This is an open-label, Phase 1 study to determine the safety, tolerability, and efficacy of APL-4098 alone, and in combination with azacitidine, and in combination with azacitidine plus venetoclax for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS)/AML and MDS-excess blasts (EB).

Inclusion Criteria:

• 18 years or older
• Confirmed diagnosis of relapsed refractory acute myeloid leukemia (R/R AML), myelodysplastic syndrome (MDS)/ AML, or MDS-excess blasts (MDS-EB) with the following characteristics: - R/R AML (primary or secondary, including treatment-related), participant is intolerant to, or considered ineligible for available therapies known to provide clinical benefit.
• WBC count ≤ 25,000/microliter
• ECOG Performance Status of ≤ 2
• Weight ≥ 40kg
• Female participants of childbearing potential must have negative serum pregnancy test at screening; must not plan to become pregnant or have ova harvested or breastfeed while on study; must be willing to use specific contraception or avoid intercourse
• Male participants must be willing to use specific contraception and not plan to impregnant a female partner or donate sperm while on study
• Participant must be willing and able to provide written informed consent and to comply with the requirements of the trial

Exclusion Criteria:

• Certain prior therapies such as: received an allogeneic stem cell transplant within 6 months of screening, received an autologous stem cell transplant within 3 months of screening, received any anti-cancer treatments within 2 weeks of Cycle 1 Day 1, prior radiation therapy within 4 weeks of screening
• Certain medical conditions such as: other malignancies, myocardial infarction within 6 months of screening, symptomatic congestive heart failure, uncontrolled active infection, history of arterial thrombosis within 6 months of screening
• Diagnostic assessments: Left ventricular ejection fraction < 45%, Fridericia's corrected QT interval > 470msec, Aspartate aminotransferase and/or alanine aminotransferase > 3 x upper limit of normal (ULN), total bilirubin > 1.5 x ULN, calculated or measured creatinine clearance < 45 mL/minute (multiply by 0.85 if female)
• Infectious disease: HIV positive, active hepatitis B and/or C