Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours.
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.
Mross
Klaus
K
Tumour Biology Center at the Albert-Ludwigs-University Freiburg, Breisacher Strasse 117, D-79106 Freiburg i. Br., Germany. mross@tumorbio.uni-freiburg.de
Drevs
Joachim
J
Müller
Marianne
M
Medinger
Michael
M
Marmé
Dieter
D
Hennig
Jürgen
J
Morgan
Bruno
B
Lebwohl
David
D
Masson
Eric
E
Ho
Yu-Yun
YY
Günther
Clemens
C
Laurent
Dirk
D
Unger
Clemens
C
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
D014408:Biomarkers, Tumor; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor