Clinical trial experience with uridine triacetate for 5-fluorouracil toxicity.

Abstract

655 Background: Life-threatening or lethal 5-FU toxicity occurs due to infusion pump/reservoir errors and 5-FU dosage miscalculations. Additionally, DPD-deficient patients often experience serious or lethal toxicity. Regardless of DPD status, some patients demonstrate severe, early-onset toxicities (as early as during 5-FU infusion) such as encephalopathy or cardiotoxicity. Uridine triacetate is an orally bioavailable prodrug of uridine, a direct antagonist of 5-FU, that competitively inhibits 5-FU incorporation in normal tissues and can counter 5-FU toxicity, reducing morbidity and mortality due to toxicity. Methods: 135 patients at excess risk of 5-FU toxicity due to overdose or accidental capecitabine ingestion (n = 111); or DPD deficiency and/or who showed rapid onset of severe toxicities (n = 24) have been treated with uridine triacetate under emergency IND or expanded access protocols. Patients were to receive uridine triacetate granules (10g q6h for 20 doses) up to 96h after the termination of 5-FU therapy. Clinical endpoints included survival compared with historical controls, time to resumption of chemotherapy, and safety. Results: A total of 130/135 (96%) patients treated with uridine triacetate recovered fully (within 30 days after receiving uridine triacetate), including rapid reversal of cardiotoxicity (EKG abnormalities, chest pain, etc) and neurotoxicity (altered mental status, ataxia, etc). Of the 111 overdose patients, 24 had a pump malfunction; 49 dose error; 5 had accidental capecitabine ingestion (2 adults/3 peds); 33 unknown. No patient who received uridine triacetate within 96 h after stopping 5-FU died. Comparatively, 38 of the 47 historical controls (81%) with 5-FU overexposure died. Of the 106 overdose patients with a diagnosis of cancer, 40 (37.7%) resumed chemotherapy within 30 days (median 20.0 days post-5-FU), highly indicative of rapid recovery from toxicity. Overall compliance was 92.5% (mean 18.3/20 doses). Mild, infrequent adverse events (diarrhea/nausea/vomiting) were attributed to uridine triacetate. Conclusions: In this study, uridine triacetate was a safe and effective life-saving antidote for 5-FU overexposure, and facilitated rapid resumption of chemotherapy. Clinical trial information: NCT01432301.