Dose-finding and pharmacokinetic study of an all-oral combination regimen of oral vinorelbine and capecitabine for patients with metastatic breast cancer

Purpose: A phase I study was performed to determine the maximal tolerated dose, recommended doses (RDs), safety and efficacy of oral vinorelbine when combined with capecitabine in an all-oral chemotherapy regimen in patients with metastatic breast cancer (MBC), with pharmacokinetic blood sampling to investigate potential drug-drug interactions. Patients and methods: Forty-four patients with MBC received as first- or second-line chemotherapy, oral vinorelbine at a dose of 60 or 80 mg/m(2) on days 1 and 8 (and 15) with escalating doses of capecitabine from 1650 to 2500 mg/m(2)/day days 1-14 every 3 or 4 weeks. Three schedules were tested: day 1, day 8 and weekly regimens of oral vinorelbine with a 14-day course of capecitabine every 3 weeks; and a days 1 and 8 regimen of oral vinorelbine with a 14-day course of capecitabine every 4 weeks. Results: With oral vinorelbine at 60 mg/m(2), the RDs were established as oral vinorelbine 60 mg/m(2) on days 1 and 8 plus capecitabine 2250 mg/m(2)/day days 1-14 and oral vinorelbine 60 mg/m(2)/week plus capecitabine 2000 mg/m(2)/day days 1-14. With oral vinorelbine at 80 mg/m(2), the RD was oral vinorelbine 80 mg/m(2) on days 1 and 8 plus capecitabine 2000 mg/m(2)/day days 1-14. Neutropenia was the main dose-limiting toxicity of the combination; it was reported in 40 patients (90.9%), with grade 3 in 14 patients (31.8%) and 6.2% of cycles, and grade 4 in 12 patients (27.3%) and 4.3% of cycles. Complications were rare with only three patients experiencing febrile neutropenia (one episode each). The most frequent non-haematological toxicity was gastrointestinal; however, the incidence of grade 3 was low, with no episode of grade 4. Hand-foot syndrome was reported in 14 patients (31.8%) and 22.6% of cycles, with grade 2 in two patients (4.5%) and 1.2% of cycles (two episodes each). No episode of grade 3 was observed. Objective responses were reported in 18 patients (three complete responses and 15 partial responses), yielding a response rate of 40.9% in the intention-to-treat population according to the investigator assessment. Results from the pharmacokinetic study demonstrated the absence of mutual pharmacokinetic interactions when both drugs were co-administered. Conclusions: The combination of oral vinorelbine and capecitabine is safe and easy to administer in an outpatient setting. This all-oral combination chemotherapy may offer a good alternative to the intravenous route for patients with MBC. Based on these promising results, a phase II study has started using oral vinorelbine 60 mg/m(2)/week with capecitabine 2000 mg/m(2)/day days 1-14 every 3 weeks as first-line chemotherapy in patients with MBC.