This clinical trial is a Phase I, open-label, dose-finding and cohort expansion study to determine the safety and preliminary efficacy of APR-246 in combination with venetoclax and azacitidine in patients with myeloid malignancies.

This study will enroll adult male and female patients of age ≥ 18 years with documented diagnosis of AML, according to WHO classification, and documented TP53 mutation which is not benign or likely benign, who also meet the eligibility requirements of this protocol.

The study will include a safety lead-in dose-finding portion followed by expansion portion. During the safety lead-in portion of the study, two cohorts will independently enroll patients following a 3 + 3 design. Each cohort will enroll up to 6 patients.

The expansion portion will begin once the recommended phase II dose (RP2D) of APR-246 in combination with venetoclax and in combination with venetoclax and azacitidine have been determined in order to assess the antitumor activity of these combinations.

Inclusion Criteria:

1. Signed informed consent and ability to comply with protocol requirements.

2. Documented diagnosis of AML according to World Health Organization WHO) classification

3. Adequate organ function as defined by the following laboratory values:

   1. Creatinine clearance > 30 mL/min
   2. Total serum bilirubin < 1.5 × ULN
   3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 × ULN

4. Age ≥18 years

5. At least one TP53 mutation

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

7. Projected life expectancy of ≥ 12 weeks.

8. Negative serum or urine pregnancy test

9. Females of childbearing potential and males with female partners of childbearing potential must be willing to use an effective form of contraception

Exclusion Criteria:

1. Prior treatment for TP53-mutant AML (*dependent upon treatment arm assigned).

2. Known history of HIV or active hepatitis B or active hepatitis C infection.

3. Any of the following cardiac abnormalities:

   1. Myocardial infarction within six months prior to registration;
   2. New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction (LVEF) < 40%;
   3. A history of familial long QT syndrome;
   4. Symptomatic atrial or ventricular arrhythmias
   5. QTcF ≥ 470 msec, unless due to underlying bundle branch block and/or pacemaker and with approval of the medical monitor.

4. Concomitant malignancies for which patients are receiving active therapy

5. Known active CNS involvement from AML.

6. Malabsorption syndrome

7. Pregnancy or lactation.

8. Active uncontrolled systemic infection (viral, bacterial or fungal).