Uridine triacetate for early onset, severe life-threatening toxicities of 5-fluorouracil and capecitabine.

e21675 Background: Uridine triacetate was approved by FDA in late 2015 for adult and pediatric patients who receive an overdose of 5-fluorouracil or capecitabine or who exhibit early-onset, severe or life-threatening toxicities. Early-onset toxicities occur in patients due to genetic susceptibilities, including DPD deficiency that affect 5-FU exposure, anabolism and actions, and can be fatal. High-risk early-onset toxicities fall into several major categories–GI (mucositis, ulceration); hematologic (leukopenia, neutropenia, thrombocytopenia); CNS toxicities (such as altered mental status, encephalopathy/coma, ataxia); and severe cardiotoxicities (such as acute left ventricular dysfunction or serious vasospasm). Uridine triacetate is an oral prodrug of uridine, a direct antagonist that dilutes and competes with toxic 5-FU metabolites, particularly FUTP incorporation into RNA, and thereby reduces morbidity and mortality due to 5-FU and capecitabine. Methods: In 2 clinical studies, 173 patients have been treated with uridine triacetate to date, including 26 who presented with early-onset (within 96 hr post 5-FU or capecitabine dosing) severe toxicities. The Sponsor (Wellstat Therapeutics) was contacted by clinical sites upon recognition of early-onset toxicities and eligibility was evaluated. Treatment with uridine triacetate was to initiate as soon as possible within 96 hr post 5-FU/capecitabine dosing. The primary efficacy endpoint was survival at 30 days following uridine triacetate administration. Results: Of the 26 patients with early-onset, severe toxicities, all 18 initiating uridine triacetate within the 96-hr treatment window recovered and survived. Of 8 patients with comparable presenting symptoms treated outside of the 96-hr time window, 5 (63%) died during the 30 day monitoring period. Conclusions: Uridine triacetate was an effective life-saving antidote for patients following early-onset, severe GI, hematologic, cardiac and neurologic toxicities due to either 5-FU or capecitabine when administered within 96 hr after the end of fluoropyrimidine dosing.