Phase I and pharmacological study of vinblastine by prolonged continuous infusion

Vinblastine is an antimitotic plant alkaloid with an elimination half-life of about 24 h. The cytotoxicity of vinblastine against solid tumor cell lines in vitro is markedly increased with prolonged exposure. Therefore, 24 patients with advanced malignancy were treated with a prolonged continuous i.v. infusion of vinblastine given via an implantable pump. The patients received vinblastine for a median of 12 wk (range, 2 to 36 wk), at dosages ranging from 0.5 to 0.9 mg/m2/day. The steady-state serum vinblastine concentration (VLBss) was determined at 2- to 3-wk intervals in each patient for correlation with toxicity. The dose-limiting toxicity was leukopenia in nine patients and peripheral neuropathy in one patient. Thirteen patients developed progressive disease prior to reaching dose-limiting toxicity, and one patient withdrew from the study because of severe local toxicity at the injection site. There was only mild toxicity at infusion rates less than or equal to 0.65 mg/m2/day, but at no dosage did reproducible toxicity occur. The maximum VLBss was significantly higher in those patients with severe leukopenia than nontoxic patients (1.91 versus 1.00 ng/ml; P = 0.001), but there was no significant difference in the maximum dosage between the two groups (0.76 versus 0.74 mg/m2/day). Our results demonstrate that prolonged infusions of vinblastine are feasible, achieving VLBss greater than 1 ng/ml, a drug concentration which is cytotoxic in vitro. The recommended starting dose of vinblastine for Phase II studies is 0.7 mg/m2/day, with dosage adjustments every 2 to 4 wk based on the white blood cell count and VLBss. Prospective monitoring of VLBss with dosage adjustment to maintain VLBss less than 1.5 to 2.0 ng/ml, may avoid the unexpected occurrence of severe myelosuppression.