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.