Safety and pharmacokinetics of motesanib in combination with panitumumab and gemcitabine-cisplatin in patients with advanced cancer

Purpose. the aim of this study was to assess the safety and tolerability of motesanib (an orally administered small-molecule antagonist of vascular endothelial growth factor receptors 1,2,and 3,platelet-derived growth factor receptor,and kit) when administered in combination with panitumumab,gemcitabine,and cisplatin. methods. this was an open-label,multicenter phase 1b study in patients with advanced solid tumors with an ecog performance status ≤1 and for whom a gemcitabine/cisplatin regimen was indicated. patients received motesanib (0mg [control],50mg once daily [qd],75mg qd,100mg qd,125mg qd,or 75mg twice daily [bid]) with panitumumab (9mg/kg),gemcitabine (1250mg/m2) and cisplatin (75mg/m2) in 21-day cycles. the primary endpoint was the incidence of dose-limiting toxicities (dlts). results. forty-one patients were enrolled and received treatment (including 8 control patients). one of eight patients in the 50mg qd cohort and 5/11 patients in the 125mg qd cohort experienced dlts. the maximum tolerated dose was established as 100mg qd. among patients who received motesanib (n = 33),29 had motesanib-related adverse events. fourteen patients had serious motesanib-related events. ten patients had motesanib-related venous thromboembolic events and three had motesanib-related arterial thromboembolic events,two of which were considered serious. one patient had a complete response and nine had partial responses as their best objective response. conclusions. the combination of motesanib,panitumumab,and gemcitabine/cisplatin could not be administered consistently and,at the described doses and schedule,may be intolerable. however,encouraging antitumor activity was noted in some cases. copyright © 2011 howard burris et al.