Clinical Trial Result Information

Title of Study:
An open-label Phase II study of intermittent oral capecitabine in the first-line treatment of patients with metastatic colorectal cancer

Fast Facts:

Protocol number:	ML17465
Sponsor:	Shanghai Roche Pharmaceutical Ltd
Company division:	Pharmaceutical
Product name:	Xeloda
Generic name:	capecitabine
Phase of development:	II
Therapeutic area, approved indication:	Colorectal Cancer
Date of report:	3/2/2004

Clinical study summary:
This is an open-label, multi-center, single-arm clinical study of capecitabine (Xeloda) in patients in 10 centers in China. Patients with locally advanced or metastatic colorectal cancer were given 1250 mg/m² of oral Xeloda tablets twice daily for 16 cycles (2 weeks on treatment, one week without treatment). After 48 weeks, patients with a response, or with stable disease, could continue on treatment. Patients with progressive disease were withdrawn from study at the time of progression. Assessments of tumor response were made every 6 weeks, and at the end of treatment. Confirmation of overall response, when applicable, was made at least 4 weeks after the first response had been recorded.

Study center(s) :
10 centers in China.

Objectives:
Primary: To assess the overall efficacy and safety profiles of Xeloda in the first-line treatment of Chinese patients with locally advanced or metastatic colorectal cancer.

Methodology:
The measurement technique and evaluation methods at baseline and during treatment were to be uniform for every target and reported lesion. Documentation by color photography was recommended for skin lesions. CT and MRI were considered the best and most reproducible methods to measure target lesions selected for response assessment; chest X-ray films were considered acceptable for lesions when they were clearly defined and surrounded by aerated lung. Assessment also included measurement of tumor markers, cytology and histology.

Number of patients (planned/analyzed):
65 enrolled; 64 eligible.

Diagnosis and main criteria for inclusion:
Male and female outpatients ≥18 years of age with an ECOG performance score of ≤1 with histologically confirmed, inoperable metastatic colorectal cancer and no previous systemic treatment for metastatic disease. Adjuvant or neo-adjuvant treatment for non-metastatic disease was allowed if completed ≥6 months prior to initiation of study treatment. Patients were to have ≥1 target lesion, with a minimum lesion size according to RECIST criteria.

Test product, dose and mode of administration or test procedure:
Xeloda, 1250 mg/m² orally, twice daily on days 1-14, every 3 weeks

Duration of treatment:
48 weeks.

Reference therapy, dose and mode of administration or reference procedure:
None.

Criteria for evaluation (efficacy, safety):
The primary endpoint, overall response rate for eligible patients, was assessed according to the RECIST criteria. Safety parameters: Adverse events and laboratory test results were graded and systematically recorded and analyzed according to National Cancer Institute Common Toxicity Criteria.

Statistical methods:
The overall response rate and 95 % confidence intervals (CIs) were calculated. Overall survival, time to response, duration of response, time to progression or death, and time to treatment failure were analysed with Kaplan-Meier survival curves, and summarized by the respective median and 95% CIs.

Summary (efficacy, safety, other results):
A total of 64 patients were randomized, with 8 unable to be re-evaluated for efficacy as planned; therefore, 56 patients participated in the per-protocol efficacy analysis. All patients participated in the analysis of adverse events (AEs).

Efficacy parameters: (1) Overall response rate: by intention-to-treat analysis (ITT, 64), 2 patients had CR and 13 had PR, and the overall response rate was 23%. Of 15 patients who responded, 13 responses were confirmed 4 weeks later (CR, 2; PR, 11). Therefore, the overall confirmed response rate in the ITT population was 20%. By per-protocol analysis (PP, 56 patients), the overall response rate was 27%, and the overall confirmed response rate was 23%.

(2) Response rate by location of lesions: liver 30.0% (9/30); lung 18% (2/11); abdominal/pelvic lymph node 30% (6/20); distant lymph node 20% (1/5), and other, 20% (1/5).

(3) Response analysis according to previous treatment

Table 1. Response analysis by previous treatment

Safety parameters: All 64 patients participated in the analysis of AEs, and the incidence was recorded as follows: hand-foot syndrome and gastro-intestinal toxicity (nausea and vomiting) were the most frequent AEs, approximately 30%, with grade III at 5%. The next most frequent AEs were diarrhea and fatigue (each 16%), with grade III at 6% and 8%, respectively. No grade IV AEs occurred. Other AEs occurring with an incidence >5% were anorexia, stomach ache, pruritis and dizziness. There were no serious adverse events or deaths during the study.

The most common laboratory abnormality was reduced hemoglobin (mainly grades I and II) experienced by 67% of patients; however, some of these patients had mild anemia before treatment. Thrombocytopenia and leucopenia occurred in 33% and 25% of patients, respectively; these abnormalities were mainly grade I. Mild increases in alanine aminotransferase (AST) and aspartate aminotransferase (AST) occurred in 30% and 23% of cases, respectively; hyperbilirubinemia occurred in 33% of patients, of which 14% was grade III.

Conclusions:
In this study of Xeloda as first-line treatment for advanced colorectal cancer, 64 patients were enrolled and 56 were eligible for efficacy assessment. Two patients had confirmed CR, 13 had confirmed PR, and the overall confirmed response rate was 20% in the ITT population and 23% according to the per protocol analysis. This was similar to published results of larger randomized international trials (26%). Adverse events and laboratory abnormalities were mainly mild, and the safety profile of Xeloda in this study was similar to that previously shown in international clinical studies. In this study, Xeloda was found to be effective and well tolerated in first line treatment of patients with advanced colorectal cancer.