Trial Information

A Phase I Trial of 5-Fluorouracil Given With 776C85 (GW776) and Low-Dose Leucovorin in Adult Patients With Solid Tumors

The primary purpose of this Phase I protocol is to develop an orally administered regimen of
fluorouracil (5-FU) given with fixed doses of leucovorin (LV) and 776C85 (GW776), a
mechanism-based inhibitor of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme
involved in the catabolism of 5-FU. In the presence of 776C85, 5-FU is cleared by renal
mechanisms. The schedule employed is intended to mimic the pharmacologic profile associated
with a 24 hour weekly continuous infusion of 5-FU without the need for an indwelling central
venous catheter. The target population is adult cancer patients with solid tumors.

The first week, each patient will receive a single dose of 5-FU given by 24 hour continuous
IV infusion at its recommended Phase II dose with low-dose oral LV. In the third week, the
patient will begin 776C85 (GW776) and LV PO on days 1, 2, 3 at fixed doses. Oral 5-FU will
be given on day 2, and the dose will be escalated in successive cohorts of patients.
Treatment will be repeated weekly for three weeks, followed by a one week break. The dose
of 5-FU will be adjusted according to individual tolerance. Cohorts of three patients will
be entered at each dose level of 5-FU, which will be escalated until dose-limiting toxicity
is seen (guidelines are outlined in the following schema). Treatment will be continued
indefinitely until evidence of disease progression, provided the patient is tolerating
therapy and wishes to continue.

Biochemical monitoring suggests that there is profound and sustained inhibition of DPD with
a single dose of 20 mg PO 776C85 days 1-3 each week for three of four weeks. Once the MTD
has been defined for the once daily dosing on days 1, 2, 3 schedule, a simplified schedule
will be evaluated in which a single dose of 776C85 on day 1 in the evening, with oral
leucovorin days 1 and 2, and 5-FU given day 2 as a single dose.

Since the pharmaceutical company has decided to go with a combined tablet of eniluracil/5-FU
for future studies, the new schedule will be oral leucovorin on days 1 & 2, with 776C85 and
5-FU both given day 2 as a single dose.