A Phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors

• Published in: Clinical cancer research Vol. 4; no. 11; pp. 2755 - 2761
• Main Authors: CASSIDY, J, DIRIX, L, BISSETT, D, REIGNER, B, GRIFFIN, T, ALLMAN, D, OSTERWALDER, B, VAN OOSTEROM, A. T
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.11.1998
• Subjects: Administration, Oral; Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Capecitabine; Chemotherapy; Deoxycytidine - administration & dosage; Deoxycytidine - adverse effects; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacokinetics; Female; Fluorouracil - analogs & derivatives; Humans; Leucovorin - administration & dosage; Leucovorin - adverse effects; Leucovorin - pharmacokinetics; Male; Medical sciences; Middle Aged; Neoplasms - drug therapy; Pharmacology. Drug treatments; Treatment Outcome; Antineoplastic agent; Human; Solid tumor; Drug combination; Capecitabine; Toxicity; Treatment efficiency; Oral administration; Tolerance; Calcium folinate; Malignant tumor; Chemotherapy; Treatment; Phase I trial; Pharmacokinetics
• ISSN: 1078-0432; 1557-3265

Capecitabine (Xeloda) is a novel rationally designed fluoropyrimidine carbamate. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes resulting in preferential release of 5-fluorouracil (5-FU) at the tumor site. Preclinical studies indicated an enhancement of the therapeutic index when capecitabine was combined with leucovorin. This Phase I trial was designed to determine the safety profile, maximal tolerated dose, and pharmacokinetic profile of the combination of capecitabine plus a fixed dose of p.o. leucovorin (60 mg/day) during administration to patients with refractory advanced cancers. The intention was to administer both drugs continuously, but the starting dose of capecitabine was also the maximum tolerated dose (1004 mg/m2/day) in six patients treated with this regimen. A cycle of treatment was then redefined as leucovorin and capecitabine given p.o., twice daily for 2 consecutive weeks followed by a 1-week rest period. Capecitabine doses from 1004 mg/m2/day to 2510 mg/m2/day were evaluated with the intermittent schedule over approximately 80 courses in an additional 25 patients. The dose-limiting toxicities that defined the maximum tolerated dose at 2000 mg/m2/day were diarrhea, nausea, vomiting, and palmar plantar erythrodysesthesia. The recommended Phase II dose using this schedule was 1650 mg/m2/day of capecitabine plus leucovorin 60 mg/day. Plasma concentrations of capecitabine, intermediate metabolites, and 5-FU were measured in 26 patients on days 1 and 14 of therapy. The pharmacokinetics of capecitabine were characterized by rapid GI absorption, with Cmax at 1 h, followed by conversion to active drug. The coadministration of leucovorin had no effect on the pharmacokinetics of capecitabine. Two patients with colorectal cancer, both previously treated with 5-FU, had partial responses. Phase II studies have confirmed the promising antitumor activity of this drug, and capecitabine is currently in Phase III evaluation.