vinzolidine and Neoplasms

Vinzolidine (VZL) is a semisynthetic vinca alkaloid with broad antitumor activity in animal models of malignancy but had unpredictable toxic effects when given orally to humans. To minimize the toxic effects due to potential erratic gastrointestinal absorption, this drug was restudied in man as an intravenous preparation given as a rapid injection every two weeks. The maximum tolerated dose (MTD) on this schedule was 9.0 mg/m2 with unpredictable leukopenia (usually occurring 5-14 days post treatment but appearing erratically), constipation, paralytic ileus, and inappropriate ADH syndrome as major toxicities. Nonhematologic toxicities were dose-limiting. Repetitive dosing at two week intervals was associated with leukopenia at D 14-15 in some but not all patients treated above 5.0 mg/m2 precluding further treatment on schedule. In contrast, the oral MTD of this agent in our prior studies was 45 mg/m2 with no evidence of delayed leukopenia. Intrapatient variability of toxicity was small; interpatient variability of toxicity was substantial and did not correlate with prior therapy. Because of the presence of delayed hematologic toxicity on repetitive dosing schedules, intravenous VZL should be given on a dosing schedule longer than 14 days. No antitumor activity was seen in this study.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Drug Administration Schedule; Drug Evaluation; Female; Humans; Injections, Intravenous; Male; Middle Aged; Neoplasms; Vinca Alkaloids

The semi-synthetic vinca alkaloid vinzolidine was administered to advanced cancer patients as an intravenous bolus on a three day schedule every 21 days. Forty-two patients were treated in this phase I trial. Five partial remissions (breast--1, melanoma--2, renal cancer--2) were seen in 30 evaluable patients. The dose limiting toxicities were myelosuppression and neuropathy. Erratic myelosuppression from course to course within the same patient as seen in previous trials with oral vinzolidine, was not observed with the intravenous formulation. The measured pharmacokinetic parameters conformed best to a 2-compartment model with a mean terminal half-life of 23 hours. The anti-tumor activity observed during this phase I trial and acceptable toxicity provide the basis for initiating phase II studies in selected forms of cancer.

Topics: Adult; Aged; Antineoplastic Agents; Drug Evaluation; Female; Humans; Injections, Intravenous; Male; Middle Aged; Neoplasms; Vinca Alkaloids