• Safety evaluation as measured by monitoring AEs, dose limiting toxicities, scheduled lab assessments, vital sign measurements, ECGs, & physical exams for study duration. Adverse changes in physical signs/symptoms will be graded according to CTC AE V.3.0. [ Time Frame: 8-42 months ] [ Designated as safety issue: Yes ]
  
• Maximum-tolerated dose [ Time Frame: 8-42 months ] [ Designated as safety issue: Yes ]
  
• Pharmacokinetic blood and urine samples will be collected and evaluated. [ Time Frame: Part 1: On 5 different days over 7 cycles, collected at predose and 11 timepoints post-dosing Part 2: On 3 different days over 6 cycles, collected at predose and 11 timepoints post-dosing. ] [ Designated as safety issue: No ]
  
• Pharmacodynamic blood and bone marrow samples will be collected and evaluated. [ Time Frame: Ongoing throughout the study. ] [ Designated as safety issue: No ]
  

• Efficacy assessed by evidence of response (MDS, CMML and AML subjects) and/or hematologic improvement (MDS and CMML subjects) examined using IWG criteria. CMML subject will be assessed according to IWG response criteria for MDS [ Time Frame: 8 - 42 months ] [ Designated as safety issue: No ]
  
• Biologically active dose based on safety, PK and PD data. [ Time Frame: 8-42 months ] [ Designated as safety issue: No ]
  

The efficacy and safety of azacitidine has been established by the SC and IV routes. The FDA-approved starting dose is 75mg/m2/day for 7 days every 28 days. However, an orally active formulation of azacitidine would provide a more desirable route of administration and eliminate the risk of injection site reactions observed when azacitidine is administered subcutaneously. The oral route may also provide a less complicated administration method for long-term, lower dose, maintenance therapy and greater access to therapy for patients unable to make daily trips to the clinic for drug administration.

This is a multicenter, open-label, Phase 1, sequential design, dose-escalation study of oral azacitidine. The study is designed to evaluate the MTD, DLTs, safety, PK profiles, and PD profiles of increasing doses and different treatment schedules of orally administered azacitidine.

The study was originally designed to determine the safety of oral azacitidine when administered once a day (QD) for 7 consecutive days in a 28-day cycle. The study design has been revised to include the evaluation of oral azacitidine administered on 14-day QD, 14-day BID, 21-day QD, and 21-day BID treatment schedules in order to determine whether one or more of these schedules should be further evaluated in a Phase 2 efficacy study. A more conservative approach to dose escalation will be used to evaluate the new treatment schedules. The basic structure of the traditional "3 + 3" dose escalation design will still be used, but each cohort will enroll a minimum of 6 subjects in order to obtain additional data for dose escalation and treatment schedule evaluation decisions. The 14-day QD schedule will be evaluated first, at a starting dose that is approximately 2 dose levels below the MTD established for the 7-day QD schedule. The decision to evaluate one or more of the other schedules (14-day BID, 21-day QD and 21-day BID) will be made based on safety observed in prior cohorts.