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 43^rd 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.

About Xeloda
Xeloda is the only FDA-approved oral chemotherapy for both metastatic breast cancer and adjuvant and metastatic colorectal cancer.  Inactive in pill form, Xeloda is enzymatically activated within the body; when it comes into contact with a naturally occurring protein called thymidine phosphorylase, or TP, Xeloda is transformed into 5-FU, a cytotoxic (cell-killing) drug.  Because many cancers have higher levels of TP than does normal tissue, more 5-FU is delivered to the tumor than to other tissue. 

Conventional, approved Xeloda dosing on a 14-on/7-off schedule is 1250 mg/m² twice daily (total of 2500 mg/m²/day). 

A clinically important drug interaction between Xeloda and warfarin has been demonstrated; altered coagulation parameters and/or bleeding and death have been reported. Clinically significant increases in prothrombin time (PT) and INR have been observed within days to months after starting Xeloda, and infrequently within one month of stopping Xeloda.  For patients receiving both drugs concomitantly, frequent monitoring of INR or PT is recommended.  Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy. 

Xeloda is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil, and in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.  Xeloda is contraindicated in patients with severe renal impairment.  For patients with moderate renal impairment, dose reduction is required.

The most common adverse events (³ 20%) of Xeloda monotherapy were diarrhea, nausea, stomatitis and hand-foot syndrome.  As with any cancer therapy, there is a risk of side effects, and these are usually manageable and reversible with dose modification or interruption.

About Roche
Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. pharmaceuticals headquarters of the Roche Group, one of the world’s leading research-oriented healthcare groups with core businesses in pharmaceuticals and diagnostics.  For more than 100 years in the U.S., Roche has been committed to developing innovative products and services that address prevention, diagnosis and treatment of diseases, thus enhancing people's health and quality of life.  An employer of choice, in 2006, Roche was named one of the Top 20 Employers (Science magazine), ranked the No. 1 Company to Sell For (Selling Power), and one of AARP’s Top Companies for Older Workers, and in 2005, Roche was named one of Fortune magazine’s Best Companies to Work For in America.  For additional information about the U.S. pharmaceuticals business, visit our websites: http://www.rocheusa.com or www.roche.us.

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