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

Department of Developmental Chemotherapy, Memorial Sloan Kettering Cancer Institute, New York 10021 [N. K., A. S., S. D., B. S.], and the Department of Surgery, Catholic Medical Center, New York, New York 11421 [D. S. M., J. C., R. C. S.]

Based on an animal model to improve the antitumor activity of 5-fluorouracil (FUra), a Phase I study of N-(phosphonacetyl)-L-aspartate, methotrexate, FUra, and leucovorin was conducted on 44 patients. Methotrexate was given in an intermediate dose (250 mg/m²) to overcome potential drug resistance, and N-(phosphonacetyl)-L-aspartate was given at a low dose (250 mg/m²) 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 evaluable patients on the weekly for 2 weeks schedule. At 24 h post-N-(phosphonacetyl)-L-aspartate-methotrexate treatment, PRPP levels were doubled in bone marrow biopsies, and increased 2.5- to 25-fold in tumor biopsies. We have currently added uridine rescue to this combination with the hope of further escalating the dose of FUra.

¹ This work was supported in part by USPHS Grants N01-CM57732 and PO1-CA25842 awarded by the National Cancer Institute, Department of Health and Human Services, and in part by the Chemotherapy Foundation of New York.

² To whom requests for reprints should be addressed.

Received 11/14/88. Revised 4/ 5/89. Accepted 5/10/89.