This phase I trial tests the safety, side effects, and best dose of entrectinib when given with ASTX727 in treating patients with acute myeloid leukemia (AML) that has come back (relapsed) or that does not respond to treatment (refractory) and has a genetic change (mutation) in the TP53 gene. ASTX727 is a combination of cedazuridine and decitabine. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Entrectinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Giving ASTX727 and entrectinib together may kill more tumor cells in patients with AML.

PRIMARY OBJECTIVE:

I. To determine the maximum tolerated dose (MTD) of decitabine and cedazuridine (ASTX727) combined with entrectinib in relapsed/refractory (R/R) AML patients with TP53 mutations.

SECONDARY OBJECTIVE:

I. To assess overall safety and preliminary anti-AML activity of combined ASTX727 and entrectinib regimen.

EXPLORATORY OBJECTIVE:

I. To assess the potential pharmacodynamic changes observed with treatment consisting of entrectinib alone and in combination with decitabine.

OUTLINE: This is a dose-escalation study of entrectinib.

Patients receive entrectinib orally (PO) once daily (QD) on days 1-28 and ASTX727 PO QD on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 1 year.

Inclusion Criteria:

• Must be able to understand and willing to sign an informed consent document.
• Participants aged 18 years or older.
• Morphologically documented AML in patients with relapsed/refractory disease, defined as having >= 20% blasts in bone marrow or peripheral blood.
• Documented TP53 mutation as seen on standard diagnostics in AML.
• Aspartate aminotransferase (AST) < 3 × upper limit of normal (ULN).
• Alanine aminotransferase (ALT) < 3 × ULN.
• Total bilirubin < 1.5 × ULN (except for patients with known Gilbert's syndrome).
• Adequate renal function as defined by calculated creatinine clearance (according to the Cockcroft-Gault equation) > 40 mL/min OR serum creatinine < 1.5 × ULN.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2.
• Must be able to take oral medication.
• Individuals of childbearing potential (IOCBP) must agree to use highly-effective method(s) of contraception during the study and six months after the last dose of study drugs. IOCBP must have a negative pregnancy test prior to study enrollment.
• Sperm producing individuals must agree to use an adequate method of contraception starting with the first dose of study therapy through 3 months after the last dose of study drugs.
• Participants must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of their cancer.

Exclusion Criteria:

• Isolated myeloid sarcoma (patients must have blood or marrow involvement with AML to enter the study).
• Acute promyelocytic leukemia (M3).
• Active central nervous system (CNS) involvement by AML.
• Clinical signs/symptoms of leukostasis which has failed urgent therapy of at least 3 days duration, which may have included hydroxyurea or leukapheresis.
• Known active human immunodeficiency virus (HIV), active hepatitis B or active hepatitis C infection.
• Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis.
• Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent or who have agent-related toxicity that has not resolved to grade 1 or less. If the half-life of an investigational agent is unknown, patients must wait 1 week after discontinuing it before receiving the first dose of study treatment. An investigational agent is one for which there is no approved indication by the United States (US) Food and Drug Administration (FDA).
• Prior entrectinib for other malignancies (prior decitabine therapy will not be excluded).
• Patients with psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up.
• Patients who are otherwise felt unable to comply with the protocol, in the opinion of the investigator.
• Any other significant medical condition, including psychiatric illness or laboratory abnormality, that would preclude the patient participating in the trial or would confound the interpretation of the results of the trial.
• Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic (New York Heart Association [NYHA] class III or IV) congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction at presentation of AML, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled.
• Patients with uncontrolled infection shall not be enrolled until infection is treated and controlled.
• Participants with prior documented history of malabsorption syndrome (e.g., short gut syndrome) that might limit the bioavailability of study medications will be excluded.