SY-2101 is a novel oral formulation of arsenic trioxide (ATO). While intravenous (IV) ATO in combination with all trans retinoic acid is highly efficacious in the treatment of acute promyelocytic leukemia (APL) there remains a significant unmet need for patients due to the treatment burden associated with receiving daily ATO infusions over nearly a year of treatment and the risk of complications associated with indwelling central catheters. The pharmacokinetics (PK), safety, and tolerability of SY-‑2101 and ATO IV following 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 AUC0-last and AUC0-inf. The GMR of SY-2101 to ATO IV Cmax was 0.76. This difference in Cmax was expected due to the different route of administration. Comparisons of SY-2101 in fed to fasted states also showed similar exposure and no clinically relevant differences with GMRs of AUC0-last, AUC0-inf, and Cmax of 1.08, 1.12, and 0.85, respectively, allowing for administration of SY-2101 with or without food. SY-2101 was well tolerated. The majority of adverse events were low grade. This study provides the first intrapatient PK crossover results directly comparing SY-2101 to ATO IV and supports the likelihood of clinical equivalence between the two formulations if used to treat patients with APL. NCT04996030.