Clinical Trial Result Information

Title of Study:
An Open-Label Randomized Phase III Study of Capecitabine in Combination with Docetaxel (Taxotere) Versus Docetaxel Monotherapy in Patients with Advanced and/or Metastatic Breast Cancer

Fast Facts:

Protocol number:	SO14999
Sponsor:	Hoffman-La Roche Inc
Company division:	Pharmaceutical
Product name:	Xeloda
Generic name:	capecitabine
Phase of development:	III
Therapeutic area, approved indication:	Breast Cancer
Date of report:	3/2/2001

Clinical study summary:
This open-label, multicenter, multinational, randomized, parallel group study compared treatment with capecitabine (Xeloda) plus docetaxel with docetaxel alone in patients with advanced and/or metastatic breast cancer.

Study center(s) :
Study sites in 16 countries: Argentina, Australia, Brazil, Canada, France, Germany, Great Britain, Israel, Italy, Mexico, New Zealand, Norway, Spain, Russia, Taiwan, and the United States.

Objectives:
Primary: To demonstrate superiority in time to disease progression in favor of the Xeloda)/docetaxel combination arm.

Secondary: (1) To observe at least equivalent survival curves for the 2 treatment groups and then demonstrate superiority of the combination arm over monotherapy; (2) to demonstrate superiority of the Xeloda/docetaxel combination arm over docetaxel monotherapy in terms of overall response rates (complete response [CR] and partial response [PR]); (3) to evaluate and compare the safety profile of each treatment arm; (4) to evaluate and compare changes from baseline in the quality of life of the 2 treatment groups; (5) to collect data on medical care utilization in the 2 treatment groups; (6) to describe the pharmacokinetics (PK) of Xeloda in 16 patients randomized to the combination arm.

Methodology:
Patients were randomized to 1 of 2 treatment arms: Xeloda/docetaxel combination arm or docetaxel monotherapy. The efficacy and safety of the 2 treatment regimens were compared after >=6 weeks of therapy.

Number of patients (planned/analyzed):
511 randomized (255 combination treatment arm; 256 monotherapy arm).

Diagnosis and main criteria for inclusion:
Patients who had locally advanced and/or metastatic breast cancer resistant to, or recurring after an anthracyline-containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy.

Test product, dose and mode of administration or test procedure:
Xeloda/1250 mg/sqm po twice daily as intermittent therapy (2 weeks on, 1 week off); Docetaxel/75 mg/sqm iv (1-hour infusion), first day of each 3-week cycle

Duration of treatment:
6 weeks

Reference therapy, dose and mode of administration or reference procedure:
Docetaxel/100 mg/sqm iv (1-hour infusion), first day of each 3-week cycle.

Criteria for evaluation (efficacy, safety):
Primary efficacy parameters: (1) Time to disease progression; (2) survival; (3) objective response (both by the investigator and an independent review committee [IRC]); (4) time to response; (5) duration of response; (6) quality of life.

Safety parameters: Monitoring of: (1) deaths; (2) serious adverse events; (3) premature withdrawals due to adverse events; (4) grade 3/4 toxicities (adverse events and/or laboratory abnormalities); (5) shifts in laboratory values; (6) vital signs and physical measurements.

Statistical methods:
A 2-sided log-rank test at the alpha level of 5% was used for testing differences in time to disease progression (primary variable) between the 2 groups.

Summary (efficacy, safety, other results):
Efficacy – The primary objective of the study was met: Time to disease progression was significantly superior with Xeloda/docetaxel combination therapy compared with docetaxel monotherapy (median of 186 days vs 128 days for all randomized patients and 179 days vs 127 days for the standard population, respectively). Overall survival was significantly longer with Xeloda/docetaxel combination therapy compared with docetaxel monotherapy (median of 418 days vs 338 days for all randomized patients, and a median of 418 days vs 306 days for the standard population, respectively). Overall tumor response rate, as assessed by the investigators, was significantly superior with Xeloda/docetaxel combination therapy compared with docetaxel monotherapy (41.6% vs 29.7% for all randomized patients and 47.2% vs 28.4% for the standard population, respectively). An IRC confirmed the statistically significantly superior response rates in the combination therapy arm. The quality of life scores for global health status were similar in both treatment groups over time.

 PK – The PK results of Xeloda and its metabolites in the Xeloda/docetaxel combination arm were inconclusive on study Days 14 and 77 due to the small number of patients. The results did suggest no major and clinically relevant differences in PK between the first and fourth cycles.

Safety – The following table summarizes the main safety findings of this study:

Conclusions:
The addition of Xeloda to docetaxel 75 mg/sqm resulted in significantly improved time to disease progression or death, overall survival, and response rates compared with docetaxel 100 mg/sqm alone. Overall, the safety profile of Xeloda/docetaxel therapy was typical of treatment with a fluoropyrimidine and taxane for the given patient population. The side effects associated with the Xeloda/docetaxel combination were manageable with appropriate medical intervention, and by treatment interruption and/or dose reductions when needed.

Given the significantly superior efficacy achieved by combining docetaxel with Xeloda and the manageable safety profile, this combination provides clear benefits compared with docetaxel monotherapy in patients with metastatic breast cancer previously exposed to anthracyclines.

Publications (references, if available):
O’Shaughnessy J et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients wih advanced breast cancer:phase III trial results. J Clin Oncol 2002; 20 (12):2812-2823