Phase I clinical trial of 5-fluoro-pyrimidinone (5FP), an oral prodrug of 5-fluorouracil (5FU)

5-Fluoro-Pyrimidinone (5FP) is an oral pro-drug of 5-Fluorouracil (5FU), and is converted to 5FU by hepatic aldehyde oxidase. Preclinically, 5FP demonstrated anti-tumor activity against colon 38 and P 388 leukemia models in mice. Using an accelerated titration trial design with one patient cohorts and initial 100% escalations, a Phase I trial was conducted to determine the maximum tolerated dose (MTD) of 5FP and describe its toxicity and pharmacokinetic profile. 5FP was administered orally once daily for 5 days every 4 weeks. The initial dose level was 23 mg/m2/d. Using single patient cohorts, escalation proceeded according to accelerated titration 4B design, initially by 100% and subsequently 30-35% escalations (exact escalation determined by pill size) until dose limiting toxicity was observed. A total of 19 patients were enrolled with a median age of 56 years and median performance status of 1. Most patients were heavily pre-treated with chemotherapy, radiation therapy, or both, and patient population included a wide variety of tumor types. Dose escalation proceeded rapidly to 1715 mg/m2/d with the only toxicities observed being nausea and vomiting. The large number of pills necessary at that point required a formulation change, which resulted in appreciable hematologic toxicity. This led to rapid de-escalation of dose in subsequent patients, with the MTD finally being determined to be 625 mg/m2/d. The DLTs observed were grade 4 neutropenia for greater than 5 days and grade 3 anemia. Other toxicities included nausea, vomiting, fatigue, constipation and mucositis. Pharmacology studies confirmed that SFP was converted to 5FU in humans at all dose levels. However, the extent of conversion decreased over the five daily treatments, but returned for the subsequent cycle. The hematologic toxicity was not related to 5FU exposure per course. 5FP is a tolerable oral outpatient therapy. Accelerated titration was an efficient way of conducting this phase I trial. The recommended phase 2 dose is 625 mg/m2/d orally for 5 days every 28 days.