Phase 1-2 Study of Low Dose ASTX727 (ASTX727 LD) in Lower Risk MDS

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 Stages A and B, and Phase 2. Randomization will be stratified
by diagnostic category (low-risk vs Intermediate-1 based on IPSS), baseline absolute
neutrophil count (ANC) (≤10^9/L vs >10^9/L), and ECOG Performance Score (0-1 vs 2).

Phase 1: In Stage A, subjects will be randomized in a 1:1:1 ratio into 3 cohorts of 6
subjects each in a 10-day schedule in 28-day cycles. When safety has been established in
Phase 1 Stage A, Phase 1 Stage B will open, wherein additional subjects (n=24 evaluable) will
be randomized in a 1:1:1:1 ratio into 4 cohorts of 6 subjects each in a 14-day schedule in
28-day cycles.

Dose Levels by Cohort (Dailyx5, Offx2, Dailyx5):

- 1: 5 mg decitabine, 100 mg cedazuridine

- 2: 10 mg decitabine, 100 mg cedazuridine

- 3: 15 mg decitabine, 100 mg cedazuridine

Phase 2: Using 2 doses/schedules 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
(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 RBCs or Hb of
<8.5 g/dL in at least 2 blood counts prior to randomization.

2. ANC of <0.5 × 10^9/L in at least 2 blood counts prior to randomization.

3. 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 defined as follows:

1. Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); aspartate
aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine
aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤5 × ULN.

2. Renal: serum creatinine ≤1.5 × ULN or calculated creatinine clearance or
glomerular filtration rate ≥50 mL/min.

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. Subjects and their partners with reproductive potential must agree to use 2 highly
effective contraceptive measures during the study and must agree not to become
pregnant or father a child for 3 months after the last dose of study treatment.

Exclusion Criteria:

1. Treatment with any investigational drug or therapy within 2 weeks before study
treatment, or 5 half-lives, whichever is longer, before the first dose of study
treatment, or ongoing clinically significant AEs from previous treatment.

2. Treatments for MDS, including erythropoietins, colony-stimulating factors (CSFs),
thrombopoietins, chemotherapy, and immunosuppression including calcineurin inhibitors,
glucocorticoids, etc., must be concluded 1 month prior to study treatment.

3. Diagnosis of chronic myelomonocytic leukemia (CMML).

4. Poor medical risk because of other conditions such as uncontrolled systemic diseases
or active uncontrolled infections.

5. Known significant mental illness or other condition, such as active alcohol or other
substance abuse or addiction, that in the opinion of the investigator predisposes the
subject to high risk of noncompliance with the protocol.

6. Life-threatening illness, medical condition or organ system dysfunction, or other
reasons including laboratory abnormalities, which, in the investigator's opinion,
could compromise the subject's safety, interfere with the absorption or metabolism of
ASTX727 LD, or compromise the integrity of the study outcomes.

7. 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.

8. Known active infection with human immunodeficiency virus or hepatitis viruses.