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

Abstract

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, longterm 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 tumor biopsies at submaximal doses.Conclusions: The recommended dose of foretinib was determined to be 240 mg, given on the first 5 days of a 14-day cycle. This dose and schedule were identified as having acceptable safety and pharmacokinetics, and will be the dose used in subsequent phase II trials.

MET As a Possible Target for Non–Small-Cell Lung Cancer

“…Three phase I studies have been completed studying the maximumtolerated dose and bioavailability. 76 Two phase II studies have been completed in patients with head and neck cancer and gastric cancer. There is currently a randomized phase I/II trial looking at adverse effects of erlotinib with or without the MET/VEGFR2 inhibitor foretinib.…”

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

“…Interestingly, a number of phase I trials of HGF/cMET targeting agents have included patients with ovarian cancer, [82,97,88,54,98,61] …”

Mechanism of action of the multikinase inhibitor Foretinib

“…It also exerts additional inhibitory activity toward KIT, Flt-3 and the PDGFR. [12][13][14][15] Foretinib inhibits HGF-induced MET phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and prevents both HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells. 16 There are also compelling in vivo evidence that Foretinib may prevent tumor growth through a direct effect on tumor cell proliferation and inhibition of invasion and angiogenesis mediated by HGF and VEGF receptors.…”

“…Recently, Foretinib has been reported to inhibit Axl, a RTK initially identified in CML cells. [12][13][14]16 We recently generated Imatinib-resistant CML cell lines that display increased expression of AXL at the mRNA and protein levels. 8 To investigate the potential role of Axl in the resistance of IM-R cells to Imatinib we used Foretinib in an attempt to inhibit Axlmediated signaling.…”