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| A phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors |
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| Author(s): Cassidy J, Dirix L, Bissett D, Reigner B, Griffin T, Allman D, Osterwalder B, Van Oosterom AT |
| Source: CLINICAL CANCER RESEARCH Volume: 4 Issue: 11 Pages: 2755-2761 Published: NOV 1998 |
| Times Cited: 53 References: 21 |
| Abstract: Capecitabine (Xeloda(TM)) 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-fluoronracil (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 capecitiabine was also the maximum tolerated dose (1004 mg/m(2)/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/m(2)/day to 2510 mg/m(2)/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/m(2)/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 C-max 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Cassidy, J (reprint author), Inst Med Sci, Aberdeen AB25 2ZD, Scotland |
Addresses:
1. Inst Med Sci, Aberdeen AB25 2ZD, Scotland
2. UZ UIA Oncol, B-1520 Edegem, Belgium
3. F Hoffmann La Roche & Co Ltd, CH-4002 Basel, Switzerland
4. Hoffmann La Roche Inc, Nutley, NJ 07110 USA
5. Quintiles Oncol, Strasbourg, France |
| Publisher: AMER ASSOC CANCER RESEARCH, PO BOX 11806, BIRMINGHAM, AL 35202 USA |
| Subject Category: Oncology |
| IDS Number: 136UK |
| ISSN: 1078-0432 |
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