PHASE I/II TRIAL OF CONTINUOUS-INFUSION VINORELBINE FOR ADVANCED BREAST-CANCER

Purpose: A phase I/II trial of vinorelbine (VRL) administered by continuous infusion (CIV) wets conducted in advanced breast carcinoma (ABC) patients to determine the maximum-tolerated dose (MTD) and to evaluate the toxicity pattern and antitumor activity of this alternative administration schedule to the currently recommended weekly short intravenous (IV) administration. Patients and Methods: Between February 1990 and July 1991, 64 consecutive, eligible patients with ABC were treated; 33 had received one or two previous palliative chemotherapy combinations and 31 had not received chemotherapy for metastatic disease. VRL was administered, after an initial IV bolus of 8 mg/m(2) on day 1, by a 4-day CIV at five different 24-hour dose levels (DLs) to be repeated every 21 or 28 days: DL1, 5.5 mg/m(2); DL2, 7 mg/m(2); DL3, 8 mg/m(2), DL4, 9 mg/m(2); and DL5, 10 mg/m(2). Results: The limiting noncumulative toxicity was neutropenia with the MTD established at 8 mg/m(2) bolus plus 10 mg/m(2)/d for 4 days (total dose per cycle, 48 mg/m(2)). At DL3 and DL4, we observed mucositis (14% of patients; five percent of cycles > grade 2), alopecia, and asthenia. By contrast, neurotoxicity was minor. The toxicity was otherwise predictable and manageable. Pharmacokinetic data obtained at DL1 and DL3 showed a mean VRL plasma concentration of 967 +/- 331 ng/mL after the initial 8 mg/m(2) IV bolus dose, which declined rapidly thereafter to reach mean steady-state levels of 12 ng/mL (n = 5) for the 30-mg/m(2) dose and 8 ng/ mL (n = 2) for the 40-mg/m(2) dose. These levels were maintained over the 96-hour CIV. The mean residence time (MRT) was 29 +/- 7 hours (terminal half-life [t(1/2)], 23 hours), the total-body clearance (CL) was 24 +/- 11 L/hr/ m(2), and the volume of distribution at steady-state (Vss) was high at 1,832 +/- 359 L/m(2). Two patients achieved a complete response (CR) and 21 a partial response (PR), for an objective response rate of 36% (95% confidence interval [CI], 23 to 49). The median duration of response was 6 months. The median survival duration was 24 months (range, 3 to 37). A relationship between given dose-intensity and objective response rate was found, with an overall response (OR) rate of 13.3% (two of 15) for 8 to 10 mg/m(2)/wk, 35.4% (11 of 31) for 10 to 12 mg/m(2)/wk, and 55.5% (10 of 18) for 12 to 14.5 mg/ m(2)/wk. Conclusion: This trial, while confirming VRL activity in ABC, shows the feasability of a CIV administration schedule. A decrease of the administered total dose per 3- to 4-week cycle to less than the weekly schedule with the same therapeutic activity suggests a better therapeutic index. The data are also suggestive of a dose-response relationship and a dose-intensity/activity correlation.