title: A phase I and pharmacokinetic study of the quinoxaline antitumour Agent R(+)XK469 in patients with advanced solid tumours.
abstract: OBJECTIVE
  To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose.
  
  
  METHODS
  R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1-5 of a 21-d cycle. Based on the demonstration of a long half-life, the dosing schedule was subsequently amended to infusion on days 1, 3 and 5 of a 21-d cycle. An alternate single-dose schedule of once every 21 d was also explored. Blood samples were collected for pharmacokinetic studies.
  
  
  RESULTS
  Dose-limiting toxicity (DLT) was neutropaenia. There was significant interindividual variability in clearance as evidenced by a coefficient of variation of 46%. A flat-dosing scheme (not based on body surface area) was justified by the absence of correlation between clearance and body surface area. A partial response was observed in a patient with nasopharyngeal carcinoma.
  
  
  CONCLUSIONS
  The recommended phase II doses are 850-1100 mg/d on days 1, 3 and 5 of a 21-d cycle and 2500 mg on day 1 of a 21-d cycle. The observed interpatient pharmacokinetic variability should prompt investigation into the presence of genetic polymorphism in relevant metabolizing enzymes.
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. sundevia@medicine.bsd.uchicago.edu
authors.forename: Samir D
authors.initials: SD
authors.lastname: Undevia
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramirez
authors.forename: Larry
authors.initials: L
authors.lastname: House
authors.forename: Apurva A
authors.initials: AA
authors.lastname: Desai
authors.forename: Linda A
authors.initials: LA
authors.lastname: Skoog
authors.forename: Deepti A
authors.initials: DA
authors.lastname: Singh
authors.forename: Theodore
authors.initials: T
authors.lastname: Karrison
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009503:Neutropenia / Q000139:chemically induced; D011810:Quinoxalines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011810:Quinoxalines; C118180:XK 469