title: Phase I clinical and pharmacokinetic study of oral carboxyamidotriazole, a signal transduction inhibitor.
abstract: OBJECTIVE
  We conducted a phase I trial of carboxyamidotriazole (CAI, NSC 609974), designed to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetic characteristics of CAI gelatin capsule (gelcap) formulation administered daily as a single oral dose.
  
  
  METHODS
  Twenty-nine patients with advanced malignancy who met standard eligibility criteria were treated with once-daily CAI given in cycles of 28 days. Pharmacokinetic sampling was performed on days 1 and 29 and trough plasma CAI levels were assessed weekly.
  
  
  RESULTS
  Patients were entered at dose levels of 50, 75, and 100 mg/m2. All three patients at the 100-mg/m2 level experienced dose-limiting neurocerebellar toxicity. Other neurotoxicities were mild. Gastrointestinal side effects were common, but generally mild, with 23 patients experiencing nausea and/or vomiting of any grade. Fatigue was a frequent complaint, with 19 patients experiencing mild to moderate symptoms. Six patients with nausea and vomiting and five with fatigue experienced relief of symptoms with a change to nocturnal administration of CAI. Peak plasma concentrations (Cp) occurred at 2.4 +/- 1.5 hours after administration of the oral gelcap dose. Patients approached steady-state trough plasma concentrations (Css) by days 8 to 15 and maintained a relatively constant Css throughout the course of treatment. For all patients, the mean variation in weekly CAI Cp was 12.4% +/- 5.3%.
  
  
  CONCLUSIONS
  The MTD for the gelcap formulation was 75 mg/m2 with dose-limiting neurocerebellar toxicity (ataxia) seen at 100 mg/m2. Other prominent side effects, including nausea, vomiting, and fatigue, were partially alleviated through altering the administration schedule to nighttime dosing.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, Madison, USA. jdberlin@facstaff.wisc.edu
authors.forename: J
authors.initials: J
authors.lastname: Berlin
authors.forename: K D
authors.initials: KD
authors.lastname: Tutsch
authors.forename: P
authors.initials: P
authors.lastname: Hutson
authors.forename: J
authors.initials: J
authors.lastname: Cleary
authors.forename: R P
authors.initials: RP
authors.lastname: Rago
authors.forename: R Z
authors.initials: RZ
authors.lastname: Arzoomanian
authors.forename: D
authors.initials: D
authors.lastname: Alberti
authors.forename: C
authors.initials: C
authors.lastname: Feierabend
authors.forename: G
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002214:Capsules; D004064:Digestive System / Q000187:drug effects; D004334:Drug Administration Schedule; D005260:Female; D005782:Gels; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy; D009420:Nervous System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D002214:Capsules; D005782:Gels; D014230:Triazoles; C062058:carboxyamido-triazole