Phase I and pharmacokinetic study of weekly oral therapy with vinorelbine in patients with advanced breast cancer (ABC)

Background: A phase I dose-escalation study of a new formulation of oral vinorelbine was conducted to determine the maximum tolerated dose (MTD) of a once weekly regimen and preliminary pharmacokinetic profile in patients with advanced breast cancer (ABC). Twenty-six patients were treated at dose levels ranging from 60 to 100 mg/m(2)/week. Pharmacokinetics was assessed during the first administration. Patients and methods: All patients had histologically confirmed locally advanced or metastatic breast cancer and had received no more than two prior chemotherapy regimens for ABC. Results: The MTD was 100 mg/m(2)/week due to the occurrence of dose-limiting neutropenia, nausea/vomiting and constipation in five of six patients. Toxicities at 80 mg/m(2)/week were manageable, neutropenia being the main toxicity (grade 3-4 seen in 10 of 13 patients). Nausea, vomiting and diarrhoea were common but rarely severe. Vinorelbine was rapidly absorbed with maximum blood concentration (C-max) of 103.8 +/- 41.6 ng.ml-1 observed 1.2 +/- 0.8 hours (T-max) after administration of 80 mg/m(2). Pharmacokinetic exposure increased linearly with dose. Area under the concentration-time curve (AUC) and concentration measured 24 hours after drug intake (C-24h) were significantly correlated with depletion of neutrophils. Objective tumour responses were reported in 6 of the 14 evaluable patients treated at doses greater than or equal to 80 mg/m(2)/week. Conclusion: The safety profile of oral vinorelbine appears comparable to that of intravenous dosing. The recommended phase II dose is 80 mg/m(2)/week and requires regular monitoring of neutrophil counts.