A phase I study of rhizoxin (NSC 332598) by 72-hour continuous intravenousinfusion in patients with advanced solid tumors

Background: Rhizoxin (NSC 332598) is a novel macrolide antitumor antibiotic that inhibits microtubule assembly and also depolymerizes preformed microt ubules. In preclinical evaluations, rhizoxin demonstrated broad antitumor a ctivity in vitro and in vivo including both vincristine- and vindesine-resi stant human lung cancers. Prolonged exposure schedules in xenograft models demonstrated optimal efficacy indicating schedule-dependent antitumor activ ity. The early phase I and II evaluations a five-minute bolus infusion sche dule was studied, however, only modest anti-tumor activity was noted, possi bly due to rapid systemic clearance. To overcome these limitations and to e xploit the potential for schedule-dependent behavior of rhizoxin, the feasi bility of administering rhizoxin as a 72-hour continuous intravenous (i.v.) infusion was evaluated. Patients and methods: Patients with advanced solid malignancies were entere d into this phase I study, in which both the infusion duration and dose of rhizoxin were increased. The starting dose was 0.2 mg/m(2) over 12 hours ad ministered every 3 weeks. In each successive dose level, the dose and infus ion duration were incrementally increased in a stepwise fashion. Once a 72- hour i.v. infusion duration was reached, rhizoxin dose-escalations alone co ntinued until a maximum tolerated dose (MTD) was determined. Results: Nineteen patients were entered into the study. Rhizoxin was admini stered at doses ranging from 0.2 mg/m(2) i.v. over 12 hours to 2.4 mg/m(2) i.v. over 72 hours every 3 weeks. The principal dose-limiting toxicities (D LT) were severe neutropenia and mucositis, and the incidence of DLT was una cceptably high at rhizoxin doses above 1.2 mg/m(2), which was determined to be the MTD and dose recommended for phase II studies. At these dose levels , rhizoxin could not be detected in the plasma by a previously validated an d sensitive high-performance liquid chromatography assay with a lower limit of detection of 1 ng/ml. No antitumor responses were observed. Conclusions: Rhizoxin can be safely administered using a 72-hour i.v. infus ion schedule. The toxicity profile is similar to that observed previously u sing brief infusion schedules. Using this protracted i.v. infusion schedule the maximum tolerated dose is 1.2 mg/m(2)/72 hours.