Study of ASTX727 vs IV Decitabine in Participants With MDS, CMML, and AML

Inclusion Criteria:

1. Able to understand and comply with the study procedures, understand the risksinvolved in the study, and provide written informed consent before the firststudy-specific procedure; specifically able to comply with the PK assessmentschedule during the first 2 treatment cycles.

2. Men or women ≥18 years who are candidates to receive IV decitabine according to FDAor European Medicines Agency (EMA) approved indications:

3. In North America: Participants with MDS previously treated or untreated with denovo or secondary MDS, including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractoryanemia with excess blasts, refractory anemia with excess blasts intransformation, and chronic myelomonocytic leukemia [CMML]), and subjects withMDS International Prognostic Scoring System (IPSS) int-1, -2, or high-risk MDS.

4. In Europe: Participants with de novo or secondary AML, as defined by the WorldHealth Organization (WHO) criteria, who are not candidates for standardinduction chemotherapy.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

6. Adequate organ function defined as follows:

7. Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); aspartatetransaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alaninetransaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤2.5 × ULN.

8. Renal: serum creatinine ≤1.5 × ULN or calculated creatinine clearance orglomerular filtration rate >50 mL/min/1.73 m2 for subjects with creatininelevels above institutional normal.

9. No major surgery within 30 days of first study treatment.

10. Life expectancy of at least 3 months.

11. Women of child-bearing potential must not be pregnant or breastfeeding and must havea negative pregnancy test at screening. Women of non-childbearing potential arethose who have had a hysterectomy or bilateral oophorectomy, or who have completedmenopause, defined as no menses for at least 1 year AND either age ≥65 years orfollicle-stimulating hormone levels in the menopausal range.

12. Subjects and their partners with reproductive potential must agree to use effectivecontraceptive measures during the study and for 3 months after the last dose ofstudy treatment. Effective contraception includes methods such as oralcontraceptives or double-barrier method (eg, use of a condom AND diaphragm, withspermicide).

Exclusion Criteria:

1. Prior treatment with more than 1 cycle of azacitidine or decitabine. Prior cytotoxicchemotherapy for AML except for hydroxyurea to control high white blood cell (WBC)counts.

2. Hospitalization for more than 2 days for documented febrile neutropenia, pneumonia,sepsis, or systemic infection in the 30 days before screening.

3. Treatment with any investigational drug or therapy within 2 weeks of studytreatment, or 5 half-lives, whichever is longer, before the first dose of studytreatment, or ongoing clinically significant adverse events (AEs) from previoustreatment.

4. Cytotoxic chemotherapy or prior azacitidine or decitabine within 4 weeks of firstdose of study treatment.

5. Concurrent MDS therapies, including lenalidomide, erythropoietin,cyclosporine/tacrolimus, granulocyte-colony stimulating factor (G-CSF),granulocyte-macrophage colony-stimulating factor, etc. (Prior treatment with theseagents is permitted, provided that completion is at least 1 week before the firstdose of study treatment.)

6. Poor medical risk because of other conditions such as uncontrolled systemicdiseases, active uncontrolled infections, or comorbidities that may put the patientat risk of not being able to complete at least 2 cycles of treatment.

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

8. Rapidly progressive or highly proliferative disease (total white blood cell count of >15 × 10^9/L) or other criteria that render the subject at high risk of requiringintensive cytotoxic chemotherapy within the next 3 months.

9. Life-threatening illness or severe organ system dysfunction, such as uncontrolledcongestive heart failure or chronic obstructive pulmonary disease, or other reasonsincluding laboratory abnormalities, which, in the investigator's opinion, couldcompromise the subject's safety, interfere with the absorption or metabolism ofASTX727, or compromise completion of the study or integrity of the study outcomes.

10. Prior malignancy, except for adequately treated basal cell or squamous cell skincancer, in situ cervical cancer, prostate cancer or breast cancer under control withhormone therapy, or other cancer from which the subject has been disease free for atleast 2 years.