An Efficacy and Safety Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML) and Low-Blast Acute Myelogenous Leukemia (AML)

1. Male or female participants 18 years or older.

2. Morphologically confirmed diagnosis of MDS or nonproliferative CMML (that is, with white blood cells \[WBC\] \<20,000 per microliter \[/mcL\]) or low blast AML based on 1 of the following:

French American British (FAB) Classifications:

* Refractory anemia with excess blasts (RAEB) - defined as having 5% to 20% myeloblasts in the bone marrow.

* CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.

OR

WHO Classifications:

* RAEB 1 - defined as having 5% to 9% myeloblasts in the bone marrow.

* RAEB 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.

* CMML 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.

* CMML 1 (Although CMML 1 is defined as having \<10% myeloblasts in the bone marrow and/or \<5% blasts in the blood, these participants may enroll only if bone marrow blasts \>=5%.

* WHO defined AML with 20% to 30% myeloblasts in the bone marrow and \<30% myeloblasts in peripheral blood who are deemed by the investigator to be appropriate for azacitidine based therapy.

3. For MDS and CMML participants, prognostic risk category, based on the Revised International Prognostic Scoring System (IPSS R), of:

* Very high (\>6 points),

* High (\>4.5 to 6 points), or

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

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

5. 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):

* Albumin \>2.7 g/dL.

* Total bilirubin \<upper limit of normal (ULN) except in participants with Gilbert's syndrome. Participants with Gilbert's syndrome may enroll if direct bilirubin \<=1.5\*ULN of the direct bilirubin.

* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<2.5\*ULN.

* Creatinine clearance \>=50 milliliter per minutes (mL/min).

* Hb \>8 g/dL. Participants may be transfused to achieve this value. Elevated indirect bilirubin due to post transfusion hemolysis is allowed.

6. For CMML participants: WBC count \<20,000/mcL before administration of the first dose of study drug on Cycle 1 Day 1; participants must have been off hydroxyurea for at least 1 week prior to WBC count assessment.

7. Ability to undergo the study required bone marrow sample collection procedures.

8. Suitable venous access for the study required blood sampling (that is, including pharmacokinetic (PK) and biomarker sampling).

9. Female participants who:

* Are postmenopausal for at least 1 year before the Screening visit , or

* Are surgically sterile, or

* If they are of childbearing potential, agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, or

* Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[example, calendar, ovulation, symptothermal, postovulation methods\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).

Male participants, even if surgically sterilized (that is, status postvasectomy), who:

* Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or

* Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[example, calendar, ovulation, symptothermal, postovulation methods for the female partner\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).

10. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

What this study is about