Summary
Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral foretinib once daily. Dose escalation was planned as a conventional “3 + 3” design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P < 0.003) and soluble VEGFR2 plasma levels significantly decreased from baseline (P < 0.03). The MTD of foretinib bisphosphate salt was determined to be 80 mg once daily.
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Acknowledgments
We thank the patients, their families, and caregivers, and all of the personnel who contributed to the patient care and data collection for study MET111648. Funding for this study was provided by GlaxoSmithKline (NCT00743067) and Exelixis Inc. Editorial support in the form of assembling the first draft, collating author comments, copyediting, and fact checking was provided by Susannah Chang at WynneWords, LLC (Wynnewood, PA); final formatting, review, and submission assistance was provided by MediTech Media, UK and was funded by GlaxoSmithKline
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All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors.
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Geoffrey I. Shapiro and Patricia LoRusso received research funding from GlaxoSmithKline and Exelixis for the study. Stewart McCallum, Laurel M. Adams, Laurie Sherman, Steve Weller, and Suzanne Swann are all compensated employees of GlaxoSmithKline and own company stock. Dale Miles is a compensated employee of Exelixis and owns company stock. At the time of the study Harold Keer and Thomas Müller were compensated employees of Exelixis and still own company stock.
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An erratum to this article is available at http://dx.doi.org/10.1007/s10637-015-0287-6.
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Shapiro, G.I., McCallum, S., Adams, L.M. et al. A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors. Invest New Drugs 31, 742–750 (2013). https://doi.org/10.1007/s10637-012-9881-z
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DOI: https://doi.org/10.1007/s10637-012-9881-z