title: Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours.
abstract: 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.
authors.affiliation: Tumour Biology Center at the Albert-Ludwigs-University Freiburg, Breisacher Strasse 117, D-79106 Freiburg i. Br., Germany. mross@tumorbio.uni-freiburg.de
authors.forename: Klaus
authors.initials: K
authors.lastname: Mross
authors.forename: Joachim
authors.initials: J
authors.lastname: Drevs
authors.forename: Marianne
authors.initials: M
authors.lastname: Müller
authors.forename: Michael
authors.initials: M
authors.lastname: Medinger
authors.forename: Dieter
authors.initials: D
authors.lastname: Marmé
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hennig
authors.forename: Bruno
authors.initials: B
authors.lastname: Morgan
authors.forename: David
authors.initials: D
authors.lastname: Lebwohl
authors.forename: Eric
authors.initials: E
authors.lastname: Masson
authors.forename: Yu-Yun
authors.initials: YY
authors.lastname: Ho
authors.forename: Clemens
authors.initials: C
authors.lastname: Günther
authors.forename: Dirk
authors.initials: D
authors.lastname: Laurent
authors.forename: Clemens
authors.initials: C
authors.lastname: Unger
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary*; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000097:blood / Q000517:prevention & control; D010793:Phthalazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D018615:Ultrasonography, Doppler, Color
chemical_list: D014408:Biomarkers, Tumor; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor