A Phase 1/1b, Open-label Study of Pevonedistat (MLN4924, TAK-924) as Single Agent and in Combination With Azacitidine in Adult East Asian Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 23
- 试验地点
- 5
- 主要终点
- Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
The purpose of this study is to evaluate the safety and tolerability of pevonedistat administered as a single agent and in combination with azacitidine in adult east Asian participants with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).
详细描述
The drug being tested in this study is called Pevonedistat. Pevonedistat is being tested to treat people with myelodysplastic syndromes MDS (including nonproliferative chronic myelomonocytic leukemia [CMML]) and AML (acute myeloid leukaemia) as a single-agent and in combination treatment with azacitidine. This study will look at the safety and tolerability, the recommended phase 2/phase 3 dose of pevonedistat administered in combination with azacitidine, pharmacokinetics and response to treatment in participants who take single agent pevonedistat compared to participants who take pevonedistat and azacitidine.
The study will enroll approximately 37 participants. Participants will be assigned into one of the four treatment groups which will remain disclosed to the patient and study doctor during the study. Participants will be first enrolled at single-agent low dose level (25 mg/m^2). If this dose is tolerable, participants will be enrolled in parallel at single-agent higher dose level (44 mg/m^2) and in combination treatment cohorts.
- Pevonedistat 25 mg/m^2
- Pevonedistat 44 mg/m^2
- Pevonedistat 10 mg/m^2 and azacitidine 75 mg/m^2 combination
- Pevonedistat 20 mg/m^2 and azacitidine 75 mg/m^2 combination Participants will receive pevonedistat infusion intravenously and azacitidine via intravenous or subcutaneous route.
This multi-center trial will be conducted in Japan, Korea and Taiwan. The overall time to participate in this study is approximately 24 months. Participants will attend the End of Study (EOS) visit for safety, 30 days after receiving their last dose of study drug or before the start of subsequent antineoplastic therapy (other than hydroxyurea).
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Arm 2, Cohort 1: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2
Pevonedistat 10 mg/m^2, 60-minute infusion, intravenously, on Days 1, 3, and 5 and azacitidine 75 mg/m^2, on Days 1 to 5, and Days 8 and 9, intravenously or subcutaneously, followed by a rest period of 19 days, in 28-day treatment cycles.
干预措施: Pevonedistat 10 mg/m^2 (Drug)
Arm 1, Cohort 1: Pevonedistat 25 mg/m^2
Pevonedistat, 25 milligram per square meter (mg/m^2), 60-minute infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in 21-day treatment cycles.
干预措施: Pevonedistat 25 mg/m^2 (Drug)
Arm 1, Cohort 2: Pevonedistat 44 mg/m^2
Pevonedistat, 44 mg/m^2, 60-minute infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in 21-day treatment cycles.
干预措施: Pevonedistat 44 mg/m^2 (Drug)
Arm 2, Cohort 1: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2
Pevonedistat 10 mg/m^2, 60-minute infusion, intravenously, on Days 1, 3, and 5 and azacitidine 75 mg/m^2, on Days 1 to 5, and Days 8 and 9, intravenously or subcutaneously, followed by a rest period of 19 days, in 28-day treatment cycles.
干预措施: Azacitidine 75 mg/m^2 (Drug)
Arm 2, Cohort 2: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2
Pevonedistat 20 mg/m^2, 60-minute infusion, intravenously, on Days 1, 3, and 5 and azacitidine 75 mg/m^2, on Days 1 to 5, and Days 8 and 9, intravenously or subcutaneously, followed by a rest period of 19 days, in 28-day treatment cycles.
干预措施: Pevonedistat 20 mg/m^2 (Drug)
Arm 2, Cohort 2: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2
Pevonedistat 20 mg/m^2, 60-minute infusion, intravenously, on Days 1, 3, and 5 and azacitidine 75 mg/m^2, on Days 1 to 5, and Days 8 and 9, intravenously or subcutaneously, followed by a rest period of 19 days, in 28-day treatment cycles.
干预措施: Azacitidine 75 mg/m^2 (Drug)
结局指标
主要结局
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
时间窗: From first dose through 30 days after the last dose of study drug: single agent arms (up to Cycle 19 [up to Day 429]) (Cycle=21 days); combination arms (up to Cycle 65 [up to Day 1850]) (Cycle=28 days)
Number of Participants With Dose Limiting Toxicities (DLTs) Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 During Cycle 1
时间窗: Cycle 1 (Cycle length = 21 days [single agent arms]; 28 days [combination arms])
DLT: Any of following events considered possibly related to study drug(s) by investigator: Grade (G) 3 or greater nausea and/or emesis despite use of optimal antiemetic prophylaxis; G3 diarrhea occurred despite maximal supportive therapy; G3 arthralgia/myalgia despite use of optimal analgesia; G3 nonhematologic toxicity with exceptions: 1) Brief fatigue, 2) hypophosphatemia; Persistent elevations of transaminases/bilirubin above G2 beyond 2 days between doses; Other study drug-related nonhematologic toxicities G2 or greater, required a dose reduction/discontinuation of pevonedistat. G3 or greater hematologic toxicities, including G3 or 4 febrile neutropenia, considered DLTs if: A delay in initiation of Cycle 2 due to lack of adequate recovery from treatment-related toxicity: 1) Of more than (\>) 4 weeks due to hematologic toxicity believed not related to leukemic infiltration. Bone marrow (BM) evaluation may have been required. 2) Of \>2 weeks due to nonhematologic toxicities.
Number of Participants With Clinically Significant Abnormal Laboratory Values
时间窗: Baseline up to Cycle 19 (up to Day 399) in single agent arms (Cycle=21days) and Cycle 65 (up to Day 1820) in combination arms (Cycle=28 days)
Cmax: Maximum Observed Plasma Concentration for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 1
时间窗: Cycle 1 Day 1: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])
Cmax: Maximum Observed Plasma Concentration for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 5
时间窗: Cycle 1 Day 5: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 5
时间窗: Cycle 1 Day 5: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])
CL: Total Clearance for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 1
时间窗: Cycle 1 Day 1: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])
CL: Total Clearance for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 5
时间窗: Cycle 1 Day 5: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])
次要结局
- Overall Response Rate (ORR) for Participants With AML(From first dose up to 30 days after last dose of study drug or before start of subsequent antineoplastic therapy, whichever comes earlier up to Cycle 19 (up to Day 429, single agent)(Cycle=21 days) and Cycle 65 (up to Day 1850, combination)(Cycle=28 days))
- ORR for Participants With MDS(From first dose up to 30 days after last dose of study drug or before start of subsequent antineoplastic therapy, whichever comes earlier up to Cycle 19 (up to Day 429, single agent)(Cycle=21 days) and Cycle 65 (up to Day 1850, combination)(Cycle=28 days))
- Percentage of Participants With CR for Participants With AML(From first dose up to 30 days after last dose of study drug or before start of subsequent antineoplastic therapy, whichever comes earlier up to Cycle 19 (up to Day 429, single agent)(Cycle=21 days) and Cycle 65 (up to Day 1850, combination)(Cycle=28 days))
- Percentage of Participants With CR for Participants With MDS(From first dose up to 30 days after last dose of study drug or before start of subsequent antineoplastic therapy, whichever comes earlier up to Cycle 19 (up to Day 429, single agent)(Cycle=21 days) and Cycle 65 (up to Day 1850, combination)(Cycle=28 days))