Phase I trial of N-(phosphonacetyl)-L-aspartate, methotrexate, and 5-fluorouracil with leucovorin rescue in patients with advanced cancer.
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.
Kemeny
N
N
Department of Developmental Chemotherapy, Memorial Sloan Kettering Cancer Institute, New York 10021.
Schneider
A
A
Martin
D S
DS
Colofiore
J
J
Sawyer
R C
RC
Derby
S
S
Salvia
B
B
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D001853:Bone Marrow / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000037:antagonists & inhibitors; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D010428:Pentosephosphates / Q000097:blood; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D010754:Phosphoribosyl Pyrophosphate
D000970:Antineoplastic Agents; D010428:Pentosephosphates; D001224:Aspartic Acid; D010754:Phosphoribosyl Pyrophosphate; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D002955:Leucovorin; D005472:Fluorouracil; D008727:Methotrexate