The pharmacokinetics of continuous venous infusion (CVI) 5-FU has not been well-characterized, primarily because of the insensitivity of available assays. The exposure to 5-FU during chronic oral dosing of 776C85/5-FU is expected but not shown to be equivalent or superior to that during prolonged infusion schedules. It is necessary to compare the pharmacokinetic profiles of 5-FU CVI and oral treatment with 776C85/5-FU in order to define the relative 5-FU exposures via the two routes of administration. Treatment with oral 776C85/5-FU could potentially: reduce costs, be more convenient thatn continuous infusion, reduce morbidity from prolonged central venous access. We are undertaking a pharmacokinetic trial of continuous venous infusion 5-Fluorouracil and combination oral 776C85/5-FU, and to seek preliminary evidence of the biologic activity of prolonged oral dosing of 776C85 and 5-FU. The eligibility criteria are histologic proof of solid tumor malignancy; lack of standard therapy for the disease that is potentially curative or definitely capable of extending life expectancy; age U18 years; adequate hepatic, renal, and bone marrow function; life expectancy U12 weeks; ECOG performance status 0-2; no concurrent or planned use of leucovorin, flucytosine, or topical 5-FU solutions and creams; and malabsorption syndrome or gastrointestinal disease or resection significantly affecting gastrointestinal function. This is an open-label crossover study comparing CVI 5-FU (300 mg/m2/day) to oral 776C85/5-FU at 1.0 mg/m2 of 5-FU twice daily for 7 days. Combination 776C85/5-FU tablets (with 776C85 at a 10:1 ratio of 5-FU) will be used and the oral dose rounded to the nearest 0.25 mg. Each subject will be randomly assigned to receive either CVI 5-FU or oral 776C85/5-FU during the first treatment period and will receive the opposite treatment during the second treatment period. This will allow each patient to serve as their own control. Seven-and 14-day washout periods will separate study periods 1 and 2, and study periods 2 and 3, respectively. Uracil concentrations will be measured prior to each subsequent study period. In study period 3, all patients will receive combination 776C85/5-FU tablets at 1 mg/m2 BID for 28 consecutive days repeated every 35 days until tumor progression or unmanageable toxicity. The primary endpoints of the study are the AUC and steady state plasma concentrations of 5-FU. A 33% differential between the two study arms will be defined as clinically significant.
Showing the most recent 10 out of 1267 publications
