A Phase I/II Trial to Assess the Efficacy and Toxicity of ASTX727 (Oral Decitabine/Cedazuridine) for the Treatment of Hematological Neoplasms After Allogeneic Stem Cell Transplantation

Diagnosis of AML and MDS according to World Health Organization (WHO) classification that underwent first or second allogeneic HSCT with either peripheral blood or bone marrow as the source of the hematopoietic stem cells.

Age 18 to 75 years old.

High risk patients defined per cohorts as below:

Cohort #1: AML and MDS patients in morphological remission with persistence or reappearance of MRD by flow cytometry or molecular after allogeneic stem cell transplantation who are beyond day 100 after allogeneic stem cell transplantation.

* When MRD is detected by flow cytometry, disease level at or above the sensitivity level of the test will be required.

* MRD level at or above 0.1%.

* When MRD is detected by molecular testing, disease level at or above the sensitivity level of the test will be required.

* The limit of detection is 0.01%

Cohort #2: High risk AML and MDS patients who are in complete remission morphologically with no evidence of minimal residual disease by flow cytometry or cytogenetic or molecular testing within 100 days after allogeneic stem cell transplantation.

MDS patients:

* Moderate-high, high or very high-risk groups by International Prognostic Scoring System-Molecular (IPSS-M) classification if classification is available (58).

* TP53 with biallelic mutations(49).

* Therapy-related MDS(50).

* Presence of mutation ASXL1, SRSF2, DNMT3A, RUNX1, U2AF1, TP53, EZH2, STAG2, CBL, NRAS, BCOR ((49, 51-54))

* Bone marrow blast count 10% or higher prior to allogeneic stem cell transplantation.

AML patients

* Cytogenetics and molecular features consistent with adverse risk group by 2017 European LeukemiaNet classification for AML(55)

* Presence of MRD by multi-color flow cytometry or cytogenetics or molecular studies by the last bone marrow evaluation prior to HSCT.

* Primary induction failure defined as absence of complete remission after two different lines of anti-leukemia therapy following diagnosis.

* Presence of active disease defined as bone marrow blast count \>5% but \<= 20% at the time of HSCT.

* Patients transplanted beyond first CR.

* Therapy-related AML.

* Overexpression of EVI1 (52)

All patients in cohort #2:

* Post-transplant bone marrow consistent with complete remission with no evidence of minimal residual disease by flow-cytometry or cytogenetics or molecular testing.

* Adequate engraftment within 7 days prior to starting study drug: Absolute neutrophil count (ANC) \>/= 1.0 x 109/L without daily use of myeloid growth factor (G-CSF) for at least 7 days; and,platelet \>/= 30 x 109/L without platelet transfusion within 1 week.

ECOG performance status of 0, 1, or 2.

Creatinine clearance greater or equal than 40 cc/min as defined by the Cockcroft-Gault Equation\*.

Males (mL/min) :(140-age) \*IBW (kg) / 72\*(serum creatinine(mg/dl)) Females (mL/min):0.85\*(140-age) \*IBW (kg) / 72\*(serum creatinine(mg/dl)).

Serum bilirubin \</= 1.5 x upper limit of normal (ULN). Aspartate transaminase (AST) or alanine transaminase (ALT) \</= 2.5 x ULN. Alkaline phosphatase \</= 2.5 x UL.

No active bleeding.

No clinical evidence of life-threatening infection. Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent.

Negative serum or urine pregnancy test for women with reproductive potential. The only subjects who will be exempt from this criterion are postmenopausal women (defined as women who have been amenorrheic for \> 12 months) or subjects who have been surgically sterilized or otherwise proven sterile.

Females of childbearing potential must refrain from becoming pregnant and commit to either apply highly effective method of birth control (two reliable methods of birth control) or continue abstinence from heterosexual intercourse during study period and for at least 6 months after last dose of ASTX727. Male subjects who are sexually active with a women of childbearing potential (WOCBP) and who have not had vasectomies must be willing to use a barrier method of contraception and refrain from sperm donation from initial study drug until 3 months after last dose of study drug.

What this study is about