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 (0?mg [control], 50?mg once daily [QD], 75?mg QD, 100?mg QD, 125?mg QD, or 75?mg twice daily [BID]) with panitumumab (9?mg/kg), gemcitabine (1250?mg/m2) and cisplatin (75?mg/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 50?mg QD cohort and 5/11 patients in the 125?mg QD cohort experienced DLTs. The maximum tolerated dose was established as 100?mg QD. Among patients who received motesanib ( ?? = 3 3 ), 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.
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