Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies.
OBJECTIVE
PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies.


METHODS
Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points.


RESULTS
A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P =.01 for oral dose; P =.0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P =.004%; and 51%, P =.006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status.


CONCLUSIONS
These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitors, such as PTK/ZK, for further clinical development.
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015415:Biomarkers; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D003287:Contrast Media; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000556:secondary; D008279:Magnetic Resonance Imaging / Q000379:methods / Q000592:standards*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009942:Organometallic Compounds; D010793:Phthalazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests; D011725:Pyridines; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D003287:Contrast Media; D009942:Organometallic Compounds; D010793:Phthalazines; D011725:Pyridines; C067541:dichlorobis(ethylenediamine)rhodium(III); C404768:vatalanib