A. Hageboutros et al., PHASE-I STUDY OF PHOSPHONACETYL-L-ASPARTATE, 5-FLUOROURACIL, AND LEUCOVORIN IN PATIENTS WITH ADVANCED CANCER, Cancer chemotherapy and pharmacology, 35(3), 1995, pp. 205-212
Low-dose phosphonacetyl-L-aspartate (PALA) may potentiate both 5-fluor
ouracil (5-FU) incorporation into RNA and thymidylate synthase inhibit
ion by 5-fluorodeoxyuridylate (5-FdUMP). The gastrointestinal toxicity
of 5-FU is not increased by PALA administration. Exogenous leucovorin
, on the other hand, which enhances thymidylate synthase inhibition, a
ppears to increase the clinical toxicity of 5-FU in a dose-dependent m
anner. As a result, the clinical use of high-dose leucovorin requires
a marked dose reduction of 5-FU. Extracellular leucovorin levels of 1
mu M suffice to maximize the enhancement of thymidylate synthase inhib
ition in several models. We conducted a trial to add leucovorin to the
PALA/5-FU regimen. We chose a leucovorin dose that was predicted to y
ield end-infusion total reduced folate concentrations of 1 mu M. The m
ajor endpoint was to determine the maximum tolerated dose of 5-FU in t
his combination. The regimen consisted of 250 mg/m(2) PALA given on da
y 1 and, 24 h later, escalating 5-FU doses ranging from 1,850 to 2,600
mg/m(2) admired with 50 mg/m(2) leucovorin and given by 24-h infusion
. Courses were repeated weekly. A total of 24 patients with a median p
erformance status of 1 were entered at three dose levels. Diarrhea was
dose-limiting; 6/13 patients had grade II or worse diarrhea at 2,600
mg/m(2). Dose modification resulted in a mean dose intensity of 2,300
mg/m(2) at both the 2,600- and 2,300-mg/m(2) dose levels. The 2,300-mg
/m(2) dose is suitable for phase II testing of this regimen. Three pat
ients (two with breast cancer and 1 with sarcoma) had a partial remiss
ion. We measured steady-state concentrations (C-ss) of 5-FU in 23 pati
ents. The mean C-ss increased with dose from 0.738 to 1.03 mu g/ml. To
tal body clearance did not vary with dose in this range. Patients with
grade II or worse diarrhea had a higher mean C-ss (1.10+/-0.19) than
those with grade O or I toxicity (0.835+/-0.25, P < 0.02). Total bioac
tive folates (bound and free) were measured using a biological assay.
Pretreatment values ranged from 2 to 52 nM and were not predictive of
toxicity. End-infusion (23-h) values were somewhat lower than predicte
d and ranged from 400 to 950 nM. The risk of diarrhea was positively c
orrelated with end-infusion total folate values. In a logistic regress
ion analysis, total folate values obtained at 23 h were a more powerfu
l predictor of diarrhea than were 5-FU C-ss values. These results conf
irm the contribution of leucovorin to the toxicity of the 5-FU/leucovo
rin combination and suggest that interpatient differences in folate ph
armacology may contribute to the therapeutic index of the 5-FU/leucovo
rin combination.