Phase I pharmacokinetic study of chronomodulated dose-intensified combination of capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer

Purpose To evaluate the maximum tolerated dose (MTD) and pharmacokinetic profile of a chronomodulated, dose-intensified regimen of capecitabine in combination with oxaliplatin (XELOX) in metastatic colorectal cancer (mCRC). Methods Patients ( N = 18) with 0 or 1 line of prior chemotherapy received oxaliplatin 100 mg/m 2 on day 1 from 1400 to 1800 hours with escalating dose levels of capecitabine (2,500, 3,000, 3,500, 4,000, 4,500, and 5,000 mg) once daily taken at 2400 hours on days 1–5. Each cycle lasted 14 days. Results The MTD of capecitabine was 4,500 mg. Transaminitis and anemia were the commonest non-hematologic and hematologic toxicities, respectively. Toxicities were generally mild, with only five occurrences of grade 3 toxicity and none of grade 4. There were no dose-limiting toxicities, defined as specific grade 3 or 4 toxicities occurring in the first two cycles of treatment. The objective response rate was 33.3 %, and median overall survival was 16.3 months (95 % CI: 11.2–18.2 months). The maximum plasma concentration ( C max ) and area under plasma concentration–time curve from time 0 to infinity (AUC [0–∞] ) of the capecitabine metabolites in our fixed-dosing chronomodulated regimen were comparable to values seen with comparably dose-intense regimens but associated with significantly reduced toxicity. Conclusions Chronomodulated dose-intensified XELOX facilitates delivery of dose-intense treatment in mCRC with a favorable therapeutic index that is promising.