A Phase Ib Study of APG-115 Single Agent or in Combination With Azacitidine or Cytarabine in Patients With AML and MDS.

Stage 1: This will be a 3+3 dose escalation to determine the DLTs and MTD/RP2D of APG-115 given according to the different dose levels once daily from Days 1 to 7 every 28 days.

Stage 2: After stage 1 of APG-115 single agent dose escalation first cycle is completed, stage 2 can be initiated with the combination regimen. This will be a 3+3 dose escalation to determine the MTD/RP2D and DLTs of APG-115 + AZA(arm A)/Cytarabine (arm B)combination.

Stage 3: dose expansion of the combination regimes.

Inclusion criteria

• Patients with a diagnosis of histologically confirmed relapsed or refractory (R/R) acute myeloid leukemia by WHO classification or relapsed/progressed high/very high risk MDS (score≥4.5) according to IPSS-R risk stratification
• Age >/= 18 years.
• Adequate organ function
• Subject must have a projected life expectancy of at least 12 weeks.
• ECOG performance status of 0-1.
• Patient must have the ability to understand the requirements of the study and signed informed consent. A signed informed consent by the patient or his legally authorized representative is required prior to their enrollment on the protocol.
• Subject has a white blood cell count< 50 × 109/L. Note: Hydroxyurea is permitted to meet this criterion.

Exclusion criteria

• Subject has acute promyelocytic leukemia.
• Patients must not have had leukemia biotherapy 4 weeks prior to starting investigational drug, or less than 5 half-lives small molecular targeted drug therapy, or 28 days any anti-cancer therapy (whichever is longer)
• Uncontrolled intercurrent illness including, but not limited to active uncontrolled infection, symptomatic congestive heart failure (NYHA Class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Active infection requiring systemic antibiotic/antifungal medication, known clinically active hepatitis B or C, or HIV infection.
• Participants who have received allogeneic HSCT, or autologous HSCT within 12 months.
• Patients with active, uncontrolled CNS leukemia will not be eligible.
• Any prior systemic MDM2-p53 inhibitor treatment
• Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.
• Subject has a history of other malignancies within 2 years prior to study entry, with the exception of:

• Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
• Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
• Previous malignancy confined and surgically resected (or treated with other modalities) with curative intention: requires discussion with sponsor.