Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloproliferative Neoplasm

Inclusion Criteria:

• A diagnosis of an MDS/MPN "overlap" syndrome with >= 5% marrow blasts (includingmonocytic blast equivalent in case of CMML). Hydroxyurea may be used to controlcounts up until the start of therapy

• White blood cell (WBC) < 25,000/mm^3. Treatment with hydroxyurea is permitted tolower the WBC to reach this criterion

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of ASTX727 in combination with venetoclax in patients < 18 years of age,children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless considered due toGilbert's syndrome)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN OR =< 5.0 x institutional ULN for patients withliver metastases

• Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial. Hormonal therapy for prioror concurrent malignancy is allowed

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity (IDMC) who have alegally authorized representative (LAR) and/or family member available will also beeligible

• Ability to swallow pills

Exclusion Criteria:

• Patients with need for emergent disease-directed therapy excluding hydroxyurea

• More than one cycle of previous MDS/MPN-directed therapy, or MDS-directed therapyincluding lenalidomide and hypomethylating agent (HMAs) such as decitabine orazacitidine, excluding hydroxyurea. Prior use of erythropoietin stimulating agents (ESA) and thrombopoietic agents is allowed, but must be discontinued 4 weeks priorto study treatment

• Patients currently or previously receiving an investigational agent or device within 4 weeks of the first dose of treatment

• Patients with symptomatic uncontrolled central nervous system (CNS) disease. Imagingto confirm the absence of brain metastases is not required. Patients with spinalcord compression unless considered to have received definitive treatment for thisand evidence of clinically stable disease for 28 days

• Patients who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days prior tothe initiation of study treatment and are unwilling to discontinue consumption ofthese throughout the receipt of study drug

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to ASTX727 or venetoclax

• Patients with uncontrolled intercurrent illness (e.g. requiring intravenous therapy)at the discretion of the investigator

• Pregnant women are excluded from this study because venetoclax and ASTX727 have thepotential for teratogenic or abortifacient effects. Because there is an unknown butpotential risk for adverse events in nursing infants secondary to treatment of themother with venetoclax, breastfeeding should be discontinued if the mother istreated with venetoclax. These potential risks may also apply to other agents usedin this study. Patients must be post-menopausal or with evidence of non-childbearingstatus for women of childbearing potential: negative urine or serum pregnancy testwithin 28 days of study treatment and confirmed prior to treatment on day 1

• Post-menopausal is defined as:

• Amenorrheic for 1 year or more following cessation of exogenous hormonaltreatments

• Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels inthe post-menopausal range for women under 50 years of age

• Radiation-induced oophorectomy with last menses > 1 year ago

• Chemotherapy-induced menopause with > 1 year interval since last menses

• Surgical sterilization (bilateral oophorectomy or hysterectomy)

• Women of child-bearing potential must agree to use adequate contraception (hormonal birth control or abstinence) prior to study entry and for theduration of study participation, and for 6 months following completion of studytreatment. Should a woman become pregnant or suspect she is pregnant while sheor her partner is participating in this study, she should inform her treatingphysician immediately. Men treated or enrolled on this protocol must also agreeto use adequate contraception (latex or synthetic condom or abstinence) priorto the study, for the duration of study participation, and 3 months aftercompletion of venetoclax and ASTX727 administration

• Patients with any other medical condition for which the expected survival is below 12 months

• Patients with a prior or concurrent malignancy whose natural history or treatmenthas the potential to interfere with the safety or assessment of the investigationalregimen

• Patients with uncontrolled infection at the time of study entry