A Study of Pevonedistat and Venetoclax Combined With Azacitidine to Treat Acute Myeloid Leukemia (AML) in Adults Unable to Receive Intensive Chemotherapy

Inclusion Criteria

• Has morphologically confirmed diagnosis of AML (World Health Organization [WHO] criteria 2008). Participants may have newly diagnosed primary de novo AML or secondary AML (sAML), defined as AML after myelodysplastic syndromes (MDS) or myeloproliferative neoplasm (MPN), or therapy-related AML (t-AML) following cytotoxic therapy, and/or radiotherapy for a malignant or nonmalignant disease.
• Is unfit for treatment with a standard arabinosylcytosine (Ara-C) and anthracycline induction regimen due to age or co-morbidities defined by 1 of the following:
• ≥75 years of age. OR
• ≥18 to 1.5 times the upper limit of the normal range (ULN).
• Has clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug):
• Total bilirubin ≤1.5 times the ULN except in participants with Gilbert's syndrome. Participants with Gilbert's syndrome may enroll with direct bilirubin ≤3 times the ULN of the direct bilirubin. Elevated indirect bilirubin due to posttransfusion hemolysis is allowed.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 times the ULN.
• Creatinine clearance (CrCl) ≥30 mL/min (calculated by the Modification of Diet in Renal Disease [MDRD] Study equation).
• Albumin >2.7 g/dL.
• White blood cell (WBC) count 350 cells/mm^3.
• Undetectable viral load.
• Maintained on modern therapeutic regimens utilizing non-cytochrome P (CYP)-interactive agents.
• No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections.
• Participant is known to be positive for hepatitis B or C infection, with the exception of those with an undetectable viral load within 3 months (hepatitis B or C testing is not required for eligibility assessment).
• Has hepatic cirrhosis.
• Has uncontrolled coagulopathy or bleeding disorder.
• Has high blood pressure which cannot be controlled by standard treatments.
• Has prolonged rate QTc interval ≥500 msec, calculated according to institutional guidelines.
• Has left ventricular ejection fraction (LVEF) <40%, based on echocardiogram or multi gated acquisition (MUGA) scan at screening (data to be available within last 3 months of screening).
• As infection is a common feature of AML, participants with active infection are permitted to enroll provided that the infection is under control and no signs of systemic inflammatory response beyond low grade fever that makes participant clinically unstable in the opinion of the investigator. Participants with uncontrolled infection shall not be enrolled until infection is treated and brought under control.