
- Independent Reviewer Assessed Disease Progression(Up to week 12)
- Median Overall Survival(Up to 13 months)