Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer

Background: Pharmacokinetic study has shown that co-administration of cyclosporin A (CsA), which acts as a P-glycoprotein (P-gp) and CYP-3A blocker, resulted in an 8-fold increase in the systemic exposure of oral paclitaxel. Two doses of oral paclitaxel on 1 day in combination with CsA resulted in higher systemic exposure than single dose administration. Patients and methods: In this phase II study, chemonaïve patients with advanced gastric cancer received oral paclitaxel weekly in two doses of 90 mg/m2 on the same day; CsA (10 mg/kg) was given 30 min before each dose of oral paclitaxel. Results: In 25 patients, the main toxicities were: nausea CTC grade 2/3, 10 patients (40%); vomiting grade 2/3, 4 patients (20%); diarrhea grade 2/3, 6 patients (24%); neutropenia grade 3/4, 5 patients (20%). In the 24 evaluable patients, eight partial responses were observed, resulting in an overall response rate (ORR) of 33% [95% confidence interval (CI) 18% to 52%]. Eleven patients had stable disease (46%) and 5 patients showed progressive disease (21%). The ORR in the total population was 32% (95% CI 17% to 50%). The median time to progression was 16 weeks (95% CI 9–22). Pharmacokinetic analyses revealed that the mean area under the plasma concentration–time curve (AUC) of orally administered paclitaxel (± standard deviation) was 3757.6 ± 939.4 ng·h/ml in week 1 and 3928.4 ± 1281 ng·h/ml in week 2. The intrapatient variability in the AUC was 12%. Conclusions: Oral paclitaxel in combination with CsA is both active and safe in chemonaïve patients with advanced gastric cancer. Toxicities were mainly gastrointestinal.