17-AAG 40 mg/m(2) (median dose, 70 mg) was well tolerated when given daily for 5 days every 3 weeks.

The recommended phase II dose of irinotecan of 10 mg/m(2)/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.

The recommended oral dosage of 5-FU (10 mg/m(2) PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy.

Purpose: In preclinical studies, sequential exposure to irinotecan (CPT-11) then fluorouracil (5-FU) is superior to concurrent exposure or the reverse sequence; a 24-hour infusion of CPT11may be better tolerated than shorter infusions. Experimental Design: CPT-11was first given at four levels (70-140 mg/m 2 /24 hours), followed by leucovorin 500 mg/m 2 /0.5 hours and 5-FU 2,000 mg/m 2 /48 hours on days 1and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m 2 /48 hours.

Gemcitabine 100-150 mg/m2 over 24 h was poorly tolerated, whereas toxicity was acceptable with 800-1000 mg/m2 over 1 h. Inhibition of the target enzyme was demonstrated at all FUDR doses.

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