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. and its metabolites were quantiﬁed by HPLC/UV [25]. Model-independent pharmacokinetic parameters were determined using Kinetica (cid:2) software (Innaphase Corp., Philadelphia, PA, USA). The normalised exposure (AUC/dose) was compared between day 1 and day 7. analyse the DLTs during the ﬁrst cycle of treatment in each DL and to determine the MTD. The were to determine the recommended DL(s) for the phase II part of the study, the safety proﬁle and the antitumour activity of the combination. For response rate, exact 95% conﬁdence intervals (CIs) were provided. The Kaplan–Meier method was used to estimate the time-dependent parameters.