Clinical Trial Result Information

Protocol number
M66115

Title of Study
Phase I/II study of the combination capecitabine and vinorelbine as chemotherapy for metastatic breast cancer.

Sponsor
Hoffmann-La Roche AG

Company division
Pharmaceutical

Product name
Xeloda

Generic name
capecitabine

Therapeutic area
Breast cancer

Clinical study summary
This open-label, phase I/II dose-escalation and feasibility study evaluated combination chemotherapy with Xeloda (capecitabine) and vinorelbine in patients with metastatic breast cancer who had relapsed after anthracycline and/or taxane adjuvant chemotherapy. Patients were given 2000 to 2500 mg/m² of Xeloda daily and 25 to 30 mg/m² of vinorelbine weekly for 1 to 6 treatment cycles.

Study center(s)
2 centers in Germany

Phase of development
II

Objectives
Primary: (1) To determine the maximum tolerated doses (MTD), the dose-limiting toxicities (DLT), and the recommended phase II doses of Xeloda and vinorelbine given in combination; (2) To evaluate the safety and tolerability of the combination regimen with dose escalation of capecitabine and vinorelbine. Secondary: (1) To evaluate the objective (complete and partial) response rate achieved with the combination regimen; (2) To determine the proportion of patients achieving stable disease and progressive disease; (3) To evaluate the duration of response and the time to progression.

Methodology
Vinorelbine was given on Days 1, 8, 22, and 29, and Xeloda was given on Days 1-14 and 22-35, with the next cycle starting on Day 43. The weekly dose of vinorelbine was escalated in a first step from 25 to 30 mg/m² and the daily dose of Xeloda from 2000 to 2500 mg/m² in a second step. Each patient received at least 1 treatment course. Treatment continued for a maximum of 6 cycles or until disease progression or significant clinical deterioration of tumor-related symptoms or unacceptable toxicity occurred.

Number of patients (planned/analyzed)
33 enrolled.

Diagnosis and main criteria for inclusion
Patients ≥18 and ≤70 years of age with histologically or cytologically proven breast cancer and a life expectancy >3 months; adjuvant and/or a maximum of 1 prior chemotherapy for metastatic disease; relapse after adjuvant chemotherapy that may contain anthracycline and/or a taxane; Karnofsky performance status 60% to 100%; lack of significant cardiac, liver, and renal disease; and adequate bone marrow function.

Test product, dose and mode of administration or test procedure
Xeloda ( capecitabine,) escalating daily dose from 2000mg/m² (dose level 1) to 2500mg/m² (dose level 2) po . Vinorelbine, escalated weekly dosing from 25 mg/m² (dose level I) to 30 mg/m² (dose level II)by iv infusion..

Duration of treatment
Maximum of 36 weeks

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

Criteria for evaluation (efficacy, safety)
Safety: MTD, DLTs, blood counts, adverse events Efficacy: objective tumor response, overall response rate (complete response [CR] + partial response [PR]), duration of response, time to progression, progression-free survival, overall survival

Statistical methods
Analyses were generally based on the intent-to-treat population. Descriptive statistics are presented for safety and efficacy variables. Kaplan-Meier curves were used to estimate survival rates.

Summary (efficacy, safety, other results)
Thirty-three patients received a total of 91 complete 6-week cycles of Xeloda and vinorelbine. The median number of administered cycles per patient was 3 (range, 1-6). Thirty-one patients were evaluable for toxicity. At dose level II, 4 of 7 patients experienced DLTs (nausea/vomiting, febrile neutropenia, grade 4 neutropenia, infection, and diarrhea). Thus, the MTD was defined. To confirm the safety and efficacy, the dose level I cohort was extended to 24 patients. Two patients showed DLTs (hospitalization due to febrile neutropenia and prolonged neutropenia, respectively). The main toxicity was neutropenia at NCI-CTC grades 3 and 4 in 39% of patients. The overall response rate for Xeloda and vinorelbine in evaluable patients was 59% (95% CI: 39%-76%), including 3 patients with a complete remission. The median duration of response was 9.5 months. The Kaplan-Meier estimate of median time to disease progression was 7.4 months. The progression-free survival rate was 55% (95% confidence interval: 40%-77%) at 6 months and 28% (95% confidence interval: 15%-50%) at 1 year. The Kaplan-Meier estimate of median overall survival was 18.9 months. The overall survival rate was 74% (95% confidence interval: 60%-93%) at 1 year and 48% (95% confidence interval: 33%-71%) at 2 years.

Conclusions
The combination of Xeloda and vinorelbine was administered with manageable toxicity and showed significant efficacy for patients with metastatic breast cancer, even after failure of an anthracycline- and/or taxane-based therapy.

Date of report
10/1/2004