title: Phase I trial of the cryptophycin analogue LY355703 administered as an intravenous infusion on a day 1 and 8 schedule every 21 days.
abstract: The cryptophycin analogue LY355703 is a potent inhibitor of microtubule polymerization that displays in vitro and in vivo activity in cell lines and tumor xenografts displaying the multidrug-resistant phenotype. In a Phase I trial, 25 patients received LY355703 as a 2-h i.v. infusion on day 1 and day 8 repeated every 3 weeks. Doses were escalated from 0.1 to 2.22 mg/m2 using a modified continual reassessment method. Neurological toxicity was found to be dose-limiting at 1.84 and 2.22 mg/m2. Among four patients treated at these doses, two had grade 4 constipation/ileus, one with severe myalgias, and one had grade 3 motor neuropathy. These findings were reversible. The 1.5 mg/m2 dose level was well tolerated. An amended twice-weekly schedule was pursued in 11 patients in an attempt to improve dose intensity and avoid dose-limiting neurotoxicity. Doses of >0.75 mg/m2 on a day 1, 4, 8, and 11 schedule every 21 days were not tolerated as a result of nausea/constipation, suggesting that LY335703 toxicity is not schedule dependent and is related to cumulative dose. LY355703 plasma concentrations measured by liquid chromatography with tandem mass spectrometry were evaluated using a population pharmacokinetic model. LY355703 was eliminated rapidly with a short terminal half-life that ranged from 0.8 to 3.9 h. Interpatient variability with respect to plasma clearance and volume of distribution, including covariates, was moderate at 32% and 39%, respectively. Maximum plasma concentration and area under the plasma concentration-time curve were linear over the dose range studied. A patient with non-small cell lung cancer previously treated with taxanes experienced a partial response lasting 4 months, and five patients had stable disease lasting > or =3 months. LY355703 at a dose of 1.5 mg/m2 is recommended for Phase II evaluation on a days 1 and 8 schedule. Twice-weekly dosing did not allow improvement in dose intensity or tolerability.
authors.affiliation: University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, USA. james.stevenson@uphs.upenn.edu
authors.forename: James P
authors.initials: JP
authors.lastname: Stevenson
authors.forename: Weijing
authors.initials: W
authors.lastname: Sun
authors.forename: Maryann
authors.initials: M
authors.lastname: Gallagher
authors.forename: Robert
authors.initials: R
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Vaughn
authors.forename: Lynn
authors.initials: L
authors.lastname: Schuchter
authors.forename: Kenneth
authors.initials: K
authors.lastname: Algazy
authors.forename: Stephen
authors.initials: S
authors.lastname: Hahn
authors.forename: Nathan
authors.initials: N
authors.lastname: Enas
authors.forename: Diane
authors.initials: D
authors.lastname: Ellis
authors.forename: Donald
authors.initials: D
authors.lastname: Thornton
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D047630:Depsipeptides; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007769:Lactams / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007783:Lactones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D008962:Models, Theoretical; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000493:pharmacokinetics*; D010641:Phenotype; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D007769:Lactams; D007783:Lactones; D010456:Peptides, Cyclic; C088419:cryptophycin; C114033:cryptophycin 52