Clinical Trial Result Information

Protocol number
ML17746

Title of Study
An open-label phase II study of intermittent oral capecitabine in combination with docetaxel (q3w) in patients with advanced and/or metastatic breast cancer.

Sponsor
Hoffmann-La Roche Inc

Company division
Pharmaceutical

Product name
Xeloda

Generic name
capecitabine

Therapeutic area
Breast Cancer

Clinical study summary
This was an open-label, single-arm, multicenter study of oral Xeloda (capecitabine) administered as intermittent treatment combined with intravenous docetaxel. Patients received a planned minimum of 4 cycles of combination treatment. Patients who obtained CR or PR response were able to continue combination treatment until disease progression.

Study center(s)
10 centers in China

Phase of development
II

Objectives
Primary: to demonstrate the efficacy (in terms of overall response rate) of Xeloda in combination with docetaxel to treat metastatic breast cancer refractory to anthracycline.

Secondary: to evaluate the safety of Xeloda in combination with docetaxel to treat metastatic breast cancer refractory to anthracycline.

Methodology
After screening, patients with locally advanced and/or metastatic breast cancer received Xeloda 1000mg/m² as an oral twice-daily intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous docetaxel 60mg/m², given on day 1 of each 3 week cycle. Treatment continued for a minimum of 4 cycles. Assessments of tumor response took place prior to the administration of docetaxel at the end of every 2 cycles. Safety parameters were monitored/recorded throughout the study.

Number of patients (planned/analyzed)
Planned: 60; Enrolled 20.

Diagnosis and main criteria for inclusion
Female patients ≥18 years with histologically confirmed locally advanced and/or metastatic breast cancer after failure from or resistance to an anthracycline-containing therapy given in the neoadjuvant, adjuvant, 1st or 2nd line setting. Patients should not have been previously treated with continuous (>24h) 5-FU infusion, capecitabine or other oral fluoropyrimidines or a taxane-containing regimen.

Test product, dose and mode of administration or test procedure
Xeloda (capecitabine) was administered at a dose of twice-daily 1000 mg/m² (a total daily dose of 2000 mg/m²) orally as intermittent therapy (3-week cycles consisting of 2 weeks of Xeloda treatment followed by 1 week without Xeloda treatment). Docetaxel was given at a dose of 60 mg/m² as a 60-minute intravenous infusion (with appropriate pre-medication) on day 1 of each 3-week cycle.

Duration of treatment
A minimum of 4 x 3-week cycles

Reference therapy, dose and mode of administration or reference procedure
N/A

Criteria for evaluation (efficacy, safety)
The primary endpoint was overall response. Response assessment was made according to RECIST criteria. Progression free survival was recorded for all patients. Secondary variable: Efficacy: rate of complete response, rate of partial response, rate of stable disease, disease-free survival, overall survival. Secondary variable: Safety: incidence of adverse events and severe adverse events, time to onset of adverse events, laboratory parameters, incidence and timing of premature withdrawals and dose reductions.

Statistical methods
The sample size of 60 patients was chosen to allow the determination of the overall response rate with acceptable precision, defined via the length of the 95% two-sided Pearson Clopper confidence interval. With regard to efficacy, interest was in the overall response rate as determined according to the RECIST criteria. Together with the associated 95% two-sided Pearson-Clopper confidence intervals, the response rate (complete and partial responders), stable disease rate, overall survival and DFS were reported for the intent to treat population (primary analysis). Due to the exploratory nature of the study, no formal statistical tests were performed. The best overall response achieved within the time from start of drug administration to progressive disease or end of study was reported. Patients with no tumor assessment after baseline were classified as non-responders. The intent-to-treat population consisted of all patients recruited to the study. The safety population comprised all patients who received at least one dose of study medication. All efficacy analyses were based on the intent-to-treat population. All safety analyses were based on the safety population.

Summary (efficacy, safety, other results)
Efficacy: The efficacy analysis was based on the ITT population, and the response was determined by RECIST criteria. For the 20 patients who were administered docetaxel in combination with Xeloda, the overall response rate was 40% (8/20), (95 CI, 0±21.4%). Of these 1 case was a CR (complete response), 7 (35%) cases were PR (partial response) and 9 (45%) cases were SD (stable disease); there were no cases of progression. Of the 8 patients who responded, the median time to response was 54 days (range 37-85). Of 17 patients who progressed during the follow-up period, the median time of TTP was 130 days (range 40-267), the median time of TTF was 86 days (40-267 days). The response rate for metastatic sites after treatment of docetaxel in combination with Xeloda was as follows: response rate of liver metastatic lesions for ITT population was 38.4% (5/13), but of the 13 cases who had liver metastatic lesion, 3 patients were not evaluated by efficacy assessment, making the response rate 50% (5/10) for PP population. Response rate for lung metastatic lesions was 42.8% (3/7), response rate of soft tissue was 55.5% (5/9). According to RECIST criteria, bone metastatic lesions were considered immeasurable. Of the 20 cases, 2 cases had bone metastatic lesions. Safety: The most common adverse events reported were hand and foot syndrome (10 patients), leucopenia (8 patients) and neutropenia (6 patients). One patient withdrew from the study after 2 treatment cycles, due to grade 3 hand and foot syndrome, and grade 3 anasarca. One patient refused to continue the study due to a grade 3 infusion-related reaction and grade 3 bone marrow depression. Two patients had dose-modifications during the study, due to adverse events.

Conclusions
Xeloda and docetaxel combination therapy was shown to be safe and well-tolerated, with the most common adverse events being hand and foot syndrome, and neutropenia. The overall response rate was 40%, with a median time to response of 54 days.

Date of report
11/21/2006