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

Abstract

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.

DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents

“…Patients with colorectal carcinoma liver metastases (mixture of disease stage and extent of prior therapy) showed a dose-dependent reduction in K i of 43% at day 2, which was greatest in higher-dose groups (X1000 mg once daily), where K i was reduced by 58% on day 2 and 53% at the end of cycle 1 (EC1). Reduction in tumour enhancement at day 2 and EC1 (measured by reduction in K i from baseline) predicted disease progression and was positively correlated with reduction in tumour size (Morgan et al, 2003). Statistically significant dosedependent changes in K i from baseline at day 2 and day 28 were identified in two subsequent studies of PTK/ZK in patients with mixed solid tumours (X1000 mg once daily) (Mross et al, 2005a;Thomas et al, 2005).…”

“…A single averageenhancement curve can be extracted and used to generate values of parameters of interest (such as IAUC or K trans ), and the same parameters can then be compared following therapy (Dowlati et al, 2002;Morgan et al, 2003;Liu et al, 2005;Mross et al, 2005a;Thomas et al, 2005). This method ignores heterogeneity within the tumour.…”

“…Most were small cohort single-centre phase I trials in patients with advanced solid tumours, although a small number of phase II trials have incorporated DCE-MRI (Wedam et al, 2006). Marked variation in tumour size (Evelhoch et al, 2004), anatomy and pathophysiology and previous treatment (Morgan et al, 2003) have made data evaluation difficult and may have masked subtle drug effects, prompting a move towards stricter inclusion criteria (Morgan et al, 2003;Mross et al, 2005a;O'Dwyer et al, 2005) or using an intra-patient dose escalation design (Jayson et al, 2002;Stevenson et al, 2003).…”

Bevacizumab in the treatment of non-small-cell lung cancer

“…Another non-invasive method of assessing changes in tumor blood flow is dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). A significant correlation between changes in tumor vasculature and clinical outcome using this technology was detected on a phase I clinical trial of PTK787 (Morgan et al, 2003). At this point, the preliminary data provide valuable information about the potential applications of these new technologies.…”

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

“…40 The MTD of PTK/ZK is 1,500 mg/day and, therefore, the biologically effective dose seems to be significantly lower than the MTD; DCE-MRI was instrumental in determining the appropriate dose (Figure 4). 41 Molecular imaging can be particularly helpful in dose-finding studies of anti-angiogenic agents because the genetic variability of the endothelial cells forming the blood supply to the tumor is likely to be smaller than that of the tumor cells. As a consequence, a relatively low interpatient variability of the drug concentration needed for endothelial cell target inhibition would be expected.…”