Inclusion Criteria:

1. Men or women, 18 years of age or older, with a confirmed diagnosis of international prognostic scoring system (IPSS) intermediate-1, intermediate-2 or high-risk MDS including Chronic Myelomonocytic Leukemia (CMML) or AML.
   • In the Dose Escalation Segment, patients who are refractory, relapsed, or unresponsive to standard treatment.
   • In the Dose Expansion Segment, hypomethylating agent (HMA) treatment-naïve MDS subjects (including CMML), and intermediate-2 or high-risk MDS subjects (including CMML) relapsed or refractory to prior HMA treatment are allowed, and treatment-naïve AML subjects who are at least 65 years of age will be allowed if they also have at least one of the following criteria
     • AML secondary to MDS, chemotherapy, or radiation therapy
     • poor cytogenetics
     • pre-existing clinically significant dysfunction of the heart or Chronic Obstructive Pulmonary Disease (COPD)
     • poor performance status, Eastern Cooperative Oncology Group (ECOG), of 2
2. Eastern ECOG performance status of 0 to 2.
3. Adequate organ function.
4. Prior allogeneic stem cell transplant, no evidence of active graft-versus host disease (GVHD) and must be ≥ 2 weeks off immunosuppressive therapy.
5. No major surgery within 4 weeks of first dose of SGI-110.
6. No chemotherapy within 2 weeks of first dose of SGI-110 (minimum of 6 weeks for nitrosoureas and 8 weeks for bone marrow transplantation) with the exception of hydroxyurea which will be allowed during course 1 of treatment.
7. Sign an approved informed consent form for this study.

Exclusion Criteria:

1. In the Dose Expansion Segment, which includes the 10-day regimen, subjects who have received 2 complete full dose cycles or more of a hypomethylating agent (HMA) decitabine or azacitidine (except for intermediate-2 or high-risk MDS subjects (including CMML) relapsed or refractory to prior HMA treatment).
2. Acute promyelocytic leukemia (M3 classification).
3. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient has been disease free for at least 3 years.
4. Life-threatening illnesses other than AML or MDS, uncontrolled medical conditions or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, or put the study outcomes at risk.
5. Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).
6. Hypersensitivity to decitabine, SGI-110, or SGI-110 excipients.
7. With the exception of treatment-naïve elderly AML patients, patients with uncontrolled congestive heart failure (CHF), coronary heart disease (CAD), chronic obstructive pulmonary disease (COPD), or left ventricular ejection fraction (LVEF) of ≤ 50% are excluded, symptomatic or uncontrolled arrhythmias or on continuous corticosteroids.