Plasma biomarkers predictive for disease control duration in the phase I study of E7080, a multitarget kinase inhibitor

Abstract

e14524 Background: E7080 is an oral multi-targeted kinase inhibitor of VEGFRs, PDGFRs, FGFRs and c-kit. In the phase I study for advanced solid tumors, E7080 was repeated every 3 weeks (twice daily by 2 wks-on/ 1 wk-off). The toxicities were manageable and the preliminary antitumor activity including one partial response was observed at doses up to MTD [ASCO 2008; abstract 3527]. This study was conducted to evaluate whether the change of plasma biomarkers in the E7080 phase I study could predict the antitumor activity or the disease control duration. Methods: The treatment duration was determined as a period from the first dosing to treatment failure. Plasma angiogenic proteins and circulating endothelial cells (CEC)/ progenitor cells (CEP) were measured in blood samples collected on Days 1 (pre-dose), 8 and 15 of Cycles 1 and 2. CEC and CEP population with (+) or (-) c-kit expression were analyzed by FACS. Correlation was determined by Spearman's rank correlation coefficient (r) and test for non-correlation (p). Results: 19 (76%) out of 25 evaluable patients had PR/SD including 6 (24%) patients with the treatment duration of ≥180 days. VEGF increase and sVEGFR1 and -R2 decreases in plasma were seen with the increased dose of E7080. But these changes had no correlations with disease control. E7080 decreased c-kit(+) CEC and CEP, but not c-kit(-) population. Importantly, patients showing the decrease of c-kit(+) CEC in Cycle 1 had received E7080 treatment for significantly longer duration (r=-0.468, p=0.018). The decrease of c- kit(+) CEC diminished during treatment-off for final 7 days in Cycle 1 and repeatedly decreased in Cycle 2 treatment. The decrease of c- kit(+) ratio in CEP correlated with the increase of plasma SCF (r=-0.457, p=0.021) and SDF1 (r=-0.466, p=0.018), but not with VEGF or thrombopoietin. Conclusions: The change of c-kit(+) CEC correlated with the disease control duration in the phase I study of E7080. SCF and SDF1 may play a role in c-kit(+) CEP accumulation. C-kit(+)-selective changes of CEC could be a candidate biomarker to predict the disease control duration in anti-angiogenic therapy of E7080. [Table: see text]