Study of MLN4924 Plus Azacitidine in Treatment-naive Participants With Acute Myelogenous Leukemia (AML) Who Are 60 Years or Older

Inclusion criteria

• Participants with world health organization (WHO)-defined AML, 60 years of age or older, who are unlikely to benefit from standard induction therapy, defined as having at least 1 of the following:

• Greater than or equal to 75 years of age.
• Antecedent hematologic disease.
• Known adverse cytogenetic risk.
• Eastern Cooperative Oncology Group (ECOG) PS = 2.
• Participant must not have received definitive treatment for AML, defined as any prior chemotherapy with antileukemic activity.
• ECOG PS 0 to 2.
• Expected survival longer than 3 months from enrollment in the study.
• Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to practice true abstinence.
• Male participants who agree to practice effective barrier contraception or agree to practice true abstinence.
• Voluntary written consent must be given before performance of any study-related procedure.
• Suitable venous access for the study-required blood sampling.
• Clinical laboratory values as specified below within 3 days before the first dose of any study drug:

•Total bilirubin must be less than or equal to (<=) the upper limit of the normal range (ULN).

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be<=2.5*ULN.
• Serum creatinine <=1.5*ULN.
• Albumin greater than or equal to (>=) 27 grams per liter (g/L).
• Hemoglobin >9 grams per deciliter (g/dL). Note: It was permissible to transfuse participants with red blood cells to achieve this criterion.
• White blood cell (WBC) count less than (<) 50,000 per microliter (/mcL) before administration of pevonedistat on Days 1, 3, and 5 of Cycle 1.

Note: Hydroxyurea could be used to control the level of circulating leukemic blast cell counts to no lower than 10,000/mcL while on pevonedistat.

• Able to undergo bone marrow aspiration and biopsy at screening.

Exclusion criteria

• Previous treatment with azacitidine or decitabine.
• Known favorable cytogenetic risk.
• Any serious medical or psychiatric illness.
• Treatment with any investigational products.
• Known hypersensitivity to azacitidine or mannitol.
• Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.
• Active uncontrolled infection or severe infectious disease.
• Major surgery within 14 days before the first dose of study drug.
• Life-threatening illness unrelated to cancer.
• Clinically uncontrolled central nervous system (CNS) involvement.
• WBC count greater than (>) 50,000/ mcL.
• Prothrombin time (PT) or activated partial thromboplastin time (aPTT) >1.5* ULN or a history of coagulopathy or bleeding disorder
• Known human immunodeficiency virus (HIV) positive.
• Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection
• Known hepatic cirrhosis or severe pre-existing hepatic impairment.
• Known cardiac/cardiopulmonary disease defined as 1 of the following:

• Uncontrolled high blood pressure (that is, systolic blood pressure >180 milliliter per mercury (mm Hg), diastolic blood pressure >95 mm Hg).
• Congestive heart failure New York Heart Association (NYHA) Class III or IV, or Class II with a recent decompensation that required hospitalization or referral to a heart failure clinic within 4 weeks before screening (see Section 15.4 of the protocol in Appendix 16.1.1).
• Cardiomyopathy or history of ischemic heart disease
• Participants with ischemic heart disease who had acute coronary syndrome (ACS), myocardial infarction (MI), and/or revascularization (example, coronary artery bypass graft, stent) in the past 6 months were excluded. However, participants with ischemic heart disease who had ACS, MI, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms could be enrolled.
• Arrhythmia (example, history of polymorphic ventricular fibrillation or torsade de pointes). However, participants with <Grade 3 atrial fibrillation (a fib) for a period of at least 6 months could enroll. Grade 3 a fib is symptomatic and incompletely controlled medically, or controlled with device (example, pacemaker), or ablation. Participants with paroxysmal a fib were permitted to enroll.
• Implantable cardioverter defibrillator.
• Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing).
• Pulmonary arterial hypertension. Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to institutional guidelines
• Left ventricular ejection fraction
• Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis.
• Body mass index >40 kilogram per square meter (kg/m^2).
• Treatment with CYP3A inducers within 14 days before the first dose of MLN4924.
• Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of study drug, except for hydroxyurea.