Background: Hypomethylating agents azacitidine and decitabine are not readily bioavailable orally due to their degradation in the gut and liver by CDA. We developed a selective, potent, and safe CDA inhibitor cedazuridine. The combination of cedazuridine with decitabine delivered orally as an FDC tablet is developed to achieve an equivalent AUC exposure to IV decitabine.
Methods: A phase 1-2 study was conducted in 124 patients eligible to receive IV decitabine. The phase 1 dose escalation (n=44 patients) established a recommended dose for both oral decitabine (35 mg), and cedazuridine (100 mg) likely to achieve a decitabine AUC exposure equivalent to decitabine IV at 20 mg/m2. The phase 2 (n=80 patients) was conducted using a randomized cross-over design comparing IV decitabine to oral ASTX727 to confirm intra-patient decitabine AUC exposure equivalence between standard IV decitabine and the selected ASTX727 FDC doses (35/100 mg decitabine/cedazuridine).
Results: In the phase 2 patients were randomized to either decitabine IV 20 mg/m2/d x5 or oral ASTX727 (decitabine/cedazuridine 35/100 mg/d) x5 Q 28 days in Cycle 1 and crossed over to the other arm in Cycle 2. All patients continued to receive oral ASTX727 from Cycle 3 onwards until progression or treatment discontinuation for other reasons. The median age was 69.7 years, median weight was 82.7 Kg (range 40-122), and median BSA was 1.99 m2 (range 1.3-2.4). The MDS-IPSS status of the patients was Int-1 in 44%, Int-2 in 24%, and HR in 11%, with 21% having CMML. No differences were observed between the 2 randomized arms. The decitabine AUC0-t (h*ng/mL) 5-Day geometric mean estimate was 745 from decitabine IV and 727 from the oral FDC tablet resulting in an oral/IV AUC ratio of 97.6% (80% CI of 80, 118%). Hypomethylating activity as measured by LINE-1 demethylation, and safety were comparable between decitabine IV and oral ASTX727 in the first 2 randomized cycles. Of note is the absence of grade 3 or higher GI AEs related to ASTX727. Overall response rate in the phase 2 population was 65% including 18% CR by the IWG 2006 MDS response criteria
Conclusions: ASTX727 FDC oral tablet at the selected doses (35/100 mg decitabine/cedazuridine) with no body weight or BSA adjustment achieved an equivalent decitabine AUC exposure to IV decitabine 20 mg/m2 over the 5-day cycle. LINE-1 demethylation and safety in the 2 randomized cycles were comparable and overall response rate was consistent with expected decitabine IV clinical response
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