Venetoclax in Combination with Decitabine for the Treatment of High-Risk Acute Myeloid Leukemia

Inclusion Criteria

• PHASE 1: DOSE ESCALATION PHASE
• High risk AML, including any of the following: * Relapsed or refractory disease * TP53 mutant AML * Adverse risk cytogenetics including any of the following: 3 or more abnormalities; deletions involving chromosomes 5, 7, or 17; abnormalities in chromosome 11 involving MLL; t(6;9); inv(3) or t(3;3)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Age >= 18 years old
• Creatinine clearance >= 30 mL/min, determined by the Cockcroft-Gault formula, or measured by a 24 hour urine collection
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN) and bilirubin =< 1.5 x ULN (unless considered due to Gilbert’s syndrome or of non-hepatic origin i.e. leukemic involvement)
• Patients must be at least 2 weeks from major surgery, radiation therapy, or participation in other investigational trials, and must have recovered from clinically significant toxicities related to these prior treatments
• Patients must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures
• Female patients of childbearing potential must have negative results for a pregnancy test
• Patients must be willing to use appropriate contraception
• PHASE 2: DOSE EXPANSION PHASE
• During the phase 2 portion of the study, the subject population will be limited to patients with previously untreated AML with a mutation in TP53. All other inclusion criteria described above will apply

Exclusion Criteria

• Concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in this protocol
• Patients suitable for and willing to receive intensive induction chemotherapy
• Use of investigational agents and/or anticancer therapy within 2 weeks of study entry (with the exception of hydroxyurea, which is permitted before and during cycle 1 of therapy until day 10 (D10), at the discretion of the investigator)
• Prior treatment with venetoclax, decitabine, or azacitidine
• Diagnosis of acute promyelocytic leukemia
• Pregnant or breastfeeding patients
• Patient known to be positive for human immunodeficiency virus (HIV)
• Known central nervous system (CNS) involvement with AML
• Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: * Uncontrolled and/or active systemic infection (viral, bacterial or fungal) * Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface [HBs] antigen negative-, anti-HBs antibody positive and anti-hepatitis B core [HBc] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate. * An active second cancer that requires treatment within 6 months of study entry
• Cardiac history including the following: * History of congestive heart failure (CHF) requiring treatment or ejection fraction =< 50% * Subject has a cardiovascular disability status of New York Heart Association Class > 2, defined as: ** Cardiac disease in which patients are comfortable at rest but ordinary physical activity ** Results in fatigue, palpitations, dyspnea, or anginal pain * Chronic stable angina
• Treatment with any of the following within 7 days prior to the first dose of study drug: * Steroid therapy for anti-neoplastic intent * Moderate or strong cytochrome P450 3A (CYP3A) inducers
• Administration or consumption of any of the following within 3 days prior to the first dose of study drug: * Grapefruit or grapefruit products * Seville oranges (including marmalade containing Seville oranges) * Star fruit