This Phase 3 study will establish PK equivalence of ASTX727 to IV decitabine in approximately
118 evaluable subjects. Eligible subjects will receive both study treatments: oral
investigational drug ASTX727, and IV decitabine, as follows: subjects will be randomly
assigned 1:1 to receive ASTX727 or IV decitabine in Cycle 1 and then cross over to the other
therapy in Cycle 2.
In the ASTX727 cycle, subjects will receive the ASTX727 tablet Daily×5. Serial PK
measurements (blood draws) will be done on Days 1, 2, and 5, along with pre-dose PK
assessments on Days 1-5 and an assessment at 3 hours post dose on Day 3. Subjects will be
required to fast from food for 4 hours on days when receiving ASTX727: at least 2 hours
before and 2 hours after dosing.
In the IV decitabine cycle, subjects will receive a 1-hour infusion of IV decitabine 20
mg/m^2 Daily×5. Serial PK measurements will be done on Days 1 and 5, along with pre-dose and
1-hour post-infusion assessments on Day 3.
In Cycles ≥3, subjects will receive the ASTX727 tablet Daily×5 in 28-day cycles. (No PK
assessments will be done from Cycle 3 onward.)
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; specifically able to comply with the PK assessment schedule during the
first 2 treatment cycles.
2. Men or women ≥18 years who are candidates to receive IV decitabine according to FDA or
European Medicines Agency (EMA) approved indications:
1. In North America: Participants with MDS previously treated or untreated with de
novo or secondary MDS, including all French-American-British subtypes (refractory
anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess
blasts, refractory anemia with excess blasts in transformation, and chronic
myelomonocytic leukemia [CMML]), and subjects with MDS International Prognostic
Scoring System (IPSS) int-1, -2, or high-risk MDS.
2. In Europe: Participants with de novo or secondary AML, as defined by the World
Health Organization (WHO) criteria, who are not candidates for standard induction
chemotherapy.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
4. Adequate organ function defined as follows:
1. Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); aspartate
transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine
transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤2.5 × ULN.
2. Renal: serum creatinine ≤1.5 × ULN or calculated creatinine clearance or
glomerular filtration rate >50 mL/min/1.73 m2 for subjects with creatinine levels
above institutional normal.
5. No major surgery within 30 days of first study treatment.
6. Life expectancy of at least 3 months.
7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a
negative pregnancy test at screening. Women of non-childbearing potential are those
who have had a hysterectomy or bilateral oophorectomy, or who have completed
menopause, defined as no menses for at least 1 year AND either age ≥65 years or
follicle-stimulating hormone levels in the menopausal range.
8. Subjects and their partners with reproductive potential must agree to use effective
contraceptive measures during the study and for 3 months after the last dose of study
treatment. Effective contraception includes methods such as oral contraceptives or
double-barrier method (eg, use of a condom AND diaphragm, with spermicide).
Exclusion Criteria:
1. Prior treatment with more than 1 cycle of azacitidine or decitabine. Prior cytotoxic
chemotherapy 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 study treatment,
or 5 half-lives, whichever is longer, before the first dose of study treatment, or
ongoing clinically significant adverse events (AEs) from previous treatment.
4. Cytotoxic chemotherapy or prior azacitidine or decitabine within 4 weeks of first dose
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 these
agents is permitted, provided that completion is at least 1 week before the first dose
of study treatment.)
6. Poor medical risk because of other conditions such as uncontrolled systemic diseases,
active uncontrolled infections, or comorbidities that may put the patient at 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 other
substance abuse or addiction, that in the opinion of the investigator predisposes the
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 requiring
intensive cytotoxic chemotherapy within the next 3 months.
9. Life-threatening illness or severe organ system dysfunction, such as uncontrolled
congestive heart failure or chronic obstructive pulmonary disease, 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, or compromise completion of the study or integrity of the study outcomes.
10. 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 2 years.
