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.
Inclusion Criteria:
1. 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.
2. 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:
1. 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).
2. 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.
3. Absolute Neutrophil Count (ANC) of <0.5 × 10^9/L in at least 2 blood counts prior
to randomization.
4. Platelet counts of <50 × 10^9/L in at least 2 blood counts prior to
randomization.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
4. Adequate organ function.
5. 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.
6. 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.
Exclusion Criteria:
1. Treatment with any investigational drug or therapy within 2 weeks before study
treatment.
2. Treatments for MDS must be concluded 1 month prior to study treatment.
3. Prior treatment with azacitidine, decitabine, or guadecitabine.
4. Diagnosis of chronic myelomonocytic leukemia (CMML).
5. Poor medical risk because of other conditions such as uncontrolled systemic diseases
or active uncontrolled infections.
6. 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.
7. Known active infection with human immunodeficiency virus or hepatitis viruses.