Clinical Trial Result Information

Title of Study:
A Phase II study of capecitabine (Ro 09-1978) in patients with metastatic breast cancer, who relapsed after treatment with a taxane-containing chemotherapy.

Fast Facts:

Protocol number:	M66103
Sponsor:	F. Hoffmann-La Roche Ltd.
Company division:	Pharmaceutical
Product name:	Xeloda
Generic name:	capecitabine
Phase of development:	IV
Therapeutic area, approved indication:	Breast Cancer
Date of report:	5/10/2004

Clinical study summary:
This was an open-label, multi-center, non-comparative study to determine the efficacy, safety, and tolerability of Xeloda in patients with metastatic breast cancer who relapsed after treatment with a taxane-containing chemotherapy. Patients who responded or maintained stable disease after the 18 week study period could continue maintenance treatment for up to a total of 48 weeks.

Study center(s) :
10 in Germany.

Objectives:
Primary: To determine that the overall response rate (defined as the ratio of the number of patients with CR and PR to the total number of patients evaluable for efficacy) is ~ 20% (12%–30%).

Secondary: (1) To assess that Xeloda is both safe and tolerable as an outpatient treatment for patients with metastatic breast cancer; (2) To evaluate the effect of Xeloda on quality of life as measured by the European Organization for Research and Treatment of Cancer Quality of Life–C30 (EORTC QLQ–C30) score; and (3) To determine the proportion of patients with SD and progressive disease, the duration of response, time to progression, and overall survival of the whole patient population.

Methodology:
In this open-label, multi-center, non-comparative study, oral Xeloda was administered twice daily for 14 days followed by a 7-day rest period. This 3-week cycle was repeated at least once. Patients with a response (CR or PR) or SD (no change) at the end of the initial 6-week treatment could receive up to 6 additional cycles. Patients who were responding or maintaining a stable phase of disease after the study period, could continue treatment up to a total of 48 weeks in a maintenance phase (ie a treatment period of 18 weeks plus an optional maintenance phase of 30 weeks). Patients with progressive disease could be withdrawn from the study at any time.

Diagnosis and main criteria for inclusion:
The study population comprised female patients, 18−80 years of age, with a histologically confirmed diagnosis of breast cancer, who had relapsed during or following a taxane-containing chemotherapeutic regimen. Patients were required to have a Karnofsky Performance Status (KPS) of ≥60% and a life expectancy of ≥3 months. A minimum interval of 3 weeks between receipt of the last chemotherapy and enrollment was required.

Test product, dose and mode of administration or test procedure:
Xeloda 1250 mg/m2 bid/po.

Duration of treatment:
Up to 48 weeks.

Reference therapy, dose and mode of administration or reference procedure:
Not applicable.

Criteria for evaluation (efficacy, safety):
Objective response of measurable disease was in accordance with criteria based on the WHO Handbook for Reporting Results of Cancer Treatment. Time to progression, survival data ( collected by the investigator on a 3- month basis after patients went off study),.time to response and duration of response were assessed.

Statistical methods:
The primary objective of this study was to confirm the anti-neoplastic efficacy of Xeloda in terms of response rate (RR), defined as the ratio of the number of patients with a CR or PR to the total number of patients evaluable for efficacy. A single-stage design according to the method of Fleming was selected to determine the actual RR, leading to a calculated requirement of 80 evaluable patients.

During the course of the study, Xeloda showed considerable activity. An analysis with 37 documented patients showed 2/37 complete remissions and 6/37 partial remissions, indicating a remission rate of about 22%. Consequently, the upper boundary of the response proportion, chosen to be 30% in the original design, was lowered to 25%, leading to an amended sample size requirement of n = 131.

Summary (efficacy, safety, other results):
One hundred and thirty-six (136) patients were enrolled. All patients had histologically proven metastatic breast cancer. Patients had a median number of 2 metastatic sites (range 1−8), with the most common sites being liver (53%) and bone (42%). Prior to study entry, patients had received a median of 2 chemotherapeutic regimens (range 1−6). The majority of patients (99%) had previously received a taxane-containing therapy; 67 (49%) had received paclitaxel, 62 (46%) docetaxel, and 5 (4%) both paclitaxel and docetaxel. In addition, 93% of patients had been previously treated with an anthracycline, and 52% had received a 5-FU–containing regimen. Patients received a median number of 4 cycles (range 1−33). Overall, the Xeloda dose was reduced in 39% of patients and in 44% of cycles. Disease stabilization occurred in 62 patients (46%), and the overall response rate was 16% (95% confidence interval 10%–23%), providing an overall tumor control rate of 62%. Median time to progression was 3.1 months, median duration of response was 7.5 months, and median overall survival was 10.1 months. Xeloda was generally well tolerated; most treatment-related adverse events were Grade 1−2 in intensity; Grade 3/4 treatment-related adverse events were hand-foot syndrome (11%), diarrhea (7%), vomiting (4%), and nausea (3%). There were no treatment-related deaths.

Conclusions:
This study confirms that Xeloda achieves a high tumor control rate in heavily pre-treated patients with metastatic breast cancer. Due to its favorable safety profile and convenient oral administration, Xeloda can be given as an outpatient therapy. Xeloda should be considered the reference treatment in this setting based on consistently high efficacy and good tolerability.