A Phase I Study to Evaluate the Safety and Tolerability and Pharmacokinetic/Pharmacodynamics of MK-8242 Administered Alone and in Combination With Chemotherapy in Subjects With Refractory or Recurrent Acute Myelogenous Leukemia (Protocol No. P07649 (005))
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 26
- 主要终点
- Number of Participants With Complete Remission With Incomplete Marrow Recovery (CRi) at RP2D
研究概览
简要总结
This is a study of MK-8242 alone and in combination with cytarabine in adult participants with refractory or recurrent acute myelogenous leukemia (AML). The study will have 2 Arms. Arm A is for participants with refractory or recurrent AML who are considered ineligible for standard chemotherapy. In Part 1 of Arm A, participants will receive MK-8242 monotherapy in escalating doses to determine the recommended phase 2 dose [RP2D]. In Part 2, participants will receive monotherapy with MK-8242 to confirm the RP2D and assess preliminary efficacy. Arm B is for participants with recurrent AML following an initial complete remission (CR) or CR with incomplete marrow recovery (CRi) of 6 to 12 months duration. In Part 1 of Arm B, participants will receive MK-8242 in escalating doses + cytarabine to determine the RP2D in combination with cytarabine. In Part 2, participants will receive MK-8242 + cytarabine to confirm the RP2D and assess preliminary efficacy. The pharmacokinetics of MK-8242 will be studied in both arms. With Amendment 4 (22 August 2013) a 21-day dosing cycle is added, with MK-8242 being given on Days 1-7 of each 21-day cycle in both the monotherapy and combination therapy arms; data from Arm A will be used to determine whether a participant receives 21-day or 28-day therapy in Arm B.
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
Pt 1 Arm A: MK-8242 30 mg QD
Participants received MK-8242 30 mg once daily (QD) monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles in Part 1 Arm A.
干预措施: MK-8242 (Drug)
Pt 1 Arm A: MK-8242 60 mg QD
Participants received MK-8242 60 mg QD monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles in Part 1 Arm A.
干预措施: MK-8242 (Drug)
Pt 1 Arm A: MK-8242 120 mg QD
Participants received MK-8242 120 mg QD monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles in Part 1 Arm A.
干预措施: MK-8242 (Drug)
Pt 1 Arm A: MK-8242 250 mg QD
Participants received MK-8242 250 mg QD monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles in Part 1 Arm A.
干预措施: MK-8242 (Drug)
Pt 1 Arm A: MK-8242 120 mg BID
Participants received MK-8242 120 mg twice daily (BID) monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 120 mg was administered QD in the morning) in Part 1 Arm A.
干预措施: MK-8242 (Drug)
Pt 1 Arm A: MK-8242 170 mg BID
Participants received MK-8242 170 mg BID monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 170 mg was administered QD in the morning) in Part 1 Arm A.
干预措施: MK-8242 (Drug)
Pt 1 Arm A: MK-8242 210 mg BID
Participants received MK-8242 210 mg BID monotherapy on Days 1-7 of a 21-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 210 mg was administered QD in the morning) in Part 1 Arm A.
干预措施: MK-8242 (Drug)
Pt 1 Arm A: MK-8242 250 mg BID
Participants received MK-8242 250 mg BID monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 250 mg was administered QD in the morning) in Part 1 Arm A.
干预措施: MK-8242 (Drug)
Pt 1 Arm A: MK-8242 300 mg BID
Participants received MK-8242 300 mg BID monotherapy on Days 1-7 of a 21-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 300 mg was administered QD in the morning) in Part 1 Arm A.
干预措施: MK-8242 (Drug)
结局指标
主要结局
Number of Participants With Complete Remission With Incomplete Marrow Recovery (CRi) at RP2D
时间窗: End of Treatment (up to 198 days)
Clinical activity of MK-8242 given as monotherapy in participants with refractory or recurrent AML measured as participants who achieved CRi according to Cheson (2003) criteria at the RP2D. The outcome analysis was not performed since the RP2D for MK-8242 monotherapy could not be established due to early termination of the study.
Number of Participants With Complete Remission (CR) at RP2D
时间窗: End of Treatment (up to 198 days)
Clinical activity of MK-8242 given as monotherapy in participants with refractory or recurrent AML measured as participants who achieved CR according to Cheson (2003) criteria at the RP2D. The outcome analysis was not performed since the RP2D for MK-8242 monotherapy could not be established due to early termination of the study.
Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Up to 28 days (Cycle 1) for non-hematologic toxicities and 42 days (Cycle 1) for hematologic toxicities
DLTs were identified using Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 for toxicities attributable to the study drug. Hematologic DLTs were defined in the absence of morphological evidence of acute leukemia in the marrow if 1) bone marrow: aplastic marrow with \<5% cellularity without erythroid, myeloid, or megakaryocytic precursors and 2) peripheral blood: absolute neutrophil count (ANC) \<100/µL, platelet count \<10,000/µL, and transfusion-dependent anemia. Non-hematologic DLTs were defined as any ≥Grade 3 toxicity with the following exceptions/clarifications: 1) infection, fatigue, anorexia, or alopecia are not included in determination of the DLT 2) Grade 3 nausea, vomiting, diarrhea, or dehydration occurring in a setting of inadequate treatment 3) any abnormal non-hematological laboratory value ≥Grade 3 will be considered a DLT after 72 hours of appropriate medical intervention if not related to an underlying disease or not attributable to another event.
次要结局
- Number of Participants With CR at Dose Levels Other Than RP2D(End of Treatment (up to 198 days))
- Urine Concentration of MK-8242 (Part 2 Arm A Only)(Day 1 (predose and postdose) and Day 7 (postdose))
- Number of Participants With CRi at Dose Levels Other Than RP2D(End of Treatment (up to 198 days))
- Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine(Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 [Day 7 only] hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose))
- Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine(Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, and 24 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], and 24 [Day 7 only] hrs postdose))
- Apparent Terminal Half-life (t1/2) for MK-8242 Alone and in Combination With Cytarabine(Cycle 1 Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24, 48 hrs postdose))
- Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine(Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 [Day 7 only] hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose))
- Accumulation Ratio (R) of MK-8242 Alone and in Combination With Cytarabine(Cycle 1 Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose))
- Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for MK-8242 Alone and in Combination With Cytarabine(Cycle 1 Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24, 48 hrs postdose))
- Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine(Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 [Day 7 only] hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose))