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Ref Type Journal Article
PMID (25278451)
Authors Molife LR, Dean EJ, Blanco-Codesido M, Krebs MG, Brunetto AT, Greystoke AP, Daniele G, Lee L, Kuznetsov G, Myint KT, Wood K, de Las Heras B, Ranson MR
Title A phase I, dose-escalation study of the multitargeted receptor tyrosine kinase inhibitor, golvatinib, in patients with advanced solid tumors.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 20
Issue 24
Date 2014 Dec 15
Abstract Text Receptor tyrosine kinases c-Met and Ron transduce signals regulating cell migration and matrix invasion. This phase I dose-escalation trial tested golvatinib, a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family plus c-Kit and Ron.Patients with advanced solid tumors received golvatinib orally, once daily, continuously. Using a "3+3" design, dosing started at 100 mg once daily, escalating to the maximum tolerated dose (MTD) defined by dose-limiting toxicities. Pharmacokinetic, pharmacodynamic, and preliminary antitumor activity was assessed during dose escalation and in a MTD expansion cohort.Thirty-four patients were treated at six dose levels. The MTD was determined as 400 mg once daily. Three dose-limiting toxicities were observed: grade 3 increased γ-glutamyltransferase and alkaline phosphatase (200 mg), repeated grade 2 fatigue, and grade 3 fatigue (50.0%). Frequent treatment-related adverse events (with incidence >10%) included diarrhea (58.8%), nausea (50%), vomiting (44.1%), fatigue (41.2%), decreased appetite (32.4%), elevated alanine aminotransferase (32.4%), elevated aspartate aminotransferase (20.6%), dry skin (11.8%), and dysgeusia (11.8%). Best overall response was stable disease (median duration 85 days, range 85-237). Pharmacokinetics demonstrated high variability, although maximum plasma concentration and area under the plasma concentration-time curve increased with dose. Soluble urokinase-type plasminogen activator receptor, VEGFR2, c-Met, and angiopoietin-2 levels increased after dose. Posttreatment decrease in either p-c-Met or p-ERK was observed in 3 of 4 paired biopsies at MTD.Golvatinib at the MTD of 400 mg once daily was well tolerated with pharmacodynamic evidence of c-Met target modulation.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Golvatinib E7050|E-7050 EPHB4 Inhibitor 6 MET Inhibitor 51 VEGFR2 Inhibitor 35 Golvatinib (E7050) is a dual kinase inhibitor of c-Met (MET) and KDR (VEGFR2), which inhibits cell growth and proliferation (PMID: 25458359, PMID: 25278451).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable Golvatinib Phase I Actionable In a Phase I trial, Golvatinib (E7050) demonstrated safety and preliminary efficacy, with stable disease as best overall response in patients with advanced solid tumors (PMID: 25278451). 25278451