A pharmacokinetic and safety study of oral arsenic trioxide in patients with acute promyelocytic leukemia

SY-2101 is a novel oral formulation of arsenic trioxide (ATO). Although IV ATO in combination with all trans retinoic acid is highly efficacious in treating acute promyelocytic leukemia (APL), there remains a significant unmet need due to the treatment burden associated with receiving daily ATO infusions for nearly a year and the risk of complications associated with indwelling central catheters. The pharmacokinetics (PK), safety, and tolerability of SY-2101 and ATO IV after single- and multiple-dose administration and the impact of food on PK for SY-2101 were evaluated in this phase 1 study in 15 participants with APL. SY-2101 in the fasted state demonstrated comparable systemic exposure to ATO IV based on the active metabolite arsenious acid [As(III)], with geometric mean ratios (GMRs) of SY-2101 to ATO IV of 1.00 for area under the plasma concentration (AUC) from 0 hour to last time point (AUC0-last) and from 0 hour to infinity (AUC0-inf). The GMR of SY-2101 to ATO IV maximum concentration (Cmax) was 0.76, as was expected due to the different routes of administration. Comparisons of SY-2101 in fed to fasted states demonstrated similar exposure with GMRs of AUC0-last, AUC0-inf, and Cmax at 1.08, 1.12, and 0.85, respectively, allowing for SY-2101 administration with or without food. SY-2101 was well tolerated. Most adverse events were of low grade. This study provides the first intrapatient PK crossover results directly comparing SY-2101 with ATO IV and supports the likelihood of clinical equivalence between the 2 formulations. This trial was registered at www.ClinicalTrials.gov as #NCT04996030.