A Phase 1 Study to Assess the Absolute Bioavailability and Safety of An Oral Solution of Decitabine In Subjects with Myelodysplastic Syndromes (MDS),

Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases indicated for treatment of myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes. The aim of this study was to determine the absolute bioavailability and safety of a single oral dose of decitabine. Methods: This is an open-label, Phase 1, dose-escalation absolute bioavailability trial in which decitabine was administered orally on Cycle 1 Day 1, and followed by a 1-hour IV infusion of the currently approved regimen (20 mg/m²) on Cycle 1 Days 2–5. Serial blood samples for decitabine pharmacokinetic (PK) assessment were collected up to 6 h post-dosing during Cycle 1 on Days 1 and 2. Three subjects were recruited at each oral dose level of 30, 60, 120 and 240 mg. Subjects were evaluated for adverse events (AEs). Results: Study results are summarized in Table 1. Sixteen subjects were screened and 12 were enrolled. Nine subjects had de novo MDS and 3 had secondary MDS (IPSS score Int-2 = 6, Int-1 = 5, Low = 1). Following oral dose, C_max was reached within 0.50 h (t_max) and after C_max the plasma profile showed biphasic decline with terminal half-life ranging between 0.36 to 0.93 hr. Increase in oral dose did not result in proportional increase in C_max and AUC. The PK parameters following oral doses showed very high variability. Based on comparison of dose normalized exposure, the absolute bioavailability ranged between 3.9 to 14.1% and increased proportionally with dose. The non-dose normalized bioavailabilities were calculated to find a dose at which mean oral bioavailability reaches ≥80% of the current IV regimen of 20 mg/m². The non-dose normalized bioavailability ranged between 11.7 and 80.5% with highest oral bioavailability observed at 240 mg dose. The most common SAEs were pneumonia (n=4) and neutropenic fever (n=4). Five patients (41.7%) experienced diarrhea and nausea (all grades). Conclusion: The study demonstrates that the absolute bioavailability ranged between 3.9 and 14.1%. Oral decitabine was generally well tolerated at doses between 30–240 mg in MDS subjects and exhibited a safety profile similar to the profile following intravenous administration. The bioavailability and safety data may allow for further testing in the phase 2 setting.

Mistry:Eisai Inc.: Employment. Jones:Eisai Inc.: Employment. Kubiak:Eisai Inc.: Employment. Garcia-Manero:Eisai Inc.: Research Funding. Litzow:Eisai Inc.: Research Funding. Mesa:Eisai Inc.: Research Funding. Tarassoff:Eisai Inc.: Employment. Cortes:Eisai Inc.: Research Funding.