title: Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK): translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases.
abstract: PTK/ZK is a novel, oral angiogenesis inhibitor that specifically targets all 3 vascular endothelial growth factor (VEGF) receptor tyrosine kinases and is currently in phase III clinical trials. In early clinical trials, PTK/ZK demonstrated a dose-dependent reduction in tumor vascular parameters as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and an acute increase in plasma VEGF levels. The reduction in tumor vascularity was significantly correlated with improved clinical outcome in patients with advanced colorectal cancer and liver metastases. To assess the predictive value of a mouse model of tumor metastases, comparisons were performed for the biological activity of PTK/ZK in the mouse model and in patients with liver metastases in the clinical phase I trials. An orthotopic, syngeneic mouse model was used: C57BL/6 mice injected in the ear with murine B16/BL6 melanoma cells which metastases to the cervical lymph-nodes. The primary tumor and spontaneous metastases express VEGF and VEGF receptors and respond to treatment with VEGFR tyrosine kinase inhibitors. PTK/ZK was administered orally, with assessments by DCE-MRI of the metastases and plasma VEGF taken predose and at 3 days posttreatment and efficacy determined at 7 days posttreatment. Dose-ranging studies in naive mice provided preclinical pharmacokinetic data, while two dose-escalation phase I studies provided clinical pharmacokinetic data. An exposure-response relationship was observed both for mouse metastases (measured as % tumor weight treated/control) and for human liver metastases (measured as % regression). In the B16/BL6 model, the active dose of 50 mg/kg PTK/ZK yielded 62.4 (+/- 16.0) h microM plasma exposure, which is comparable to the plasma area under the concentration time curve (AUC) achieved by the 1000 mg dose of PTK/ZK used in clinical trials. At this exposure level in clinical trials, DCE-MRI showed a reduction in the area under the enhancement curve (IAUC) to 47% of baseline. At a similar exposure in the PTK/ZK-treated mice, a reduction in IAUC to 75% of baseline was observed. Furthermore, at doses of 50 mg/kg PTK/ZK and above, an increase in plasma VEGF level 10 h after drug administration was observed in mice which was consistent with findings from the clinical trials. In conclusion, the preclinical pharmacodynamics of PTK/ZK correlate well with clinical activity in phase I trials over comparable exposures to the drug. Thus, data from this preclinical model proved to be consistent with and thus predictive of the biologic effects of PTK/ZK in phase I/II clinical trials.
authors.affiliation: Translational and Clinical Development, Oncology Business Unit, Novartis Pharmaceutical, One Health Plaza Bldg 105, East Hanover, NJ 07936, USA. lucy.lee@novartis.com
authors.forename: Lucy
authors.initials: L
authors.lastname: Lee
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.forename: Bruno
authors.initials: B
authors.lastname: Morgan
authors.forename: Peter
authors.initials: P
authors.lastname: Allegrini
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.forename: Josef
authors.initials: J
authors.lastname: Brueggen
authors.forename: Robert
authors.initials: R
authors.lastname: Cozens
authors.forename: Mark
authors.initials: M
authors.lastname: Horsfield
authors.forename: Clemens
authors.initials: C
authors.lastname: Guenther
authors.forename: Will P
authors.initials: WP
authors.lastname: Steward
authors.forename: Joachim
authors.initials: J
authors.lastname: Drevs
authors.forename: David
authors.initials: D
authors.lastname: Lebwohl
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wood
authors.forename: Paul M J
authors.initials: PM
authors.lastname: McSheehy
mesh_terms: D020533:Angiogenesis Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D015415:Biomarkers; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008279:Magnetic Resonance Imaging; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010793:Phthalazines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000097:blood*
chemical_list: D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C404768:vatalanib; D011505:Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor