Clinical Trial Result Information

Protocol number
M66020

Title of Study
An open-label phase II study to analyze the efficacy and tolerability of capecitabine in metastatic colorectal cancer patients with regards to the expression profile of key enzymes in the capecitabine metabolism.

Sponsor
Hoffmann-La Roche AG

Company division
Pharmaceutical

Product name
Xeloda

Generic name
capecitabine

Therapeutic area
Colorectal Cancer

Clinical study summary
This was an open-label, multicenter, non-comparative, national phase II clinical trial to assess the safety and efficacy profiles of intermittent therapy with Xeloda (capecitabine) as first-line chemotherapy in patients with colorectal cancer metastases followed by a second line treatment option with Xeloda + oxaliplatin combination therapy. An exploratory analysis of the expression profile of key enzymes determined with immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction in metastases and primary tumor tissue in correlation with efficacy results was planned. However, the study was prematurely terminated due to low recruitment.

Study center(s)
2 centers in Germany

Phase of development
II

Objectives
Primary: Analysis of the expression profile on the key enzymes thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidylate synthase determined by immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction in metastases and primary tumor tissue in correlation with efficacy results of first- and secondline palliative chemotherapy with Xeloda in metastatic colorectal cancer patients.

Methodology
Biologic samples taken prior to chemotherapy, TP, DPD, TS, hCNT-1 and DNA methylation pattern analyzed in metastatic and primary tumor tissues. DPD, TP and TS also analyzed in PBMNCs.

Number of patients (planned/analyzed)
80 planned. 36 patients received firstline therapy; 19 also received secondline therapy.

Diagnosis and main criteria for inclusion
Histologically confirmed metastatic colorectal cancer (Dukes D) with a measurable lesion accessible for biopsy and planned firstline palliative chemotherapy with Xeloda. No prior treatment with Xeloda.

Test product, dose and mode of administration or test procedure
Firstline: Xeloda (capecitabine) 1250mg/m² bid po d1-14 q3w.
Secondline: Xeloda 1000mg/m² (or 80% of the reduced dose in case of dose reduction in firstline therapy) bid po d1-14 and oxaliplatin 130mg/m2 d1, q3w.

Duration of treatment
Firstline: Minimum 6 cycles, maximum 48 weeks. Secondline: Minimum 2 cycles, may be continued until progression/unacceptable toxicity or after CR observed after 2 therapy cycles.

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

Criteria for evaluation (efficacy, safety)
Objective response rate, time to response, duration of response, time to disease progression or death, overall survival (analyzed after first- and secondline therapy).

Statistical methods
Descriptive analyses of enzyme levels and other biomarker results. Logistic regression and Cox regression techniques for exploration expression profile and outcome.

Summary (efficacy, safety, other results)
Efficacy:

	Intent to Treat (N=36)	Standard Analysis (N=30)
First-Line confirmed Response Rate (95% CI)	8.33% (1.75-22.47%)	10.00 (2.11-26.53)
Second-Line Confirmed Response Rate (95% CI)	26.32% (9.15-51.20%)	20.00 (4.33-48.09)
Median Time to Disease Progression First-Line (95% CI)	5.03 months (2.76-6.21)	5.16 (2.96-6.31)
Median Time to Disease Progression Second-Line (95% CI)	5.85 months (3.22-7.49)	4.50 (3.19-6.21)
Median Duration of Response First-Line (95% CI)	5.55 months (5.52-NA)	5.55 months (5.52-NA)
Median Duration of Response Second-Line (95% CI)	5.91 months (4.57-8.38)	5.85 (4.57-7.49)
Median overall survival time First-Line (95% CI)	17.08 months (12.55-22.27)	18.59 (12.78-27.66)
Median overall survival time Second-Line (95% CI)	13.70 months (9.49-24.34)	13.70 months (9.23-24.34)

Safety: The most common treatment-related AEs, of severity grade 3, were hand-and-foot syndrome (4 patients), increased bilirubin (3 patients) and diarrhea (3 patients). Grade 3 nausea and thrombocytopenia were each reported by 1 patient.

Conclusions
In this prematurely terminated trial, the efficacy and toxicity data were similar to formerly published data. A valid analysis regarding the primary endpoints (analysis of the biomarker expression profile) was not possible due to the low number of patients in the study.

Date of report
1/15/2008

Click here for the protocol registry listing of this trial.