A Japanese phase I study of continuous oral capecitabine in patients with malignant solid tumors

This study aimed to evaluate the tolerability and pharmacokinetics of capecitabine, given twice daily for 6 weeks without interruption, and to identify the maximum tolerated dose (MTD) and the suggested phase II schedule.

The initial dose of capecitabine was 251 mg/m2 twice daily, without interruption, and a dose escalation schedule was planned according to a modified Fibonacci scheme. Patients received oral capecitabine twice daily for at least 6 weeks unless grade 3 or 4 toxicity was observed. Blood and urine samples were collected for pharmocokinetic analysis on days 1 and 15.

Sixteen patients with malignant solid tumors (seven breast, seven colorectal, and two gastric) were enrolled, all of whom were evaluable. Among 4 patients treated with capecitabine 1255 mg/m2 twice daily, one experienced grade 4 hemorrhagic gastric ulcer and one experienced grade 3 skin toxicity. Consequently, this dose was defined as the MTD, and gastrointestinal and cutaneous effects were identified as dose-limiting toxicities. There was no grade 3/4 diarrhea at any dose level. There was also no grade 4 hematologic toxicity at doses below the MTD, and there were no treatment-related deaths. Two patients with breast cancer had partial responses, at capecitabine doses of 502 mg/m2 and 1255 mg/m2, twice daily. Pharmacokinetic data show that high concentrations of doxifluridine (5'-DFUR) occur in tumor cells within 2 h after administration of capecitabine.

The MTD of continuous oral capecitabine over 6 weeks was 1255 mg/m2 twice daily. Because of the higher occurrence of skin disorders reported in this study with a continuous treatment regimen, an intermittent treatment regimen of 828 mg/m2, administered twice daily for 3 weeks, followed by a 1-week rest period, was recommended for phase II studies. This regimen is being evaluated in phase II studies in Japanese patients with gastric, colorectal, and breast cancers.