Roche trials database

Protocol number:

M66112

Title of Study:

An open-label study of the effect of Xeloda on time to disease progression in patients with metastatic or locally advanced breast cancer previously treated with an anthracycline and a taxane

Sponsor:

Roche SAS

Company division:

Pharmaceutical

Product name:

capecitabine

Generic name:

capecitabine

Therapeutic area:

• Breast Cancer

Clinical study summary:

This was an open, multicenter, non-randomized trial evaluating capecitabine administered orally in 2 daily doses in patients treated on an outpatient basis.

Study center(s):

25 centers in France

Phase of development:

II

Objectives:

The primary objective was to determine the time to progression (TTP) of the study population.

Secondary objectives were as follows: to determine the anticancer efficacy of capecitabine monotherapy by assessing the objective response rates (complete response [CR] + partial response [PR]) after 3 cycles of treatment (WHO criteria); to determine the duration of response in patients with measurable disease; to evaluate the overall survival of the study population; to evaluate the safety of treatment in all patients receiving treatment with capecitabine (NCI criteria); and to evaluate the quality of life of patients, assessed by the EORTC QLQ-30 questionnaire.

Methodology:

In this open, multicentre, non-randomised trial evaluating capecitabine administered orally in 2 daily doses in patients treated on an outpatient basis, patients were treated for a minimum of 3 cycles and a maximum of 15 cycles. The anticancer efficacy was assessed every 3 cycles of treatment; patients in progression were withdrawn from the study, but were included in the final analysis.

Number of patients (planned/analyzed):

126 patients enrolled and treated

Diagnosis and main criteria for inclusion:

Patients with metastatic or locally advanced breast cancer confirmed by cytology or histology, previously treated with an anthracycline and a taxane.

Test product, dose and mode of administration or test procedure:

Capecitabine 2500 mg/m²/day in 2 daily doses for 14 days, followed by a 7-day rest period (1 cycle). Capecitabine was to be taken about 30 minutes after the meal (breakfast and dinner) and approximately at the same time each day.

Duration of treatment:

Minimum of 3 cycles, maximum of 15 cycles

Reference therapy, dose and mode of administration or reference procedure:

N/A

Criteria for evaluation (efficacy, safety):

Efficacy: TTP; tumor response rate at C3; best response rate; time to response; response duration; overall survival; quality of life

Safety: Adverse events; biochemistry and hematology; vital signs

Statistical methods:

Time to progression (primary criteria), duration of response and overall survival were assessed using the Kaplan-Meier method. Results were provided with their 95% CI. Patients dropping out of the trial or lost to follow-up before progression or death were censored at the date of drop-out or last review. Patients with documented progression or death after trial completion were first censored at the date of trial completion. Then, this information was updated when data related to post-treatment follow-up were integrated. Clinical cut-off for the study analysis was 22 April 2002.

The primary efficacy analysis was performed on the ITT population. Moreover, a secondary analysis was carried out on per protocol population (PP). At cycles 3, 6, 9, 12 and 15, absolute and relative frequencies observed in the four classes of tumour response with a corresponding 95% confidence interval were provided. The best response was also described.

Summary (efficacy, safety, other results):

Efficacy:  Efficacy was evaluated in the intent-to-treat (ITT) population (n=126). Median TTP was 4.6 months (95% CI; 4.0–6.2). Objective responses (OR) occurred in 35 patients (28%; 95% CI: 20–36), with complete responses (CR) in 5 patients (4%) and partial responses (PR) in 30 patients (24%). Disease was stabilised in an additional 44 patients (35%). After three cycles of therapy, as a first evaluation for efficacy, CR or PR were observed in 24 patients (19%; 95% CI: 12–26), with disease stabilisation in a further 53 patients (42%). The median duration of response was 5.7 months (95% CI: 4.5–10.9).

Currently, after a follow-up of 48 months, median overall survival is 15.9 months (95% CI: 13.5–21.3). The one year, two year and three year survival probabilities estimated by the Kaplan-Meier methodology were respectively 63%, 37% and 17%.

For the 35 patients with an objective best response, 31 patients out of 35 died during the post-trial follow-up. The median time to response was 69 days (95% CI: 62–90). Median overall survival for these 35 patients was 22.9 months (95% CI: 16.5–28.8).

Safety: Patients received a total of 874 cycles of treatment during the study, with a median of six cycles (range 1-15) per patient. The median daily dose administered was 1210 mg/m² twice daily. Median treatment duration was 4.1 months (range 0.1–13.0).

The most common (≥ 20%) treatment-related adverse events (AEs) per cycle were hand-foot syndrome (31%), nausea (16%), diarrhoea (21%), asthenia (11%). All other AEs occurred in less than 10% of cycles. The majority of treatment-related adverse events were mild to moderate in intensity and no grade 3 or 4 adverse event occurred in more than 5% of cycles. There were two treatment-related deaths: one hepatic failure and one septic shock.

Dose decrease due to adverse events (all grades) was required for 46 patients (36.5%). The adverse events which most commonly (> 5% of patients) led to dose reduction were hand-foot syndrome (17%), neutropenia (8%) and diarrhoea (6%). In patients in whom the capecitabine dose had to be decreased because of adverse events (n = 46), the median daily dose administered was 1190 mg/m² twice daily (from 915 to 1316).

Treatment discontinuation due to adverse events (all grades) was required for 86 patients (68.3%). The adverse events which most commonly (> 5% of patients) led to dose reduction were hand-foot syndrome (25%), neutropenia (14%), diarrhea (13%), asthenia (10%), vomiting (8%) and nausea (6%). In patients in whom the capecitabine dose had to be discontinued because of adverse events (N=86), the median daily dose administered was 1202 mg/m² twice daily (from 784 to 1325).

The most common grade 3 or 4 laboratory abnormalities were lymphocytopenia and hyperbilirubinemia, which occurred in 59% and 15% of patients respectively. Grade 3 or 4 neutropenia was recorded as a laboratory abnormality in 6% of patients.

Conclusions:

This study demonstrates that oral capecitabine is an effective and well tolerated agent that also improves quality of life in patients with anthracycline- and taxane-pretreated metastatic breast cancer. The high activity of capecitabine has now been confirmed across several studies in this setting. Given the clear preference among patients with advanced cancer for oral therapy, capecitabine merits consideration as standard therapy for anthracycline and taxane-pretreated patients.

Publications (references, if available):

Fumoleau P, Largillier R, Clippe C et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer. 2004 Mar; 40(4):536-42.

Largillier R, Fumoleau P, Clippe C et al. Long median survival with capecitabine (X) single-agent therapy for patients (pts) with anthracycline- and taxane-pretreated metastatic breast cancer (MBC). Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006:10710.

Largillier R, Fumoleau P, Clippe C et al. Capecitabine (X) monotherapy after anthracycline and taxane failure in metastatic breast cancer: long term survival data. Annals of Oncology 2006;17(Suppl 9).

Date of report:

23.07.2009

Click here for the protocol registry listing of this trial.