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Pharmacology and Phase I Trial of High-Dose Oral Leucovorin plus 5-Fluorouracil in Children with Refractory Cancer: A Report from the Children's Cancer Study Group¹

Division of Hematology-Oncology, Children's Hospital, Los Angeles, California 90054 [R. P., J. K. S., J. S. H.]; Division of Pediatrics, City of Hope National Medical Center, Duarte, California 91010 [E. M. N., D. G. V.]; Children's National Medical Center, Washington, DC 20010 [G. H. R.]; Harbor-UCLA Medical Center, Torrance, California 90806 [J. Z. F.]; University of Southern California School of Medicine, Los Angeles, California 91006 [M. D. K., G. D. H.]

Because of the synergy seen in adult trials when 5-fluorouracil is combined with leucovorin, we initiated a Phase I trial of this combination in children's refractory cancer. Leucovorin, an equal mixture of the (6R,S)-diastereoisomers, was administered p.o. for 6 consecutive days as 4 equal doses at 0, 1, 2, and 3 h totaling 500 mg/m²/day. 5-Fluorouracil was given daily on days 2 to 6 as an i.v. bolus immediately following the last dose of leucovorin. The leucovorin dose was held constant while the 5-fluorouracil dose was escalated in cohorts of patients from 300 mg/m²/day to its maximally tolerated dose. Thirty-five patients (19 with acute leukemia and 16 with solid tumors) were evaluable for toxicity. The maximally tolerated dose of FUra was 450 mg/m²/day for 5 treatments for patients with solid tumors and 650 mg/m²/day for 5 treatments for the children with leukemia. The dose-limiting toxicities were myelosuppression and stomatitis. Other side effects included transient, mild elevations of serum transaminases, mild nausea, vomiting, and diarrhea. The pharmacokinetics of high-dose p.o. leucovorin was studied in 23 children. There was considerable interpatient variability in the plasma concentrations of total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid. The maximum plasma concentration (C_max) of TBAF was 821 ± 97 (SE) nM, occurring at a median of 8 h; the C_max of (6S)-leucovorin was 77 ± 11 nM, occurring at 4 h. The TBAF concentration fell to 146 ± 42 nM by 24 h. (6S)-5-Methyltetrahydrofolic acid accounted for 90 ± 7% of the TBAF at the C_max. The plasma concentration of (6R)-leucovorin, the unnatural isomer, was equal to that of TBAF. Thus, p.o. leucovorin reduced the 5-fold excess of (6R)-leucovorin over TBAF seen after i.v. doses. The relative amounts of the three major plasma species were approximately the same as in adults, even though the C_max of each compound was lower.

¹ Supported by the Burroughs Wellcome Company and the Division of Cancer Treatment, National Cancer Institute, NIH, Department of Health and Human Services (Support Grants CA38053 and CCSG). Contributing Children's Cancer Study Group investigators, institutions, and grants are given in Appendix Table 1.

² To whom requests for reprints should be addressed, at Children's Cancer Study Group, 440 East Huntington Drive, Suite 300, P.O. Box 60012, Arcadia, CA 91006-6012.

Received 3/13/91. Accepted 7/ 8/91.

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