A Phase1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 With Oral Decitabine in Subjects With Myelodysplastic Syndromes (MDS)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 130
- 试验地点
- 17
- 主要终点
- Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1
研究概览
简要总结
This first-in-human, 3-stage, open-label study evaluated the safety and pharmacokinetics of ASTX727, as well as determined the dose for later stages.
详细描述
The trial was designed to define daily doses of the individual components (cedazuridine [E7727] or decitabine) so that decitabine exposure after oral administration would be comparable to exposure after IV decitabine at the approved daily dose of 20 mg/m^2. The main objective of Phases 1 and 2 was to establish and confirm the doses of the 2 components to be used in the final fixed-dose combination (FDC) product (ASTX727) using mainly pharmacokinetics and pharmacodynamics as endpoints.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •International Prognostic Scoring System (IPSS) low, intermediate -1, intermediate-2, or high risk MDS (including chronic myelomonocytic leukemia; CMML) in Dose Escalation and Dose Confirmation-Randomization; only intermediate-2, or high risk MDS in Dose Confirmation-Open Label
- •Eastern Cooperative Oncology Group (ECOG) 0 to 2
- •No major surgery within 2 weeks of starting study treatment
- •No cytotoxic chemotherapy within 2 weeks of starting study treatment
- •Able to swallow pills
排除标准
- •Previous treatment with 2 or more courses of decitabine (all stages) or azacitidine (Dose Confirmation stage only)
- •Treatment with investigational therapy within 2 weeks of study treatment
- •Uncontrolled medical disease(s) or active, uncontrolled infection
- •Diagnosed with acute myeloid leukemia (AML)
- •Active uncontrolled gastric or duodenal ulcer
- •Known history of HIV or hepatitis C or B
研究组 & 干预措施
Phase 1 Dose Escalation
Starting cohort was administered 40 mg oral cedazuridine and 20 mg oral decitabine. Participants were enrolled into successive cohorts in which either the cedazuridine or decitabine oral dose was varied in Course 1 Day 2 through Course 1 Day 5 for comparison with a single dose of IV decitabine at 20 mg/m^2 administered on Day 1 by continuous IV infusion over 1 hour (28 days per course).
干预措施: ASTX727 Dose Escalation (Drug)
Phase 2 Dose Confirmation
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (E7727) (100 mg) + decitabine (35 mg) capsules Dailyx5 in Course 1 followed by IV decitabine (20 mg/m^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
干预措施: ASTX727 Dose Confirmation (Drug)
Phase 2 Fixed-Dose Combination
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine (E7727)/35 mg decitabine) Dailyx5 in Course 1 followed by IV decitabine (20 mg/m^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, all participants received the FDC tablet Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
干预措施: ASTX727 Fixed-Dose Combination (Drug)
结局指标
主要结局
Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1
时间窗: Day 5
Mean AUC0-t of oral decitabine given with cedazuridine (E7727) following IV decitabine 20 mg/m\^2 infusion on Day 5. AUCs were calculated by the linear up/log down method using the measured concentration-time values above the BQL (below the limit of quantification).
Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2
时间窗: Pre-dose to Day 5
Decitabine 5-day AUC ratio following IV decitabine 20 mg/m\^2 infusion versus concomitant oral administration of decitabine + cedazuridine (E7727) or ASTX727 in the dose combination and fixed-dose combination stages, respectively. AUC0-t (the area under the concentration-time curve from time zero to the time of the last (tlast) quantifiable concentration (Ct)) by dose/cohort and course/days was used for estimating decitabine cumulative 5-day AUC0-t exposures.
Number of Participants With Dose-limiting Toxicity in Phase 1
时间窗: Up to Day 28 in Course 1 (28 days per course)
Number of participants with protocol-specified dose-limiting toxicities (DLTs) in the dose escalation stage. DLTs were defined using the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAEv4.0), specifically ≥ Grade 3 non-hematologic toxicity (except Grade 3 nausea, vomiting, or diarrhea that is controllable by anti-emetics or optimal therapy or related to underlying disease or disease progression), specific Grade 3 laboratory tests, related prolonged Grade 4 thrombocytopenia or neutropenia that was not present prior to dosing, does not resolve within 14 days, and is not related to underlying disease, or any toxicity related to study treatment that results in treatment delays of \>4 weeks after Day 28.
Mean Maximum %LINE Demethylation in Phase 2
时间窗: Pre-dose to Day 28 in Course 2 (28 days per course)
Mean maximum % long interspread nuclear element-1 (LINE-1) demethylation after oral decitabine + cedazuridine (E7727) or ASTX727 (Course 1 or Course 2 - Treatment) compared with IV decitabine 20 mg/m\^2 (Course 1 or Course 2 - IV Decitabine) in the dose confirmation and fixed-dose combination stages, respectively. Least squares mean of maximum %LINE-1 methylation change from baseline.
Number of Participants With Overall Response in Phase 2
时间窗: Up to approximately 29 months
The evaluation of response was based on International Working Group (IWG) 2006 MDS Response Criteria, with overall response calculated as number of participants with complete response+partial response+marrow complete response+hematological improvement (CR+PR+mCR+HI).
次要结局
- Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death(Up to 32 months)
- Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer(At specified timepoints from 0 to 24 hours post-dose)
- Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer(At specific timepoints from 0 to 24 hours post-dose)
- Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer(At specific timepoints from 0 to 24 hours post-dose)
- Maximum Observed Plasma Concentration (Cmax) of Decitabine(At specific timepoints from 0 to 24 hours post-dose)
- Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2(At specific timepoints from 0 to 24 hours post-dose)
- Duration of Complete Response in Phase 1(Up to 32 Months)
- Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate(Up to approximately 29 months)
- Mean Maximum %LINE Demethylation in Phase 1(Pre-dose to Day 28 in Course 2 (28 days per course))
- Number of Participants With Overall Response in Phase 1(Up to 32 months)
- Number of Participants With Adverse Events(Up to 5 years)
- Number of Participants With Hematological Improvement(Up to 32 months)
- Number of Participants With Transfusion Independence(Up to 32 months)
- Number of Participants With Overall Survival(Up to 32 months)