Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS)

Primary  To evaluate safety and tolerability of pevonedistat administered as a single agent in East Asian patients with relapsed/refractory (R/R) AML or R/R higher-risk (HR) MDS.  To evaluate safety and tolerability and determine the recommended phase 2/phase 3 dose of pevonedistat administered in combination with azacitidine in East Asian patients with AML or HR MDS.  To characterize the pharmacokinetics (PK) of pevonedistat administered as a single agent or in combination with azacitidine in East Asian patients. Secondary  To evaluate disease response in both AML and MDS that may be observed with the singleagent pevonedistat or with a combination of pevonedistat and azacitidine.

Pevonedistat (MLN4924, TAK-924)

pevonedistat hydrochloride (C21H26ClN5O4S)

Injection

10 mg/ml

Primary Outcome Measures :
1. • Number of Participants Reporting one or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Throughout study from Baseline up to 30 days after the last dose of study drug ]
2. Number of Participants With Dose Limiting Toxicities (DLTs) During Cycle [ Time Frame: Cycle 1 Day 1 up to end of Cycle 1 (Day 21 for single-agent groups and Day 28 for combination groups) ]
Toxicity will be evaluated according to NCI CTCAE, Version4.03. DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications.

3. Number of Participants With Markedly Abnormal Laboratory Values [ Time Frame: Baseline and up to 30 days after the last dose of study drug ]
4. Cmax: Maximum Observed Plasma Concentration for Pevonedistat [ Time Frame: Day 1: Pre-infusion and at multiple time points (up to 48 hours) post-infusion ]
5. AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time tau Over the Dosing Interval for Pevonedistat [ Time Frame: Day 1: Pre-infusion and at multiple time points (up to 48 hours) post-infusion ]
6. CL: Clearance [ Time Frame: Days 1 and 5: Day 1: Pre-infusion and at multiple time points (up to 48 hours) post-infusion ]

Secondary Outcome Measures :
1. Percentage of Participants With Overall Response [ Time Frame: Screening until CR or PR, assessed within 6 days before Day 21 for single-agent groups and Day 20 to 28 for combination groups of Cycle 2, 4 and every 3 cycles thereafter up to Day 35 for single-agent groups and Day 39 for combination groups ]
2. Percentage of Participants With CR [ Time Frame: Screening until CR or PR, assessed within 6 days before Day 21 for single-agent groups and Day 20 to 28 for combination groups of Cycle 2, 4 and every 3 cycles thereafter up to Day 35 for single-agent groups and Day 39 for combination groups ]

Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. East Asian patients aged 18 years or older (if local regulation requires a minimum age
for informed consent of more than 18 years, then patients must be the minimum age or
older per the local regulation) when written study informed consent is obtained must
meet 1 of the following diagnosis criteria for either the Single-Agent Arm or the
Combination Arm:
 Single-Agent Arm:
o Male and female patients with WHO-defined AML [1], including leukemia
secondary to prior chemotherapy or resulting from an antecedent hematologic
disorder, who have failed to achieve CR or who have relapsed after prior therapy
(R/R) and are not candidates for potentially curative treatment, or
o Male and female patients with WHO-defined MDS [2] that meets the
International Prognostic Scoring System [IPSS-R] criteria for the very high, high,
or intermediate risk group (Section 15.1) [3], for whom standard curative, lifeprolonging treatment does not exist or is no longer effective (R/R), or
o Male and female patients with WHO-defined CMML-2 or CMML-1 that meets
the IPSS-R criteria for the very high, high, or intermediate risk group
(Section 15.1), [3] for whom standard curative, life-prolonging treatment does
not exist or is no longer effective (R/R); CMML-1 patients must have bone
marrow blasts ≥5% [2].
 Combination Arm:
o Male and female patients with WHO-defined AML [1], including leukemia
secondary to prior chemotherapy or resulting from an antecedent hematologic
disorder, who have failed to achieve CR or who have relapsed after prior therapy
(R/R) and are not candidates for potentially curative treatment, or
o Male and female patients aged 60 years or older with previously untreated AML
who have bone marrow blasts <30% and who are not candidates for standard
induction chemotherapy, or
o Male and female patients with WHO-defined MDS [2] that meets the IPSS-R
criteria for the very high, high, or intermediate risk group (Section 15.1) [3], for
whom standard curative, life-prolonging treatment does not exist or is no longer
effective (R/R), or
o Male and female patients with previously untreated MDS [2] that meets the
IPSS-R criteria for the very high, high, or intermediate risk group (Section 15.1)
[3].
o Male and female patients with WHO-defined CMML-2 or CMML-1 that meets
the IPSS-R criteria for the very high, high, or intermediate risk group
(Section 15.1) [3]; CMML-1 patients must have bone marrow blasts ≥5% [2].
2. For all AML patients: white blood cell (WBC) count <50,000/µL before administration
of the first dose of pevonedistat on Cycle 1 Day 1. Note: hydroxyurea may be used to
control the level of WBC counts to no lower than 10,000/µL during the study.
3. For the CMML patients: morphologically confirmed nonproliferative CMML, ie, WBC
<20,000/µL before administration of the first dose of pevonedistat on Cycle 1 Day 1.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
(see Section 15.2).
5. Clinical laboratory values within the following parameters within 3 days before the first
dose of study drug:
 Albumin ≥2.7 g/dL.
 Total bilirubin ≤upper limit of normal (ULN).
 Alanine aminotransferase and AST ≤2.5×ULN.
 Calculated creatinine clearance ≥50 mL/min (see Section 15.3).
 Hemoglobin >8 g/dL. Patients may be transfused to achieve this value. Elevated
indirect bilirubin due to post-transfusion hemolysis is not exclusionary.
6. Able to undergo bone marrow aspiration and biopsy at Screening.
7. Suitable venous access for the study-required blood sampling (ie, including PK and
pharmacodynamic sampling).
8. Female patients who:
 Are postmenopausal (not due to other medical reasons) for at least 1 year before the
Screening visit, or
 Are surgically sterile, or
 If they are of childbearing potential, agree to practice 2 effective methods of
contraception, at the same time, from the time of signing the informed consent
through 4 months after the last dose of pevonedistat (for patients in the Single-Agent
Arm), or through 4 months after the last dose of azacitidine (for patients in the
Combination Arm), or
 Agree to practice true abstinence, when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal,
postovulation methods] and withdrawal are not acceptable methods of
contraception.)
Male patients, even if surgically sterilized (ie, 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 subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal,
postovulation methods for the female partner] and withdrawal are not acceptable
methods of contraception.)
9. 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 patient at any time without prejudice to future medical care.

Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Acute promyelocytic leukemia (as diagnosed by morphologic examination of bone
marrow, by fluorescent in situ hybridization or cytogenetics [t(15:17)] of peripheral
blood or bone marrow, or by other accepted analysis) or AML associated with t(9;22)
karyotypes or molecular evidence of such translocations.
2. (Combination Arm only) More than 3 prior lines of therapy.
3. (Combination Arm only) Prior therapy with hypomethylating agents (eg, azacitidine,
decitabine).
4. Eligibility for a hematopoietic stem cell transplant.
5. Female patients who are in the lactation period, even if they discontinue breastfeeding,
or who 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.
6. Any serious medical or psychiatric illness that could, in the investigator’s opinion,
potentially interfere with the completion of study procedures.
7. Treatment with any investigational products within 14 days before the first dose of any
study drug.
8. (Combination Arm only) Known hypersensitivity to azacitidine or mannitol.
9. Active, uncontrolled infection or severe infectious disease, such as severe pneumonia,
meningitis, septicemia, or methicillin-resistant Staphylococcus aureus infection.
10. Major surgery within 14 days before first dose or a scheduled surgery during the study
period.
11. Life-threatening illness unrelated to cancer.
12. Known central nervous system involvement.
13. Prothrombin time (PT) or activated partial thromboplastin time (aPTT) >1.5ULN or
active uncontrolled coagulopathy or bleeding disorder.
14. Known human immunodeficiency virus (HIV) seropositive.
15. Known hepatitis B surface antigen (HBsAg) seropositive or known or suspected active
hepatitis C infection. Note: patients who have isolated positive hepatitis B core antibody
(HBcAb) and/or positive hepatitis B surface antibody (HBsAb) (ie, in the setting of
negative HBsAg) may be included if they have an undetectable hepatitis B viral load.
Patients who have positive hepatitis C antibody may be included if they have an
undetectable hepatitis C viral load.
16. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
17. Known cardiopulmonary disease, defined as unstable angina, clinically significant
arrhythmia, or congestive heart failure (New York Heart Association Class III or IV; see
Section 15.4), myocardial infarction within 6 months of first dose of study drug, or
severe pulmonary arterial hypertension.
18. Left ventricular ejection fraction (LVEF) <50% as assessed by echocardiogram.
19. Treatment with moderate or strong CYP3A inhibitors or inducers within 14 days before
the first dose of pevonedistat as described in Section 15.5. Patients must have no history
of amiodarone use in the 6 months before the first dose of pevonedistat.
20. Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of
any study drug, except for hydroxyurea.