Inclusion Criteria:

• Cytologically or histologically confirmed diagnosis of AML (except M3 acute promyelocytic leukemia) according to WHO classification.
• Performance status (ECOG) of 0-3. Adults with previously untreated AML except for hydroxyurea or corticosteroids. Prior hydroxyurea or lenalidomide treatment for myelodysplastic syndrome (MDS) is allowed.
• Not considered candidates for intensive remission induction chemotherapy at time of enrollment based on EITHER:
  • ≥75 years of age OR
  • <75 years of age with at least 1 of the following:

1. Poor performance status (ECOG) score of 2-3.
2. Clinically significant heart or lung comorbidities, as reflected by at least 1 of:
   1. Left ventricular ejection fraction (LVEF) ≤50%.
   2. Lung diffusing capacity for carbon monoxide (DLCO) ≤65% of expected.
   3. Forced expiratory volume in 1 second (FEV1) ≤65% of expected.
   4. Chronic stable angina or congestive heart failure controlled with medication.
3. Liver transaminases >3 × upper limit of normal (ULN).
4. Other contraindication(s) to anthracycline therapy (must be documented).
5. Other comorbidity the investigator judges incompatible with intensive remission induction chemotherapy, which must be documented and approved by the study medical monitor before randomization.

• Creatinine clearance as estimated by the Cockroft-Gault (C-G) or other medically acceptable formulas ≥30 mL/min.

Exclusion Criteria:

• Candidate for intensive remission induction chemotherapy at the time of enrollment.
• Candidate for best supportive care only, ie, not a candidate for any active therapy with the TC comparators.
• Known extramedullary central nervous system (CNS) AML.
• Second malignancy currently requiring active therapy except breast or prostate cancer stable on or responding to endocrine therapy.
• Prior treatment with decitabine or azacitidine.
• Hypersensitivity to decitabine, SGI-110, or SGI-110 excipients.
• Known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals is allowed.
• Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol.
• Refractory congestive heart failure unresponsive to medical treatment; active infection resistant to all antibiotics; or advanced pulmonary disease requiring >2 liters per minute (LPM) oxygen.