A phase I study of continuous infusion 5-fluorouracil plus calcium leucovorin in combination with N-(phosphonacetyl)-L-aspartate in metastatic gastrointestinal adenocarcinoma.
Preclinical studies suggest that the biochemical effects of N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate carbamoyltransferase (ACTase), may increase the metabolic activation of 5-fluorouracil (5-FU) and enhance its cytotoxicity through both RNA- and DNA-directed mechanisms. In this Phase I trial, 22 evaluable patients with adenocarcinoma of the gastrointestinal tract were entered at escalating doses of 5-FU starting at 1150 mg/m2/day given as a concurrent 72-h i.v. infusion with a fixed dose of leucovorin (LCV), 500 mg/m2/day. The dose of 5-FU was escalated within patients according to individual tolerance, and then PALA at 250 mg/m2 was added 24 h prior to the initiation of the 5-FU/LCV infusion of the subsequent cycle. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 3 of 5 patients treated with 2300 mg/m2/day 5-FU; therefore, the recommended dose of 5-FU with concurrent LCV is 2000 mg/m2/day. Twenty-seven additional patients were then treated with escalating doses of PALA ranging from 375 to 2848 mg/m2, i.v., followed 24 h later by 2000 mg/m2/day 5-FU with high-dose LCV. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 2 of 3 patients entered at 2848 mg/m2 PALA. Dose-limiting mucositis and skin rash ultimately required both PALA and 5-FU dose reductions in 4 of 6 patients treated with 1899 mg/m2 PALA. Toxicity was similar, however, in patients receiving PALA at doses ranging from 375 to 1266 mg/m2. The mean steady-state plasma concentration of 5-FU at 2000 mg/m2/day was 6.5 +/- 0.9 microM; patients with 5-FU levels > 9 microM had a significantly higher incidence of serious gastrointestinal and hematological toxicity. Compared to each patient's own baseline, a significant trend for decreasing ACTase activity with increasing PALA dose was evident using cytosol isolated from peripheral blood mononuclear cells 24 h after PALA treatment (P2 = 0.01). PALA < or = 844 mg/m2 failed to appreciably inhibit ACTase activity at 24 h in most patients; furthermore, a decrease in ACTase activity by > 50% from baseline was seen in only 29% of cycles. More consistent inhibition of ACTase activity was seen with PALA > or = 1266 mg/m2. Even with the highest PALA doses, however, ACTase activity returned to baseline by 96 h in most patients.(ABSTRACT TRUNCATED AT 400 WORDS)
Grem
J L
JL
Clinical Oncology Program, National Institutes of Health, Bethesda, Maryland 20892.
McAtee
N
N
Steinberg
S M
SM
Hamilton
J M
JM
Murphy
R F
RF
Drake
J
J
Chisena
T
T
Balis
F
F
Cysyk
R
R
Arbuck
S G
SG
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use / Q000633:toxicity*; D001221:Aspartate Carbamoyltransferase / Q000037:antagonists & inhibitors / Q000097:blood; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D009362:Neoplasm Metastasis; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity
D000970:Antineoplastic Agents; D001224:Aspartic Acid; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D010746:Phosphonoacetic Acid; D002955:Leucovorin; D005472:Fluorouracil