PHASE-I AND PHARMACOLOGICAL STUDY OF CI-980, A NOVEL SYNTHETIC ANTIMICROTUBULE AGENT

CI-980 (NSC 613862) is one of a novel class of 1,2-dihydropyrido[3,4-b ]pyrazines that inhibits tubulin polymerization, presumably by binding to the colchicine binding site of tubulin. In a Phase I and pharmacol ogical study, 16 patients with advanced solid neoplasms were treated w ith CI-980 on a continuous 72-h infusion schedule at doses ranging fro m 3.0-5.4 mg/m(2)/day every 3 weeks. High rates of central nervous sys tem (CNS) toxicity and neutropenia occurred in both minimally and heav ily pretreated patients who were treated with CI-980 doses above 3.75 mg/m(2)/day, which is the maximum tolerated dose and the recommended d ose for additional evaluations, CNS effects, characterized by neurocor tical, mood, and cerebellar manifestations, were generally observed to ward the end of the infusion and immediately posttreatment and usually resolved within 48 h after the completion of treatment, Toxicity was mild to modest at the 3.75 mg/m(2)/day dose level, Neither clinical no r pharmacological risk factors that may predispose patients to the dev elopment of CNS effects were evident, Although no objective antineopla stic activity was observed in this Phase I study, CI-980 steady-state plasma concentrations achieved at the recommended dose of 3.75 mg/m(2) /day (mean +/- SE, 5.74 +/- 0.54 nM) approached and exceeded concentra tions that have been associated with significant activity in preclinic al studies, indicating that additional disease-directed evaluations of CI-980 may be warranted.