Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	20	24	2014 Dec 15	6284-94	Clin Cancer Res

URL

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
Golvatinib	Golvatinib	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Golvatinib		E7050\|E-7050	EPHB4 Inhibitor 6 MET Inhibitor 59 VEGFR2 Inhibitor 37	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