Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute Myelogenous Leukemia (AML)

Inclusion Criteria:

1. Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or CMML (i.e., with white blood cell [WBC] <13,000/microliter [mcL]) or low-blast acutemyelogenous leukemia (AML).

2. Has MDS or CMML and must also have one of the following Prognostic Risk Categories,based on the Revised International Prognostic Scoring System (IPSS-R):

• Very high (>6 points).

• High (>4.5-6 points).

• Intermediate (>3-4.5 points): a participant determined to be in theIntermediate Prognostic Risk Category is only allowable in the setting of >=5%bone marrow myeloblasts.

3. Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2.

4. Participants with AML (20%-30% blasts) must have a treatment-related mortality (TRM)score >=4 for intensive, induction chemotherapy as calculated using the simplifiedmodel described by Walter and coworkers.

Calculation of TRM score:

• 0 for (age <61 years), +2 for (age 61-70 years), +4 for (age >=71 years).

• • 0 for (PS=0), +2 for (PS=1), +4 for (PS >1).
• • 0 for (platelets <50), +1 for (platelets >=50).

Exclusion Criteria:

1. Has previous treatment for HR MDS or CMML or low-blast AML with chemotherapy orother antineoplastic agents including hypomethylating agent (HMAs) such asdecitabine or azacitidine. Previous treatment is permitted with hydroxyurea and withlenalidomide, except that lenalidomide may not be given within 8 weeks before thefirst dose of study drug.

2. Has acute promyelocytic leukemia as diagnosed by morphologic examination of bonemarrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood orbone marrow, or by other accepted analysis.

3. Participants with AML with a WBC count >50,000/mcL. Participants who are cytoreducedwith leukapheresis or with hydroxyurea may be enrolled if they meet the eligibilitycriteria.

4. Is eligible for intensive chemotherapy and/or allogeneic stem cell transplantation.The reason a participant is not eligible for intensive chemotherapy and/orallogeneic stem cell transplantation may consist of one or more of the followingfactors:

• Age >75.

• Comorbidities.

• Inability to tolerate intensive chemotherapy (e.g., participants with AML with 20%-30% blasts and TRM >=4).

• Physician decision (e.g., lack of available stem cell donor).

• The reason a participant is not eligible should be documented in the electroniccase report form (eCRF).

5. Has either clinical evidence of or history of central nervous system involvement byAML.

6. Has active uncontrolled infection or severe infectious disease, such as severepneumonia, meningitis, or septicemia.

7. Is diagnosed or treated for another malignancy within 2 years before randomizationor previously diagnosed with another malignancy and have any evidence of residualdisease.

8. Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded ifthey have undergone resection.

9. Has prothrombin time (PT) or aPTT >1.5× upper limit of normal (ULN) or activeuncontrolled coagulopathy or bleeding disorder. Participants therapeuticallyanticoagulated with warfarin, direct thrombin inhibitors, direct factor Xainhibitors, or heparin are excluded from enrollment.

10. Has known human immunodeficiency virus (HIV) seropositive.

11. Has known hepatitis B surface antigen seropositive, or known or suspected activehepatitis C infection. Note: Participants who have isolated positive hepatitis Bcore antibody (i.e., in the setting of negative hepatitis B surface antigen andnegative hepatitis B surface antibody) must have an undetectable hepatitis B viralload.

12. Has known hepatic cirrhosis or severe preexisting hepatic impairment.

13. Has known cardiopulmonary disease defined as unstable angina, clinically significantarrhythmia, congestive heart failure (New York Heart Association Class III or IV),and/or myocardial infarction within 6 months before first dose, or severe pulmonaryhypertension.

14. Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before thefirst dose of pevonedistat.