PRIMA-1 Analog APR-246 and Azacitidine in Treating Patients with TP53 Mutant Myeloid Cancers

Inclusion Criteria

• Patient has signed the informed consent (ICF) and is able to comply with protocol requirements
• Serum creatinine =< 2 x upper limit of normal (ULN)
• Total serum bilirubin < 1.5 x ULN or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert’s syndrome or hemolysis or who required regular blood transfusions
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN
• Documented diagnosis of myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML) by World Health Organization (WHO) criteria or AML with 20-30% myeloblasts (refractory anemia with excess blasts in transformation [RAEB-T] by French-American-British [FAB)] criteria)
• Documentation of a TP53 gene mutation by next generation sequencing (NGS) based on central or local evaluation
• Revised International Prognostic Scoring System (IPSS-R) criteria for intermediate, high-risk or very high-risk
• An Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 is required
• If of childbearing potential, negative pre-treatment urine or serum pregnancy test
• If of childbearing potential (males and females), willing to use an effective form of contraception such as latex condom, hormonal birth control, intrauterine device or double barrier method during chemotherapy treatment and for at least six months thereafter

Exclusion Criteria

• Patient has a known history of human immunodeficiency virus (HIV) or active hepatitis B or active hepatitis C infection (testing not mandatory)
• Patient has any of the following cardiac abnormalities (as determined by treating Doctor of Medicine [MD]): * Symptomatic congestive heart failure * Myocardial infarction =< 6 months prior to enrollment * Unstable angina pectoris * Serious uncontrolled cardiac arrhythmia * Corrected QT interval (QTc) >= 470 msec
• Concomitant malignancies or previous malignancies with less than a 1-year disease free interval at the time of signing consent; patients with adequately resected basal or squamous cell carcinoma of the skin, or adequately resected carcinoma in situ (e.g. cervix) may enroll irrespective of the time of diagnosis
• Prior exposure to azacitidine, decitabine or investigational hypomethylating agent
• Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are not commercially available) for the treatment of MDS, MDS/MPN, CMML or AML within 14 days of the first day of study drug treatment
• No concurrent use of erythroid stimulating agents, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) is allowed during study except in cases of febrile neutropenia where G-CSF can be used for short term; growth factors must be stopped 14 days prior to study
• Patients with history of allogeneic stem cell transplantation
• Pregnant women are excluded from this study because APR-246 has not been studied in pregnant subjects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with APR-246, breastfeeding should be discontinued if the mother is treated with APR-246