A Randomized, Double-blind, Placebo-controlled, Phase III, Multi-centre Study of Eltrombopag or Placebo in Combination With Azacitidine in Subjects With IPSS Intermediate-1, Intermediate 2 and High-risk Myelodysplastic Syndromes (MDS) SUPPORT: A StUdy of eltromboPag in myelodysPlastic SyndrOmes Receiving azaciTidine
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 356
- 试验地点
- 1
- 主要终点
- Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy
研究概览
简要总结
Eltrombopag olamine (SB-497115-GR) is an orally bioavailable, small molecule thrombopoietin receptor agonist that may be beneficial in medical disorders associated with thrombocytopenia. Eltrombopag has been shown to increase platelet counts in patients with thrombocytopenia from various etiologies (Idiopathic thrombocytopenic purpura [ITP], liver disease, aplastic anemia and chemotherapy induced thrombocytopenia). Approximately 350 subjects will be randomized in a 1:1 ratio (175 into the eltrombopag arm and 175 into the placebo arm). Approximately 55 subjects will be enrolled into the azacitidine. Subjects with intermediate-1, intermediate-2 or high risk MDS by IPSS, and baseline platelet count of <75 Giga (10^9) per liter (Gi/L) will only be enrolled. This is a randomized, double-blind, parallel group, placebo-controlled study designed to explore the platelet supportive care effects of eltrombopag versus placebo in combination with the standard of care hypomethylating agent, azacitidine. The primary objective of this study is to determine the effect of eltrombopag versus placebo on the proportion of subjects who are platelet transfusion free during the first 4 cycles of azacitidine therapy. Key secondary endpoints include overall survival, disease response, and disease progression.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
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
- •Age >=18 years (For subjects in Taiwan, Age >= 20 years)
- •MDS by World Health Organization (WHO) or French-American-British (FAB) classification
- •Intermediate 1, intermediate 2 or high risk MDS by IPSS
- •At least one platelet count < 75 Gi/L
- •Eastern Cooperative Oncology Group (ECOG) Status 0-2
- •Adequate baseline organ function defined by the criteria below: total bilirubin =< 1.5x the upper limit of normal (ULN) except for Gilbert's syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect [haemolytic] bilirubin in the absence of alanine aminotransferase [ALT] abnormality); ALT =< 2.5xULN; creatinine =< 2.5xULN
- •Subjects with a corrected QT interval (QTc) <450 milliseconds (msec) or <480msec for subjects with bundle branch block. The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF), machine or manual overread. For subject eligibility and withdrawal, QTcF will be used. For purposes of data analysis, QTcF will be used. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period
- •Subject is able to understand and comply with protocol requirements and instructions
- •Subject has signed and dated informed consent
- •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 of first dose of study treatment and agree to use effective contraception during the study and for 3 months following the last dose of study treatment
- •Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from time of randomization until 16 weeks after the last dose of study treatment
- •French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category
排除标准
- •Previous treatment with hypomethylating agent or induction chemotherapy for MDS
- •Proliferative type chronic myelomonocytic leukemia with white blood cell count >12 Gi/L at any time during the 28 days before Day 1
- •History of treatment with eltrombopag, romiplostim or other thrombopoietin receptor (TPO-R) agonists
- •Previous allogeneic stem-cell transplantation
- •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
- •Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of investigational product (eltrombopag/placebo)
- •Active and uncontrolled infections, including hepatitis B or C
- •Human Immunodeficiency Virus (HIV) infection
- •Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or its excipient, or azacitidine, that contraindicates the subjects' participation
- •Pregnant or lactating female
- •Any serious and/or unstable pre-existing medical condition (including any advanced malignancy other than the disease under study), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance with the study procedures
- •French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days
研究组 & 干预措施
Eltrombopag
Eligible subject will receive a starting dose of eltrombopag of 200 milligrams (mg) (100 mg for subjects of East Asian heritage). Dose modifications of eltrombopag will be permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at a safe and effective level (i.e. a level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive azacitidine 75 mg/meter^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
干预措施: Eltrombopag (Drug)
Eltrombopag
Eligible subject will receive a starting dose of eltrombopag of 200 milligrams (mg) (100 mg for subjects of East Asian heritage). Dose modifications of eltrombopag will be permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at a safe and effective level (i.e. a level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive azacitidine 75 mg/meter^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
干预措施: Azacitidine (Drug)
Placebo
Eligible subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
干预措施: Azacitidine (Drug)
Placebo
Eligible subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy
时间窗: 4 cycles (Cycle = 28 days)
A subject is defined as being platelet transfusion independent if they received no platelet transfusions within the first 4 cycles of treatment with azacitidine. Subjects who died or withdrew from investigational product within the first four cycles were treated as failures (i.e. not transfusion independent) in the analysis
次要结局
- Summary of Progression Free Survival From Central Review (ITT)(First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years)
- Overall Survival (OS)(Randomization until death or end of study, approximately 2 years)
- Summary of Progression Free Survival From Investigator Assessment (ITT)(First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years)
- Summary of AML Progression From Investigator Assessment and Central Review (ITT)(First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years)
- Best Disease Response From Investigator Assessment (ITT)(At end of Cycle 6 (cycle=28 days) or end of therapy, whichever came first)
- Best Disease Response From Central Review (ITT)(At end of Cycle 6 (cycle=28 days) or end of therapy, whichever came first)
- Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT)(From Day 1 to 4-week follow-up (samples collected weekly in Cycle 1, Days 1 and 15 in Cycles 2-6 and Day 1 of Cycles >=7))
- Bleeding Adverse Events (AEs) >= Grade 3(From Day 1 to 4-week follow-up up to approximately 2 years)
- Functional Assessment of Chronic Disease Therapy-fatigue Subscale (FACIT-Fatigue) (ITT)(From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years)
- Number of Participants Who Were Platelet Transfusion Independent (ITT Set)(From Day 1 to end of study treatment up to approximately 2 years)
- Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions(From Day 1 to 4-week follow-up up to approximately 2 years)
- Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™)(From Day 1 to 4-week follow-up up to approximately 2 years)
- Medical Resource Utilization (MRU): Event -Hospitalizations Inpatient and Outpatient(From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years)
- Medical Resource Utilization (MRU): Event and Use of Site Specific Medical Resources - Non-study Laboratory Tests(From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years)
- Summary of Post-Hoc Estimates of Steady-state Eltrombopag Cmax and Cmin Pharmacokinetic Parameters for a 50 mg Dose(Cycle 1, Week 2: Pre-dose, 1.5 and 3 hour post dose; Cycle 1, Week 3: 4, 5.5, and 7 hours post dose)
- AUC0-infinity -Pharmacokinetic(s) Parameter of Azacitidine(Cycle 2 Day 1: Pre-dose, 15 min, 0.5, 1, 2 and 4 hr post dose)
- Cmax -Pharmacokinetic Parameter of Azacitidine(Cycle 2 Day 1: Pre-dose, 15 min, 0.5, 1, 2 and 4 hr post dose)
- Medical Resource Utilization (MRU): Use of Site Specific Medical Resources(From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years)
- Summary of Post-Hoc Estimates of Steady-state Eltrombopag AUC0 Infinity Pharmacokinetic Parameters for a 50 mg Dose(Cycle 1, Week 2: Pre-dose, 1.5 and 3 hour post dose; Cycle 1, Week 3: 4, 5.5, and 7 hours post dose)