APR-246 in Combination With Venetoclax and Azacitidine in TP53-Mutant Myeloid Malignancies

Inclusion Criteria

• Signed informed consent and ability to comply with protocol requirements.
• Documented diagnosis of AML according to World Health Organization WHO) classification
• Adequate organ function as defined by the following laboratory values:
• Creatinine clearance > 30 mL/min
• Total serum bilirubin < 1.5 × ULN
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 × ULN
• Age ≥18 years
• At least one TP53 mutation
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Projected life expectancy of ≥ 12 weeks.
• Negative serum or urine pregnancy test
• Females of childbearing potential and males with female partners of childbearing potential must be willing to use an effective form of contraception

Exclusion Criteria

• Prior treatment for TP53-mutant AML (*dependent upon treatment arm assigned).
• Known history of HIV or active hepatitis B or active hepatitis C infection.
• Any of the following cardiac abnormalities:
• Myocardial infarction within six months prior to registration;
• New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction (LVEF) < 40%;
• A history of familial long QT syndrome;
• Symptomatic atrial or ventricular arrhythmias
• QTcF ≥ 470 msec, unless due to underlying bundle branch block and/or pacemaker and with approval of the medical monitor.
• Concomitant malignancies for which patients are receiving active therapy
• Known active CNS involvement from AML.
• Malabsorption syndrome
• Pregnancy or lactation.
• Active uncontrolled systemic infection (viral, bacterial or fungal).