A phase 1 trial of XK469: toxicity profile of a selective topoisomerase IIbeta inhibitor

Invest New Drugs. 2007 Apr;25(2):147-54. doi: 10.1007/s10637-006-9024-5. Epub 2006 Nov 11.


Purpose: XK469, a member of the quinoxaline family of antitumor agents, is believed to be unique in its ability to selectively target topoisomerase IIbeta. Based on encouraging pre-clinical data, a phase I trial was conducted to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD).

Methods: A 2B accelerated titration schema was employed. XK469 was administered as a 5 or 20 min IV infusion on days 1-5 every 21 days. The starting dose was 9 mg/m(2). Pharmacokinetics (PK) were conducted in cycles 1-3.

Results: 22 patients (21 evaluable, mean age: 56 years, median performance status: 1) were enrolled. At dose level 11 (260 mg/m(2)/daily X 5), 1/6 patients experienced a DLT of grade 4 neutropenia. At 346 mg/m(2)/daily X 5, 2/2 patients experienced DLT's with one episode of febrile neutropenia and one grade 3 infection. The MTD was identified as 260 mg/m(2)/day. XK469 peak plasma levels and systemic exposure were proportional to dose indicating linear pharmacokinetics. However, secondary peaks in the PK profiles and a rapid decline in drug level from 23 to 24 h occurred in some patients. Drug infusion in the afternoon followed by dense sampling of levels during the elimination phase supported the hypothesis that the drug was being sequestered. No anti-tumor activity was identified.

Conclusions: Traditional PK sampling designs were inadequate to describe XK469 disposition. XK469 and related structures work through a unique mechanism of action. A further understanding of the specific mechanism of these compounds might uncover a unique avenue for future drug development.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Combined Modality Therapy
  • DNA Topoisomerases, Type II
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / adverse effects*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Injections, Intravenous
  • Male
  • Middle Aged
  • Neutropenia / chemically induced
  • Protein Binding
  • Quinoxalines / adverse effects*
  • Quinoxalines / pharmacokinetics
  • Quinoxalines / therapeutic use
  • Topoisomerase II Inhibitors*
  • Treatment Outcome


  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Quinoxalines
  • Topoisomerase II Inhibitors
  • XK 469
  • DNA Topoisomerases, Type II