Novel Xeloda Dosing Schedule May Offer Well-Tolerated Alternative for Treatment of Advanced Breast Cancer

- Investigational Study Results Published in Journal of Clinical Oncology Pave Way for Phase II Efficacy Trial -

NUTLEY, N.J., April 18, 2008 /PRNewswire/ -- A novel biweekly dosing schedule of Xeloda(R) (capecitabine) enabled safe delivery of higher daily doses in the treatment of advanced breast cancer, according to an investigational study published in the April 10, 2008 issue of the Journal of Clinical Oncology. The data showed that a seven-days-on/seven-days-off (7-on/7-off) regimen, called "dose dense," was generally well-tolerated up to 2,000 mg twice daily (4,000 mg/day), providing a potential alternative to the standard Xeloda dosing of 14 days on and seven days off (14-on/7-off).

"As we predicted using the Norton-Simon mathematical model -- the basis for the dose dense approach to therapy that was pioneered at MSKCC -- these results demonstrate that a biweekly regimen of capecitabine appears to be well-tolerated, at dosing levels that are higher than previously thought possible," said Tiffany A. Traina, M.D., a medical oncologist in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York and lead author of the study. "We're currently conducting later-phase trials to determine the efficacy of this 7-on/7-off dosing schedule."

Efficacy of the 7-on/7-off schedule using Xeloda is being determined in a Phase II clinical trial program in patients with advanced breast cancer and is also being tested in combination with Avastin(R) (bevacizumab).

Breast cancer is the most common cancer among women, other than skin cancer. According to the American Cancer Society (ACS), about 182,460 women in the United States will be found to have invasive breast cancer in 2008. Breast cancer is the second leading cause of cancer death in women, after lung cancer -- about 40,930 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 27 percent. Currently, there are two and a half million breast cancer survivors in the United States. 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) -- which explores how the growth characteristics of a cancer affect response to chemotherapy -- 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 Xeloda administered orally for seven days, followed by a seven-day rest (7-on/7-off), in patients with advanced-stage breast cancer. MTD was defined as the highest dose for which the incidence of dose-limiting toxicity (DLT) is less than 33 percent. DLT was defined as grade 3/4 hematologic toxicity lasting greater than two weeks despite growth factor support, or any grade 3/4 nonhematologic toxicity.

The Phase I study dose escalation scheme was a standard "3+3" design, using flat dosing that begins at 1,500 mg twice daily and increases by 500 mg/dose level until the MTD is reached. All patients in a cohort were observed for 28 days before enrollment to the next level is permitted to monitor for delayed toxicity.

The study showed that the dose dense regimen was well-tolerated in patients with advanced breast cancer, allowing safe delivery of higher daily doses than routinely used in practice. Of the 21 patients recruited for the trial, 18 were treated with Xeloda and reached a maximum tolerated dose of 2,000 mg twice daily. There were no grade 4/5 toxicities and grade 3 toxicities (which included one dose-limiting incident of hand-foot syndrome at 2,000 mg twice daily and two at 2,000 mg/2,500 mg, and one dose-limiting incident of diarrhea at 2,000 mg/2,500 mg) were transient and medically manageable. The most frequently reported treatment-related grade 2/3 adverse events were hand-foot syndrome (29 percent), leukopenia/neutropenia (24 percent) and fatigue (19 percent).

About XELODA (capecitabine)

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.

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 (greater than or equal to 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 2007 Roche was named Top Company of the Year by Med Ad News, one of the Top 20 Employers (Science) and ranked the No. 1 Company to Sell For (Selling Power). In previous years, Roche has been named as a Top Company for Older Workers (AARP) and one of the Best Companies to Work For in America (Fortune).

Posted: April 2008

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