title: Phase I and pharmacokinetic study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of tasidotin (ILX651), a dolastatin-15 analogue, when administered on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors.
  
  
  METHODS
  Thirty-two patients were treated with 92 courses of tasidotin through seven dose levels determined by a modified Fibonacci scheme ranging from 3.9 to 45.7 mg/m(2). Pharmacokinetic samples were collected during the first course.
  
  
  RESULTS
  Neutropenia was the principal DLT at the 45.7 mg/m(2)/d dose level. In addition, one patient also experienced grade 3 neutropenia complicated with grade 3 esophageal candidiasis and grade 3 dehydration. Only 1 of 11 patients treated at the MTD, 34.4 mg/m(2), experienced dose-limiting neutropenia. Other common, drug-related toxicities included mild to moderate fatigue, anemia, nausea, anorexia, emesis, alopecia, and diarrhea. The best observed antitumor response consisted of stable disease and was noted in 10 patients (31%); the median duration on study for those patients with stable disease was 99.5 days compared with 37.5 days for those patients with progressive disease. Tasidotin plasma concentrations declined biphasically with an effective half-life of < or =55 minutes, and approximately 11% was excreted unchanged in the urine.
  
  
  CONCLUSIONS
  The recommended dose for phase II studies and the MTD when tasidotin is administered on days 1, 3, and 5 every 3 weeks is 34.4 mg/m(2). The favorable toxicity profile of tasidotin compared with other antitubulin agents, including other dolastatin analogues, and its novel mechanism of action support further disease-directed evaluation of this agent.
authors.affiliation: Tyler Cancer Center, Texas, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Cunningham
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Appleman
authors.forename: Miora
authors.initials: M
authors.lastname: Kirvan-Visovatti
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Eileen
authors.initials: E
authors.lastname: Regan
authors.forename: Svetislava
authors.initials: S
authors.lastname: Vukelja
authors.forename: Peter L
authors.initials: PL
authors.lastname: Bonate
authors.forename: Francis
authors.initials: F
authors.lastname: Ruvuna
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fram
authors.forename: Antti
authors.initials: A
authors.lastname: Jekunen
authors.forename: Steve
authors.initials: S
authors.lastname: Weitman
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hammond
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Eder
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; C504233:tasidotin