title: 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.
  
  
  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.affiliation: The Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78229, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: C
authors.initials: C
authors.lastname: Aylesworth
authors.forename: J
authors.initials: J
authors.lastname: Rizzo
authors.forename: E
authors.initials: E
authors.lastname: Izbicka
authors.forename: E
authors.initials: E
authors.lastname: Campbell
authors.forename: J
authors.initials: J
authors.lastname: Kuhn
authors.forename: G
authors.initials: G
authors.lastname: Weiss
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018942:Macrolides; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced
chemical_list: D000903:Antibiotics, Antineoplastic; D007783:Lactones; D018942:Macrolides; C041443:rhizoxin