A phase I and pharmacokinetic study of the quinoxaline antitumour Agent R(+)XK469 in patients with advanced solid tumours

Eur J Cancer. 2008 Aug;44(12):1684-92. doi: 10.1016/j.ejca.2008.05.018. Epub 2008 Jul 21.


Purpose: 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics*
  • Drug Administration Schedule
  • Female
  • Humans
  • Infusions, Intravenous
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism*
  • Neutropenia / chemically induced
  • Quinoxalines / administration & dosage
  • Quinoxalines / adverse effects
  • Quinoxalines / pharmacokinetics*
  • Treatment Outcome


  • Antineoplastic Agents
  • Quinoxalines
  • XK 469