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

Abstract

BACKGROUND:

Rhizoxin (NSC 332598) is a novel macrolide antitumor antibiotic that inhibits microtubule assembly and also depolymerizes preformed microtubules. In preclinical evaluations, rhizoxin demonstrated broad antitumor activity in vitro and in vivo including both vincristine- and vindesine-resistant human lung cancers. Prolonged exposure schedules in xenograft models demonstrated optimal efficacy indicating schedule-dependent antitumor activity. The early phase I and II evaluations a five-minute bolus infusion schedule was studied, however, only modest anti-tumor activity was noted, possibly due to rapid systemic clearance. To overcome these limitations and to exploit the potential for schedule-dependent behavior of rhizoxin, the feasibility of administering rhizoxin as a 72-hour continuous intravenous (i.v.) infusion was evaluated.

PATIENTS AND METHODS:

Patients with advanced solid malignancies were entered into this phase I study, in which both the infusion duration and dose of rhizoxin were increased. The starting dose was 0.2 mg/m2 over 12 hours administered every 3 weeks. In each successive dose level, the dose and infusion duration were incrementally increased in a stepwise fashion. Once a 72-hour i.v. infusion duration was reached, rhizoxin dose-escalations alone continued until a maximum tolerated dose (MTD) was determined.

RESULTS:

Nineteen patients were entered into the study. Rhizoxin was administered at doses ranging from 0.2 mg/m2 i.v. over 12 hours to 2.4 mg/m2 i.v. over 72 hours every 3 weeks. The principal dose-limiting toxicities (DLT) were severe neutropenia and mucositis, and the incidence of DLT was unacceptably high at rhizoxin doses above 1.2 mg/m2, 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 and 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. infusion schedule. The toxicity profile is similar to that observed previously using brief infusion schedules. Using this protracted i.v. infusion schedule the maximum tolerated dose is 1.2 mg/m2/72 hours.

• Authors: A W Tolcher, C Aylesworth, J Rizzo, E Izbicka, E Campbell, J Kuhn, G Weiss, D D Von Hoff, E K Rowinsky
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 11 Issue 3 Pg. 333-8 (Mar 2000) ISSN: 0923-7534 [Print] England
• PMID: 10811501 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• Lactones
• Macrolides
• rhizoxin

Topics

• Adult
• Aged
• Antibiotics, Antineoplastic (administration & dosage, adverse effects, pharmacokinetics)
• Humans
• In Vitro Techniques
• Lactones (administration & dosage, adverse effects, pharmacokinetics)
• Macrolides
• Middle Aged
• Neoplasms (drug therapy)
• Neutropenia (chemically induced)