A Phase 1b, Open-Label, Dose-Escalation Study of MLN4924 Plus Azacitidine in Treatment-Naïve Patients With Acute Myelogenous Leukemia Who Are 60 Years or Older

Inclusion Criteria:

- Patients with WHO-defined AML, 60 years of age or older, who are unlikely to benefit
from standard induction therapy, defined as having at least 1 of the following:

1. Greater than or equal to 75 years of age

2. Antecedent hematologic disease

3. Known adverse cytogenetic risk

4. Eastern Eastern Cooperative Oncology Group (ECOG) PS = 2

- Patient must not have received definitive treatment for AML, defined as any prior
chemotherapy with antileukemic activity

- ECOG PS 0 to 2

- Expected survival longer than 3 months from enrollment in the study

- Female patients who are post menopausal, surgically sterile, or agree to practice 2
effective methods of contraception or agree to practice true abstinence

- Male patients who agree to practice effective barrier contraception or agree to
practice true abstinence

- Voluntary written consent must be given before performance of any study-related
procedure

- Suitable venous access for the study-required blood sampling

- Adequate clinical laboratory values during the screening period as specified in the
protocol

- Able to undergo bone marrow aspiration and biopsy at screening

Exclusion Criteria:

- Previous treatment with azacitidine or decitabine

- Known favorable cytogenetic risk

- Any serious medical or psychiatric illness

- Treatment with any investigational products

- Known hypersensitivity to azacitidine or mannitol

- 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

- Active uncontrolled infection or severe infectious disease

- Major surgery within 14 days before the first dose of study drug

- Life-threatening illness unrelated to cancer

- Clinically uncontrolled central nervous system (CNS) involvement

- Known human immunodeficiency virus (HIV) positive

- Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C
infection

- Known hepatic cirrhosis or severe pre-existing hepatic impairment

- Known cardiac/cardiopulmonary disease

- Left ventricular ejection fraction

- Known moderate to severe chronic obstructive pulmonary disease, interstitial lung
disease, and pulmonary fibrosis

- Body mass index > 40 kg/m²

- Treatment with CYP3A inducers within 14 days before the first dose of MLN4924

- Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose
of study drug, except for hydroxyurea

- Patients who are unwilling or unable to refrain from using hydroxymethylglutaryl
coenzyme A (HMG CoA) reductase inhibitors (statins) starting 5 days before the
initial study drug administration and throughout the study will not be permitted to
enroll