Study of Venetoclax in Combination With Decitabine in Subjects With 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)
• ECOG performance status 0-2
• Age 18 years or older
• Adequate organ function as defined by all of the following:

• Creatinine clearance ≥30 mL/min, determined by the Cockroft-Gault formula, or measured by a 24 hour urine collection
• AST and ALT ≤3 x 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 i 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

• Key exclusion criteria (apply to both Phase 1 and Phase 2 portions of the study):

• 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 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 HIV
• Known 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 (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 CHF requiring treatment or Ejection Fraction ≤ 50%
• Subject has a cardiovascular disability status of New York Heart Association

Class > 2, defined as:

i. Cardiac disease in which patients are comfortable at rest but ordinary physical activity ii. Results in fatigue, palpitations, dyspnea, or anginal pain c. 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