PHASE-I STUDY OF N-(PHOSPHONACETYL)-L-ASPARTATE WITH FLUOROURACIL ANDWITH OR WITHOUT DIPYRIDAMOLE IN PATIENTS WITH ADVANCED CANCER

We conducted a combined biochemical modulation trial of N-(phosphonace tyl)-L-aspartate (PALA), dipyridamole (DP), and fluorouracil (5-FU) in patients with cancer, Eighty-eight patients with advanced cancer were entered into this Phase I trial, During the first part of the study, four doses of PALA (125, 250, 500, and 1000 mg/m(2), administered on d ay 1) were evaluated to determine the PALA dose with maximal suppressi on of aspartate transcarbamylase (ATCase) activity that was clinically tolerable. Patients were randomized to receive DP (or no DP), 50 mg/m (2), p.o. every 6 h on days 1-6, and all patients received 5-FU, 400 m /m(2), by bolus administration on days 2-5. Prior to and during therap y, WBCs were collected and assayed for ATCase activity, After the maxi mally tolerated PALA dose with 400 mg/m(2) 5-FU +/- 50 mg/m(2) DP was defined, the 5-FU dose was escalated using the same administration sch edule of 5-FU, PALA, and DP, The dose of 5-FU was escalated by 25% in each of the DP cohorts until dose-limiting toxicity was reached, ATCas e activity was inhibited in a dose-dependent manner with PALA doses of 125, 250, 500, and 1000 mg/m(2), resulting in 0, 13, 17, and 49% inhi bition of ATCase activity, Only at the higher PALA doses (i.e., 500 an d 1000 mg/m(2)) was ATCase activity suppressed during days 2-5, but th e activity returned to pretreatment levels by day 15. Based on the cli nical tolerance and significant suppression of ATCase activity, a PALA dose of 500 mg/m(2) was selected for the 5-FU dose escalation phase. At a 5-FU dose of 625 mg/m(2), dose-limiting toxicity (leukopenia, sto matitis, and diarrhea) occurred in both DP cohorts, We recommend that for this monthly treatment schedule, 500 mg/m(2) PALA and 500 mg/m(2) 5-FU, with or without 50 mg/m(2) DP, be used in subsequent Phase II tr ials.