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)

The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to
treat people with MDS or CMML, or low-blast AML as a combination treatment with azacitidine.
This study will look at the overall survival, event free survival and response to treatment
in people who take pevonedistat and azacitidine when compared to people who take single-agent
azacitidine.

The study will enroll 120 participants. Once enrolled, participants will be randomly assigned
(by chance, like flipping a coin) to one of the two treatment groups in 28-day treatment
cycles:

- Pevonedistat 20 mg/m^2 and azacitidine 75 mg/m^2 combination

- Single-agent azacitidine 75 mg/m^2

All participants will receive azacitidine via intravenous or subcutaneous route. Participants
randomized to the combination arm will also receive pevonedistat intravenous infusion.

This multi-center trial will be conducted worldwide. The overall time to participate in this
study is approximately 44 months. Participants will attend the end-of-treatment visit 30 days
after the last dose of study drug or before the start of subsequent anti-neoplastic therapy
if that occurs sooner. Participants will enter event-free survival follow-up or response
follow-up (study visits every 3 months) if their disease has not transformed to AML (for
participants with HR MDS or CMML) or progressed (for participants with low-blast AML), and
they have not started subsequent therapy. Participants will also enter overall survival
follow-up (contacted every 3 months to document subsequent therapies and survival status).

Inclusion Criteria:

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. 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 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.

Exclusion Criteria:

1. Previous treatment with decitabine or azacitidine or other hypomethylating agent.

2. 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.

3. Eligible for allogenic stem cell transplantation.

4. Participants with MDS, CMML, or low blast AML, whose only site of disease is
extramedullary, example, the skin.

5. Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of study procedures or could limit
participant expected survival to less than 6 months.

6. Treatment with any anti leukemic/anti MDS therapies (example, lenalidomide,
cytarabine, anthracyclines, purine analogs) or with any investigational products
within 14 days before the first dose of any study drug.

7. Known hypersensitivity to mannitol.

8. Active uncontrolled infection or severe infectious disease, such as severe pneumonia,
meningitis, or septicemia.

9. Major surgery within 14 days before first dose or a scheduled surgery during study
period; insertion of a venous access device (example, catheter, port) is not
considered major surgery.

10. Diagnosed or treated for another malignancy within 2 years before randomization or
previously diagnosed with another malignancy and have any evidence of residual
disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type
are not excluded if they have undergone resection.

11. Life threatening illness unrelated to cancer.

12. Prothrombin time (PT) or prolongation of the activated thromboplastin time (aPTT) >1.5
ULN or active uncontrolled coagulopathy or bleeding disorder.

13. Known human immunodeficiency virus (HIV) seropositive.

14. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis
C infection. Note: Participants who have isolated positive hepatitis B core antibody
(that is, in the setting of negative hepatitis B surface antigen and negative
hepatitis B surface antibody) must have an undetectable hepatitis B viral load.

15. Known hepatic cirrhosis or severe pre-existing hepatic impairment.

16. Known cardiopulmonary disease defined as unstable angina, clinically significant
arrhythmia, congestive heart failure (New York Heart Association [NYHA] Class III or
IV) and/or myocardial infarction within 6 months prior to first dose, or severe
pulmonary hypertension. As an example, well controlled atrial fibrillation would not
be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion.

17. Treatment with strong cytochrome P450 (CYP) 3A inhibitors or inducers within 14 days
before the first dose of study drug.

18. Systemic antineoplastic therapy or radiotherapy for other malignant conditions within
12 months before the first dose of any study drug, except for hydroxyurea.

19. Female participants who are lactating and breast feeding 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.

20. Female participants who intend to donate eggs (ova) during the course of this study or
4 months after receiving their last dose of study drug(s).

21. Male participants who intend to donate sperm during the course of this study or 4
months after receiving their last dose of study drug(s).