Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours

Eur J Cancer. 2005 Jun;41(9):1291-9. doi: 10.1016/j.ejca.2005.03.005.


The family of VEGF receptors are important mediators of angiogenesis, which is essential for tumour growth and metastasis. PTK/ZK is a multiple VEGF receptor inhibitor that blocks the activity of all known VEGF receptor tyrosine kinases. This phase I/II trial evaluated the safety, pharmacokinetics and efficacy of PTK/ZK in patients with liver metastases from solid tumours. Patients were administered oral PTK/ZK monotherapy once daily at doses of 300-1200 mg/day in 28-day cycles until unacceptable toxicity or tumour progression occurred. Twenty-seven patients were enrolled and treatment with PTK/ZK was generally well tolerated. The most frequently reported adverse events were fatigue, nausea, dizziness, and vomiting (mostly National Cancer Institute Common Toxicity Criteria grade 1 or 2). The area under the concentration-time curve (AUC) of PTK/ZK increased between 300 and 1000 mg/day with no further increase from 1000 to 1200 mg/day; the AUC decreased by 50% between day 1 and day 15. The DCE-MRI showed a statistically significant early reduction of tumour blood supply (measured as Ki) at day 2 at doses > or = 750 mg/day. Disease progression was significantly correlated with percent change from baseline Ki. Thirteen patients had stable disease for at least two cycles (56 days). Median overall survival was 11.8 months (95% CI = 6.6, 17.1 months). Long-term therapy with PTK/ZK demonstrated predictable pharmacokinetics, was safe and feasible in patients with metastatic disease, and showed promising clinical activity. The minimum biologically active dose was established at 750 mg/day whereas the recommended dose for phase III studies is 1200 mg/day.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Analysis of Variance
  • Area Under Curve
  • Biomarkers, Tumor / blood
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Humans
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / secondary*
  • Magnetic Resonance Imaging
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neovascularization, Pathologic / blood
  • Neovascularization, Pathologic / prevention & control
  • Phthalazines / administration & dosage
  • Phthalazines / adverse effects
  • Phthalazines / pharmacokinetics*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Pyridines / administration & dosage
  • Pyridines / adverse effects
  • Pyridines / pharmacokinetics*
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
  • Treatment Outcome
  • Ultrasonography, Doppler, Color


  • Biomarkers, Tumor
  • Phthalazines
  • Protein Kinase Inhibitors
  • Pyridines
  • vatalanib
  • Receptors, Vascular Endothelial Growth Factor