DCE-MRI assessment of the effect of vandetanib on tumor vasculature in patients with advanced colorectal cancer and liver metastases: a randomized phase I study.

Abstract

BackgroundVandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling pathways. In patients with advanced colorectal cancer and liver metastases, the effect of vandetanib on tumor vasculature was assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).MethodsEligible patients received vandetanib 100 or 300 mg/day. DCE-MRI (iAUC60 and Ktrans) was used to quantify the primary endpoints of tumor perfusion and vascular permeability. An exploratory assessment of tumor oxygenation was performed using MRI/T2*. All MRI parameters were measured at baseline (twice) and on days 2, 8, 29 and 57.ResultsTwenty-two patients received vandetanib (n = 10, 100 mg; n = 12, 300 mg). Baseline measurements of iAUC60 and Ktrans were reproducible, with low intrapatient coefficients of variation (11% and 24%, respectively). Estimates of mean % changes from baseline were -3.4% (100 mg) and -4.6% (300 mg) for iAUC60, and -4.6% (100 mg) and -2.7% (300 mg) for Ktrans; these changes were not significantly different between doses. The exploratory T2* measurement showed a significant increase at 300 mg versus 100 mg (P = 0.006). Both doses of vandetanib were generally well tolerated; common toxicities were fatigue, rash and diarrhea (majority CTC grade 1 or 2). The pharmacokinetic profile of vandetanib was similar to that observed previously. There were no RECIST-defined objective responses; five patients experienced stable disease ≥8 weeks.ConclusionIn this study in patients with advanced colorectal cancer, vandetanib did not modulate gadolinium uptake in tumor vasculature and tissue measured by the DCE-MRI parameters iAUC60 and Ktrans.Trial registrationNCT00496509 (ClinicalTrials.gov); D4200C00050 (AstraZeneca)