SGI-110 in Patients With Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML)

• Dose Escalation Segment (Safety Lead-in): Determine the optimal BED or MTD and the frequency of drug administration. [ Time Frame: Assessed at the end of Course 1 (4 weeks) for each dose cohort. ] [ Designated as safety issue: Yes ]
  • Number of patients with adverse events.
  • Incidence of dose limiting toxicities.
  • Degree of hypomethylation as measured by LINE-1.
• Dose Expansion Segment: Assess the activity of SGI-110 as measured by overall remission rate. [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
  Overall survival measured in weeks.

• Determine the pharmacokinetic profile of SGI-110 and decitabine. [ Time Frame: Assessed at the end of Course 1 (4 weeks) for each cohort. ] [ Designated as safety issue: No ]
  Cmax, Cmin, AUC and other secondary PK parameters of SGI-110 and decitabine in patients during Course 1.
• Remission duration, hematological improvements and transfusion independence rates. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Assess remission duration, hematological improvement and transfusion independence rates as measured by weeks.
• Determine epigenetic modulation in peripheral blood and bone marrow samples. [ Time Frame: 12 months ] [ Designated as safety issue: No ]

• Determine the pharmacokinetic profile of SGI-110 and decitabine. [ Time Frame: Assessed during course one ] [ Designated as safety issue: No ]
• Remission duration, hematological improvement, and transfusion independence rates. [ Time Frame: Assessed at each visit ] [ Designated as safety issue: Yes ]
• Determine epigenetic modulation in peripheral blood and bone marrow samples and whether any putative biomarkers for SGI-110 response exist. [ Time Frame: At each course ] [ Designated as safety issue: No ]

Phase 1-2 dose escalation randomized study in patients with intermediate or high risk myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML). The Dose Escalation Segment will evaluate the biological activity, preliminary safety and efficacy of SGI-110 with two dosing schedules in MDS and AML patients while the Dose Expansion Segment will further evaluate safety and efficacy at the biological effective dose (BED) or maximum tolerated dose (MTD)as defined in the Dose Escalation Segment.

Once the BED and MTD is determined in the Dose Escalation Segment, the Dose Expansion Segment will randomize patients with MDS, treatment naïve elderly AML, and relapsed/refractory AML patients to receive the BED or MTD dose. Relapsed/refractory AML patients may also receive SGI-110 on a daily x 10 schedule based on the total dose per cycle evaluated in the Dose Escalation Segment using the 5-daily regimen.

• MDS
• CMML
• AML

• Drug: SGI-110
  • SGI-110 subcutaneous injection administered on Days 1-5
  • SGI-110 subcutaneous injection administered on Days 1-5 and 8-12
• Drug: SGI-110
  • SGI-110 administered weekly on Days 1, 8 and 15
  • SGI-110 administered weekly on Days 1, 4, 8, 11, 15, and 18

• Experimental: Daily Regimen
  • SGI-110 daily x5 dosing on a 28-day course
  • SGI-110 daily x10 dosing on a 28-day course
  Intervention: Drug: SGI-110
• Experimental: Weekly Regimen
  • SGI-110 weekly dosing for three weeks on a 28-day course
  • SGI-110 twice weekly dosing for three weeks on a 28-day course
  Intervention: Drug: SGI-110

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.