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Phase I Study of a Novel Capecitabine Schedule Based on the Norton-Simon Mathematical Model in Patients With Metastatic Breast Cancer

Tiffany A. Traina, Maria Theodoulou, Kimberly Feigin, Sujata Patil, K. Lee Tan, Charles Edwards, Ute Dugan, Larry Norton, Clifford Hudis

From the Memorial Sloan-Kettering Cancer Center, New York, NY; and Roche Laboratories, Nutley, NJ

Corresponding author: Tiffany A. Traina, MD, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: trainat{at}mskcc.org

Purpose: This study was conducted to determine, in patients with advanced-stage breast cancer, the maximum tolerated dose (MTD) of capecitabine administered orally for 7 days followed by a 7-day rest (7/7), a schedule based on a mathematical method for the optimization of anticancer drug scheduling.

Patients and Methods: Eligible patients had measurable, metastatic breast cancer. There was no limit to number of prior treatments. A standard, three-patients-per-cohort dose-escalation scheme used flat-dose capecitabine beginning at 1,500 mg orally twice daily (bid) on a 7/7 schedule. Each cohort was monitored for 28 days before escalation to the next cohort to assess for delayed toxicity. Response was evaluated radiographically every 12 weeks; toxicity was assessed every 2 weeks.

Results: Twenty-one patients were treated on study. The most frequently reported treatment-related grade 2/3 adverse events were hand-foot syndrome (29%), leukopenia/neutropenia (24%), and fatigue (19%). Grade 3 toxicity was transient and easily managed. Three patients experienced grade 3 hand-foot syndrome; one of these patients had grade 3 diarrhea. There were no grade 4 events. The MTD of capecitabine 7/7 is 2,000 mg twice daily.

Conclusion: As predicted by mathematical modeling, capecitabine dosing for 7 days followed by a 7-day rest is well tolerated. Efficacy of this schedule is being determined in a phase II clinical trial in patients with advanced breast cancer.

Supported by Roche Laboratories Inc.

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007 Chicago, IL (abstr 1045) and at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 14-17, 2006 (abstr 6077). This article is an update and the first complete reporting of the Phase I study.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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