Safety, Pharmacokinetics, and Pharmacodynamics of Oral Azacitidine in Subjects With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myelogenous Leukemia

• 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: 60 months ] [ Designated as safety issue: Yes ]
  
• Maximum-tolerated dose [ Time Frame: 60 months ] [ Designated as safety issue: Yes ]
  
• Pharmacodynamic blood and bone marrow samples will be collected and evaluated. [ Time Frame: 60 months ] [ Designated as safety issue: No ]
  

• Efficacy assessed by evidence of response (MDS subjects) and/or hematologic improvement (MDS subjects) examined using IWG criteria. [ Time Frame: 60 months ] [ Designated as safety issue: No ]
  
• Biologically active dose based on safety, PK and PD data. [ Time Frame: 60 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 was 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 was used to evaluate the new treatment schedules. The basic structure of the traditional "3 + 3" dose escalation design was used, but each cohort enrolled a minimum of 6 subjects in order to obtain additional data for dose escalation and treatment schedule evaluation decisions.

The study design has been revised to restrict enrollment to International Prognostic Scoring System (IPSS) low and intermediate (Int-1) risk MDS subjects in order to establish additional safety data in this population, as well as to determine a recommended dose and schedule for evaluation in this population in future efficacy studies. Up to 20 low and/or Int-1 risk MDS subjects may be evaluated in each of one or more treatment schedules. In addition, PK sampling will be eliminated as sufficient PK data has been generated in this and other studies evaluating oral azacitidine. The requirement for fasting around oral azacitidine dosing will also be relaxed. Subjects will be able to ingest oral azacitidine in a fasted state or with a light meal.