Phase I-II vinorelbine (Navelbine((R))) by continuous infusion in patientswith metastatic breast cancer: Cumulative toxicities limit dose escalation

Vinorelbine (Navelbine (R)) has significant activity against breast carcino ma and is less neurotoxic than vinblastine. Because vinblastine has improve d activity when administered by continuous infusion, we conducted a Phase I -II study to determine the maximum tolerated dose (MTD) of vinorelbine when given by continuous infusion and the response rates to it in heavily pretr eated metastatic breast cancel patients. Between April 1994 and August 1997 , 87 patients were entered in the study. All were female and had proven met astatic breast cancer Ninety-five percent of them had received prior doxoru bicin treatment, and 74% had received prior paclitaxel treatment. In Phase I of the study, all patients received 8 mg of vinorelbine by intravenous (i .v.) bolus followed by a continuous infusion of vinorelbine over 96 hr: Whe n the MTD was determined, patients were entered in the Phase II aem to asse ss treatment responses and cumulative toxic reactions. In the Phase I arm ( 43 patients, 182 cycles), we determined the MTD of vinorelbine to be 8 mg b y i.v. bolus followed by a continuous infusion of 11 mg/m(2)/day over 4 day s. The dose-timing toxic reaction was grade 3-4 granulocytopenia in 35% of the cycles and neutropenic fever in 15% of the cycles. Forty-four patients (193 cycles) were treated at the MTD. Seven (16%) of them had a response (2 complete responses, 5 partial responses). The median duration of response and survival were 4.3 and 8.6 months, respectively. However cumulative toxi c reactions ((neutropenic fever nad stomatitis) in 22 patients (50%) requir ed dose reductions. A continuous infusion of vinorelbine can be safely admi nistered but with a narrow therapeutic index because of cumulative toxic re actions. We recommended a modified MTD of vinorelbine: 8 mg by i.v. bolus f ollowed by a continuous infusion of 10 mg/m(2)/day over 4 days. However thi s treatment schedule offers no apparent advantage over the commonly used we ekly vinorelbine schedule.