title: Phase I study of N-(phosphonacetyl)-L-aspartate with fluorouracil and with or without dipyridamole in patients with advanced cancer.
abstract: We conducted a combined biochemical modulation trial of N-(phosphonacetyl)-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/m2, administered on day 1) were evaluated to determine the PALA dose with maximal suppression of aspartate transcarbamylase (ATCase) activity that was clinically tolerable. Patients were randomized to receive DP (or no DP), 50 mg/m2, p.o. every 6 h on days 1-6, and all patients received 5-FU, 400 mg/m2, by bolus administration on days 2-5. Prior to and during therapy, WBCs were collected and assayed for ATCase activity. After the maximally tolerated PALA dose with 400 mg/m2 5-FU +/- 50 mg/m2 DP was defined, the 5-FU dose was escalated using the same administration schedule 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. ATCase activity was inhibited in a dose-dependent manner with PALA doses of 125, 250, 500, and 1000 mg/m2, resulting in 0, 13, 17, and 49% inhibition of ATCase activity. Only at the higher PALA doses (i.e., 500 and 1000 mg/m2) was ATCase activity suppressed during days 2-5, but the activity returned to pretreatment levels by day 15. Based on the clinical tolerance and significant suppression of ATCase activity, a PALA dose of 500 mg/m2 was selected for the 5-FU dose escalation phase. At a 5-FU dose of 625 mg/m2, dose-limiting toxicity (leukopenia, stomatitis, and diarrhea) occurred in both DP cohorts. We recommend that for this monthly treatment schedule, 500 mg/m2 PALA and 500 mg/m2 5-FU, with or without 50 mg/m2 DP, be used in subsequent Phase II trials.
authors.affiliation: Comprehensive Cancer Center of Wake Forest University, Winston-Salem, North Carolina 27157, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Fleming
authors.forename: R L
authors.initials: RL
authors.lastname: Capizzi
authors.forename: H B
authors.initials: HB
authors.lastname: Muss
authors.forename: S
authors.initials: S
authors.lastname: Smith
authors.forename: D J
authors.initials: DJ
authors.lastname: Fernandes
authors.forename: H
authors.initials: H
authors.lastname: Homesley
authors.forename: B W
authors.initials: BW
authors.lastname: Loggie
authors.forename: L
authors.initials: L
authors.lastname: Case
authors.forename: R
authors.initials: R
authors.lastname: Morris
authors.forename: G B
authors.initials: GB
authors.lastname: Russell
authors.forename: F
authors.initials: F
authors.lastname: Richards
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001221:Aspartate Carbamoyltransferase / Q000037:antagonists & inhibitors; D001224:Aspartic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004176:Dipyridamole / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D014544:Uridine Triphosphate / Q000378:metabolism
chemical_list: D001224:Aspartic Acid; D004176:Dipyridamole; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D010746:Phosphonoacetic Acid; D005472:Fluorouracil; D014544:Uridine Triphosphate