A Phase 1 Study of Milademetan (DS 3032b), an Oral MDM2 Inhibitor, In Dose Escalation as a Single Agent and In Dose Escalation/Expansion In Combination With 5 Azacitidine In Subjects With Acute Myelogenous Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 74
- 试验地点
- 5
- 主要终点
- Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)
研究概览
简要总结
This study will take place in parts:
- Dose Escalation (Part 1): Participants receive milademetan alone with different dose schedules
- Dose Escalation (Part 1A): Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules
The recommended dose for Part 2 will be selected.
- Dose Expansion (Part 2): After Part 1A, participants will receive the recommended Part 2 dose schedule. There will be three groups - those with:
- refractory or relapsed acute myelogenous leukemia (AML)
- newly diagnosed AML unfit for intensive chemotherapy
- high-risk myelodysplastic syndrome (MDS)
- End-of-Study Follow-Up: Safety information will be collected until 30 days after the last treatment. This is the end of the study.
The recommended dose for the next study will be selected.
详细描述
The primary analysis will occur after all participants have either discontinued the study or completed at least 6 months of treatment. After the primary analysis, the main study will be closed. Participants who are still on study at least 6 months after enrollment of the last participant in the study may be eligible to continue receiving study drug in a separate extension phase of the protocol
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
Part 1, Milademetan Alone
Participants receive milademetan alone with different dose schedules
干预措施: Milademetan (Drug)
Part 1A, Milademetan with 5-azacytidine (AZA)
Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules
干预措施: Milademetan (Drug)
Part 1A, Milademetan with 5-azacytidine (AZA)
Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules
干预措施: AZA (Drug)
Part 2, Cohort 1
Participants with refractory or relapsed acute myelogenous leukemia (AML) receive the recommended dose for Part 2 of milademetan or milademetan with5-azacytidine (AZA)
干预措施: AZA (Drug)
Part 2, Cohort 1
Participants with refractory or relapsed acute myelogenous leukemia (AML) receive the recommended dose for Part 2 of milademetan or milademetan with5-azacytidine (AZA)
干预措施: Milademetan (Drug)
Part 2, Cohort 2
Participants with newly diagnosed acute myelogenous leukemia (AML) unfit for intensive chemotherapy receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA)
干预措施: AZA (Drug)
Part 2, Cohort 2
Participants with newly diagnosed acute myelogenous leukemia (AML) unfit for intensive chemotherapy receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA)
干预措施: Milademetan (Drug)
Part 2, Cohort 3
Participants with high-risk myelodysplastic syndrome (MDS) receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA)
干预措施: AZA (Drug)
Part 2, Cohort 3
Participants with high-risk myelodysplastic syndrome (MDS) receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA)
干预措施: Milademetan (Drug)
结局指标
主要结局
Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)
时间窗: From the date the participant signed the informed consent form up to 5 years of first participant enrolled
A DLT was defined as any treatment-emergent adverse event not attributable to disease or disease-related processes occurring during the observation period (Cycle 1) in each dose-level cohort and is Grade (Gr) 3 or higher according to NCI CTCAE Version 5.0 (Version 4.03 before 01 Apr 2018), with these exceptions: for elevations in hepatic function enzymes, a DLT is defined as: Gr ≥3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels lasting \>3 days; AST/ALT \>5 × ULN if accompanied by ≥Gr 2 elevation in bilirubin. Potential DLTs include: Participants who are unable to complete at least 75% of milademetan or AZA in Cycle 1 as a result of non-disease-related Gr ≥2 events; Persistent bone marrow aplasia in the absence of malignant cell infiltration, and failure to recover a peripheral absolute neutrophil count ≥0.5 × 10\^9/L and platelets ≥20 × 10\^9/L while withholding study drug, resulting in \>2-week delay in initiating Cycle 2.
Number of Participants (≥10%) With Treatment-emergent Adverse Events (TEAEs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)
时间窗: From the date the participant signed the informed consent form up to 30 days after the last dose in the last participant, up to approximately 6 years of first participant enrolled
A treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during the treatment period (up to 30 days after last dose), having been absent at pre-treatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-treatment state, when the adverse event is continuous.
次要结局
- Trough Plasma Concentration (Ctrough) Following Administration of Milademetan Alone(Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days))
- Maximum Plasma Concentration (Cmax) Following Administration of Milademetan Alone(Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days))
- Time to Maximum Concentration (Tmax) Following Administration of Milademetan Alone(Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days))
- Time to Maximum Concentration (Tmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)(Predose, 0.5 hour (hr), 1 hr, 2 hr, 3 hr, 6 hr of Cycle 1, Day 1 (AZA); Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Day 5, Day 7 (predose) (Cohorts 10e and 12e), Day 8 (Cohorts 11f and 13f), and Day 14 (Cohorts 10e-13f) (each cycle is 28 days))
- Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)(Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Cycle 1, Day 5 (Cohorts 10e and 12e) and Predose of Cycle 1, Day 14 (Cohorts 10e, 11f, and 12e) (each cycle is 28 days))
- Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)(Day 5 (predose) up to Day 22 (predose), up to approximately 6 years of first participant enrolled)
- Maximum Plasma Concentration (Cmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)(Predose, 0.5 hour (hr), 1 hr, 2 hr, 3 hr, 6 hr of Cycle 1, Day 1 (AZA); Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Day 5, Day 7 (predose) (Cohorts 10e and 12e), Day 8 (Cohorts 11f and 13f), and Day 14 (Cohorts 10e-13f) (each cycle is 28 days))
- Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan Alone(Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days))
- Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan Alone(Day 1 (6 hours postdose) up to Day 21-22 (predose), up to approximately 6 years of first participant enrolled)