Phase I Trial of 7V-(Phosphonacetyl)-L-aspartate, Methotrexate, and 5-Fluorouracil with Leucovorin Rescue in Patients with Advanced Cancer1

Based on an animal model to improve the antitumor activity of 5fluorouracil (FUra), a Phase I study of A/-(phosphonacetyl)-i .-aspartate, methotrexate, FUra, and leucovorin was conducted on 44 patients. Meth otrexate was given in an intermediate dose (250 mg/nr) to overcome potential drug resistance, and ¿V-(phosphnnacetyl)-i.-aspartatewas given at a low dose (250 mg/nr') in order to allow escalation of FUra to toxicity. These two drugs were given 24 h before FUra to enhance maximal incorporation of FUra into RNA. Two schedules of administration were used; one every other week and one weekly for 2 weeks. The every other week schedule was well tolerated, with minimal gastrointestinal and hematological toxicity. However, the weekly for 2 weeks schedule was more toxic with increased mucositis, diarrhea requiring therapy, and decreased performance status of 20% in 4 of 6 patients. There were no responders in the every other week schedule. There was one partial response and three patients with stable disease in four évaluable patients on the weekly for 2 weeks schedule. At 24 h post-/V-(phosphonacetyl)-i.aspartate-methotrexate treatment, PRPP levels were doubled in bone marrow biopsies, and increased 2.5to 25-fold in tumor biopsies. We have currently added uridine rescue to this combination with the hope of further escalating the dose of FUra.