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.
- 18 years or older.
- Diagnosis of low or Int-1 risk MDS
- Low platelet count, and/or low hemoglobin, and/or RBC transfusion-dependent and/or platelet transfusion-dependent
- ECOG Performance status 0-2
- Standard safety inclusion for serum creatinine, AST, ALT, bilirubin.
- Serum bicarbonate greater than or equal to 20 mEq/L.
- Use of acceptable birth control.
- Signed, written informed consent.
- Diagnosis of acute PML.
- Previous or concurrent malignancy.
- Prior treatment with azacitidine or other demethylating agents.
- Treatment with any anticancer therapy or investigational drugs within 21 days.
- Hypersensitivity to azacitidine or mannitol.
- Presence of GI disease.
- Active, uncontrolled infection.
- Known Human Immunodeficiency Virus (HIV) or Hepatitis C, or known active viral Hepatitis B.
- Breastfeeding or Pregnant females;
- Presence of serious illness, medical condition, or other medical history which would be likely to interfere with a subject's participation in the study or with the interpretation of the results.
- Current congestive heart failure (NY Heart Association Class III-IV), unstable angina or angina requiring surgical or medical intervention within 6 months, myocardial infarct within 6 months, or uncontrolled cardiac arrhythmia.
Last updated: 05/18/2012
NCT ID: NCT00528983