Biweekly Xeloda® Dosing Regimen Is Well Tolerated in Advanced Breast Cancer

Results of the first ever study of biweekly Xeloda® (capecitabine) in metastatic breast cancer patients demonstrated that a seven-days-on/seven-days-off (7-on/7-off) dosing regimen was well tolerated, enabling safe delivery of higher daily doses of Xeloda. Standard Xeloda dosing is typically 14 days on and seven days off (14-on/7-off).
These data from a Phase I study assessing tolerability of higher doses of Xeloda in patients with measurable metastatic breast cancer were presented today by Dr. Maria Theodoulou, M.D., attending physician, Breast Medicine Service at New York’s Memorial Sloan-Kettering Cancer Center at the 43rd Annual American Society of Clinical Oncology in Chicago.

The study also demonstrated an acceptable safety profile when using a flat dose of Xeloda at 2000 mg twice daily on a 7-on/7-off schedule (total of 4000 mg/day).

“Based on the Norton-Simon mathematical model, in this investigational study we have established that capecitabine can potentially be administered safely and effectively at a dose level higher than historically believed feasible because of this new 7-on/7-off dosing schedule,” said Clifford Hudis, M.D., chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York. “This new dosing regimen for capecitabine will serve as a platform for combination treatment with targeted therapies.”

Breast cancer is the most common cancer among women, other than skin cancer; according to the American Cancer Society (ACS), about 178,480 women in the United States will be found to have invasive breast cancer in 2007. Breast cancer is the second leading cause of cancer death in women, after lung cancer – about 40,460 women will die from the disease this year. Metastatic breast cancer, or cancer that has spread from the breast to other parts of the body, has an especially poor prognosis, with a five-year survival rate of 20 percent. Currently, there are slightly more than 2 million women living in the United States who have been treated for breast cancer. According to the ACS, breast cancer death rates are going down; the decline may be the result of early detection and treatment.

About the Study
Prior to study initiation, the Norton-Simon mathematical model (Norton et al, AACR 2005) was applied to determine that the maximum impact of Xeloda treatment in breast cancer patients occurs after seven days. Based on this finding, the single-center, open-label phase I/II trial was designed to determine the maximum tolerated dose (MTD) of flat-dose Xeloda administered for seven days, followed by a seven-day rest (7-on/7-off), in patients with advanced breast cancer. MTD is defined as the highest dose for which the incidence of dose-limiting toxicity (DLT) is less than 33 percent. DLT is defined as grade 3/4 hematologic toxicity lasting greater than two weeks or any grade 3/4 non-hematologic toxicity.

The Phase I study dose escalation scheme is a standard “3+3” design, using flat dosing that begins at 1500 mg twice daily and increases by 500 mg/dose level until the MTD is reached. All patients in a cohort are observed for two cycles before enrollment to the next level is permitted to monitor for delayed toxicity.

The study showed that the 7-on/7-off dosing regimen is well tolerated in patients with advanced breast cancer, allowing safe delivery of higher daily doses than routinely used in practice. Seven (7) patients (of 21 recruited) had been treated with Xeloda and a maximum tolerated dose of 2000 mg twice daily was reached. There were no grade 4/5 toxicities and grade 3 toxicities (which included one dose-limiting incident of hand-foot syndrome at 2000 mg twice daily and two at 2000 mg/2500 mg, and one dose-limiting incident of diarrhea at 2000 mg/2500 mg) were transient and medically manageable.