A Randomized, Open-Label, Phase 1-2 Study of ASTX727 Low Dose (ASTX727 LD) Extended Schedule in Subjects With Lower Risk (IPSS Low or Intermediate-1) Myelodysplastic Syndromes (MDS)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 160
- 试验地点
- 43
- 主要终点
- Incidence of drug-related Grade ≥3 Adverse Events (AEs) or dose-limiting toxicities (DLTs) (if any) for each cohort dose/schedule
研究概览
简要总结
Multicenter, open-label study of various ASTX727 LD doses and schedules to assess safety, pharmacodynamics, pharmacokinetics, and hematologic response in subjects with International Prognostic Scoring System (IPSS) risk category of low-risk or Intermediate-1 MDS. This study will be conducted in two phases. In phase 1 subjects will be randomized into 3 cohorts in a 28-day cycles. Phase 2, 80 new subjects will be randomized in a 1:1 ratio into 2 doses/schedules.
详细描述
A Phase 1-2, multicenter, open-label study of various ASTX727 LD doses and schedules to assess the safety, pharmacodynamics (PD), pharmacokinetics (PK), and hematologic response in subjects with IPSS risk category of low-risk or Intermediate-1 MDS. The study will be conducted in 2 phases.
Phase 1: In Stage A, subjects will be randomized into 3 cohorts of 6 subjects each testing different doses of oral decitabine with cedazuridine in 28-day cycles. When safety has been established in Phase 1 Stage A, Phase 1 Stage B will open, wherein additional 30 subjects will be randomized in a 1:1:1 ratio into 3 cohorts of 10 subjects.
Phase 2: Using 2 doses/schedules one of which will be selected from Phase 1, 40 additional subjects per dose/schedule will be randomized in a 1:1 ratio. The selected doses/schedules will be evaluated for safety (drug-related AEs), efficacy (including hematologic response), PD (long interspersed nucleotide element-1 (LINE-1 methylation, and fetal hemoglobin as fraction of total hemoglobin), and PK.
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
- •Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before the first study-specific procedure.
- •Men or women ≥18 years with IPSS low risk or Int-1 MDS (all subjects). Subjects must have had at least 1 of the following disease-related criteria during the 8 weeks before randomization:
- •Red blood cell (RBC) transfusion dependence of 2 or more units of RBC transfusions (RBC transfusion administered for hemoglobin (Hb) levels ≤9.0 g/dL are counted).
- •Hb of <9.0 g/dL in at least 2 blood counts prior to randomization or in 1 blood count if RBC transfusion was received.
- •Absolute Neutrophil Count (ANC) of <0.5 × 10^9/L in at least 2 blood counts prior to randomization.
- •Platelet counts of <50 × 10^9/L in at least 2 blood counts prior to randomization.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Adequate organ function.
- •Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening.
- •Women of child-bearing potential must agree to use contraceptive measures of birth control for 6 months after completing treatment; men must use contraceptive measures and agree not to father a child for at least 3 months after completing treatment.
排除标准
- •Treatment with any investigational drug or therapy within 2 weeks before study treatment.
- •Treatments for MDS must be concluded 1 month prior to study treatment.
- •Prior treatment with azacitidine, decitabine, or guadecitabine.
- •Diagnosis of chronic myelomonocytic leukemia (CMML).
- •Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
- •Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate cancer or breast cancer under control with hormone therapy, or other cancer from which the subject has been disease free for at least 1 year.
- •Known active infection with human immunodeficiency virus or hepatitis viruses.
研究组 & 干预措施
Phase 1 Stage B
3 cohorts of 10 subjects each in 28-day cycles of ASTX727 LD
干预措施: ASTX727 LD (Drug)
Phase 2
80 additional subjects randomized in a 1:1 ratio studying two different doses
干预措施: ASTX727 LD (Drug)
Phase 2
80 additional subjects randomized in a 1:1 ratio studying two different doses
干预措施: ASTX727 SD (Drug)
Phase 1 Stage A
3 cohorts of 6 subjects each in a schedule in 28-day cycles of ASTX727 LD
干预措施: ASTX727 LD (Drug)
结局指标
主要结局
Incidence of drug-related Grade ≥3 Adverse Events (AEs) or dose-limiting toxicities (DLTs) (if any) for each cohort dose/schedule
时间窗: 18-24 months
Phase 1: Safety
Hematologic response based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence)
时间窗: 18-24 months
Phase 2: Efficacy
次要结局
- %LINE-1 methylation change from baseline(18-24 months)
- Area under the curve (AUC)(18-24 months)
- Time to bone marrow blasts >5%(18-24 months)
- Hematologic response (Phase 1 only) based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence)(18-24 months)
- Maximum plasma concentration (Cmax)(18-24 months)
- Time to reach maximum concentration (Tmax)(18-24 months)
- Half life (t1/2)(18-24 months)
- Leukemia-free survival(18-24 months)
- Overall survival(18-24 months)