Phase I study of vinorelbine and docetaxel with granulocyte colony-stimulating factor support in the treatment of metastatic breast cancer

Purpose: Vinorelbine and docetaxel are two active agents in the treatment of metastatic breast cancer. When given together, these drugs exhibit synergistic antitumor activity without significant pharmacokinetic interaction. The doselimiting toxicities of this combination are neutropenic fever and mucositis. Adding granulocyte colony-stimulating factor (G-CSF) might lessen the toxicity and increase the maximum tolerated dose (MTD) of this combination. The aim of this study was to determine the MTD of vinorelbine and docetaxel given in combination with G-CSF. Patients and methods: Between August 1997 and December 1998, 14 patients with metastatic breast cancer were enrolled in this study. All patients had received doxorubicin-based therapy, and 46% had received paclitaxel in the adjuvant or neoadjuvant setting. Patients were treated with vinorelbine at a starting dose of 20 mg/m² intravenously over 10 min on days 1 and 5 and docetaxel at a starting dose of 85 mg/m² intravenously over 1 hr on day 1, following the vinorelbine. Treatments were repeated every 21 days. Prophylactic G-CSF 5 mcg/kg was given subcutaneously on days 3-10. Toxicity was graded according to the National Cancer Institute's grading system. Results: A total of 65 cycles was administered at dose levels 0, -1, -2, and -3. The median absolute granulocyte count nadir for all courses was 200 mm^-3 (range, 0.1-7700 mm^-3), and the median nibrahim@mdanderson.org time to this nadir was 9 days (range, 7-30). The median platelet nadir was 163 (range, 27-401k), and the median time to this nadir was 8 days (range, 7-30). The most common grade 3 nonhematologic toxicities for all courses were fatigue and myalgia, which occurred in 32 and 10 cycles, respectively. Neutropenic fever was encountered in 11 cycles. Three patients developed colitis-like pictures, two of whom died as a result. Consequently, the protocol was closed to accrual before a MTD was reached. Conclusion: The combination of vinorelbine, docetaxel, and G-CSF in our hands has proven to be a toxic regimen, even when relatively low doses of vinorelbine and docetaxel are given. Meticulous observation of patients receiving this combination is warranted since the combination resulted in two deaths in this study.