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dc.contributor.authorMolife, L
dc.contributor.authorDean, Emma J
dc.contributor.authorBlanco Codesido, M
dc.contributor.authorKrebs, Matthew G
dc.contributor.authorBrunetto, A
dc.contributor.authorGreystoke, Alastair
dc.contributor.authorDaniele, G
dc.contributor.authorLee, L
dc.contributor.authorKuznetsov, G
dc.contributor.authorMyint, K
dc.contributor.authorde Las Heras, B
dc.contributor.authorWood, K
dc.contributor.authorRanson, Malcolm R
dc.date.accessioned2014-11-10T09:36:23Z
dc.date.available2014-11-10T09:36:23Z
dc.date.issued2014-10-02
dc.identifier.citationA phase I, dose-escalation study of the multi-targeted receptor tyrosine kinase inhibitor, Golvatinib, in patients with advanced solid tumors. 2014: Clin Cancer Resen
dc.identifier.issn1078-0432
dc.identifier.pmid25278451
dc.identifier.doi10.1158/1078-0432.CCR-14-0409
dc.identifier.urihttp://hdl.handle.net/10541/333869
dc.description.abstractPurpose: 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. Experimental Design: 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. Results: Thirty-four patients were treated at 6 dose levels. The MTD was determined as 400 mg once daily. Three dose-limiting toxicities were observed: grade 3 increased gamma glutamyltransferase and alkaline phosphatase (200 mg), repeated grade 2 fatigue, and grade 3 fatigue (450 mg). 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 post-dose. Post-treatment decrease in either p-c-Met or p-ERK was observed in 3 of 4 paired biopsies at MTD. Conclusions: Golvatinib at the MTD of 400 mg once daily was well tolerated with pharmacodynamic evidence of c-Met target modulation.
dc.languageENG
dc.language.isoenen
dc.rightsArchived with thanks to Clinical cancer research : an official journal of the American Association for Cancer Researchen
dc.titleA phase I, dose-escalation study of the multi-targeted receptor tyrosine kinase inhibitor, Golvatinib, in patients with advanced solid tumors.en
dc.typeArticleen
dc.contributor.departmentDrug Development Unit, Royal Marsden Hospitalen
dc.identifier.journalClinical Cancer Researchen
refterms.dateFOA2020-04-20T15:05:18Z
html.description.abstractPurpose: 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. Experimental Design: 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. Results: Thirty-four patients were treated at 6 dose levels. The MTD was determined as 400 mg once daily. Three dose-limiting toxicities were observed: grade 3 increased gamma glutamyltransferase and alkaline phosphatase (200 mg), repeated grade 2 fatigue, and grade 3 fatigue (450 mg). 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 post-dose. Post-treatment decrease in either p-c-Met or p-ERK was observed in 3 of 4 paired biopsies at MTD. Conclusions: Golvatinib at the MTD of 400 mg once daily was well tolerated with pharmacodynamic evidence of c-Met target modulation.


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