Study to Compare Azacitidine Plus Pevonedistat Versus Azacitidine in Patients With Acute Myeloid Leukemia Not Eligible for Standard Chemotherapy

Randomized phase III, multicentre, open label clinical trial to compare pevonedistat in combination with azacytidine versus azacytidine alone, which can be considered a standard of care for patients with newly diagnosed acute myeloid leukemia not eligible for intensive chemotherapy (thus not eligible for an allogeneic hematopoietic stem cell transplant.

Inclusion Criteria: 1. Male or female patients 18 years or older 2. Morphological diagnosis of Acute Myeloid Leukemia (AML) (WHO criteria 2008) 3. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 3 (ECOG 0-2 for patients greater than or equal to 75 years old). 4. Newly diagnosed AML 5. Patient must be considered be ineligible for treatment with a standard Ara-C and anthracycline induction regimen due to age or co-morbidities defined by one of the following: 1. ≥ 75 years of age 2. Or ≥ 18 to 74 years of age with at least one of the following: * ECOG Performance Status of 2 or 3; * Cardiac history of cardiac heart failure requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina; * Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) ≤ 65% or Forced Expiratory Volume in 1 second (FEV1) ≤ 65% or significant history of chronic pulmonary obstructive disease; * Glomerular filtration rate (GFR) ≥ 30 mL/min to \< 50 ml/min or levels of creatinine between the upper limit of the normal range (ULN) and 2.5 mg/dL (≤ 250 μmol/l). * Hepatic impairment with total bilirubin \> 1.5 to ≤ 3 × ULN or with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \> 2.5×ULN to ≤ 5×ULN * Non active/controlled prior neoplastic disease * Any other patient´s comorbidity or disease condition that the physician judges to be incompatible with intensive chemotherapy must be reviewed, documented, and approved by the Sponsor before study enrollment). 6. 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 × ULN except in patients with Gilbert's syndrome or ≤ 3 × ULN if elevation is attributed to underlying leukemia. Patients with Gilbert's syndrome may enroll with direct bilirubin ≤3 × ULN of the direct bilirubin. Elevated indirect bilirubin due to posttransfusion hemolysis is allowed. * ALT and AST ≤ 2.5×ULN or ≤ 5×ULN if elevation is attributed to underlying leukemia. * Adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min (calculated by the Cockcroft Gault formula, (see Appendix 5). * Albumin \>2.7 g/dL. 7. Subject has a white blood cell count \ 50 × 109/L. 9. Contraindications for PEVO or AZA. 10. Known hypersensitivity to pevonedistat or its excipients. 11. Female patients who intend to donate eggs (ova) during the course of this study or for 4 months after receiving their last dose of study drug(s). 12. Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug. 13. Male patients who intend to donate sperm or father a child during the course of this study or for 4 months after receiving their last dose of study drug(s). 14. Subject is known to be positive for HIV (HIV testing is not required for eligibility assessment). Known HIV positive patients who meet the following criteria will be considered eligible: * Cluster of differentiation 4 (CD4) count \> 350 cells/mm3 * Undetectable viral load * Maintained on modern therapeutic regimens utilizing non-cytochrome P450 (CYP)-interactive agents * No history of AIDS-defining opportunistic infections 15. Subject 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). 16. Known hepatic cirrhosis or severe preexisting hepatic impairment. 17. Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV; see Appendix 7), and/or ST elevation myocardial infarction within 6 months before first dose, or severe symptomatic pulmonary hypertension requiring pharmacologic therapy, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. As an example, well-controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled. 18. Subject has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study. 19. Treatment with strong Cytochrome P450, family 3, subfamily A (CYP3A) inducers (see Appendix 8) within 14 days before the first dose of pevonedistat. 20. Patients with uncontrolled coagulopathy or bleeding disorder. 21. High blood pressure which cannot be controlled by standard treatments 22. Prolonged rate corrected QT (QTc) interval ≥ 500 msec, calculated according to institutional guidelines. 23. As infection is a common feature of AML, patients 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 patient clinically unstable in the opinion of the investigator. Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control. 24. Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent and until toxicity from this has resolved to grade 1 or less; if the half-life of the agent is unknown, patients must wait 4 weeks prior to first dose of study treatment. 25. Systemic antineoplastic therapy for malignant conditions other than myeloid neoplasms within 14 days before the first dose of any study drug.