A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and Vascular Endothelial Growth Factor Receptor 2

作者：Joseph P. Eder, Geoffrey Ira Shapiro, Leonard Joseph Appleman, Andrew Xiuxuan Zhu, Dale Miles, Harold N Keer, Belinda Cancilla, Felix Chu, Suzanne Hitchcock‐Bryan, Laurie Jill Sherman, Stewart W. McCallum, Elisabeth I. Heath, Scott Anthony Boerner, Patricia Mucci LoRusso · 发表于：Clinical Cancer Research · 年份：2010 · DOI：10.1158/1078-0432.ccr-10-0574 · 被引用次数：197 · 研究领域：Liver physiology and pathology、Phagocytosis and Immune Regulation、Fibroblast Growth Factor Research

PURPOSE: Foretinib is an oral multikinase inhibitor targeting Met, RON, Axl, and vascular endothelial growth factor receptor. We conducted a phase I, first-time-in-human, clinical trial using escalating doses of oral foretinib. The primary objectives are to identify a maximum tolerated dose and determine the safety profile of foretinib. Secondary objectives included evaluation of plasma pharmacokinetics, long-term safety after repeated administration, preliminary antitumor activity, and pharmacodynamic activity. EXPERIMENTAL DESIGN: Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard measures exist. All patients received foretinib orally for 5 consecutive days every 14 days. Dose escalation followed a conventional "3+3" design. RESULTS: Forty patients were treated in eight dose cohorts. The maximum tolerated dose was defined as 3.6 mg/kg, with a maximum administered dose of 4.5 mg/kg. Dose-limiting toxicities included grade 3 elevations in aspartate aminotransferase and lipase. Additional non-dose-limiting adverse events included hypertension, fatigue, diarrhea, vomiting, proteinuria, and hematuria. Responses were observed in two patients with papillary renal cell cancer and one patient with medullary thyroid cancer. Stable disease was identified in 22 patients. Foretinib pharmacokinetics increased linearly with dose. Pharmacodynamic evaluation indicated inhibition of MET phosphorylation and decreased proliferation in select tum...