Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Biomarker for the Pharmacological Response of PTK787/ZK 222584, an Inhibitor of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, in Patients With Advanced Colorectal Cancer and Liver Metastases: Results From Two Phase I Studies

  • Bruno Morgan
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Anne L. Thomas
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Joachim Drevs
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Juergen Hennig
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Martin Buchert
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Asvina Jivan
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Mark A. Horsfield
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Klauss Mross
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Howard A. Ball
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Lucy Lee
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • William Mietlowski
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Stefan Fuxius
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Clemens Unger
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Ken O’Byrne
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Andrew Henry
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Graham R. Cherryman
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Dirk Laurent
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Margaret Dugan
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • Dieter Marmé
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.
  • William P. Steward
    From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ.

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<jats:p> Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. </jats:p><jats:p> Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. </jats:p><jats:p> Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. </jats:p><jats:p> Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development. </jats:p>

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