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    A phase I, dose-escalation study of the multi-targeted receptor tyrosine kinase inhibitor, Golvatinib, in patients with advanced solid tumors.

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    Authors
    Molife, L
    Dean, Emma J
    Blanco Codesido, M
    Krebs, Matthew G
    Brunetto, A
    Greystoke, Alastair
    Daniele, G
    Lee, L
    Kuznetsov, G
    Myint, K
    de Las Heras, B
    Wood, K
    Ranson, Malcolm R
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    Affiliation
    Drug Development Unit, Royal Marsden Hospital
    Issue Date
    2014-10-02
    
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    Abstract
    Purpose: 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.
    Citation
    A phase I, dose-escalation study of the multi-targeted receptor tyrosine kinase inhibitor, Golvatinib, in patients with advanced solid tumors. 2014: Clin Cancer Res
    Journal
    Clinical Cancer Research
    URI
    http://hdl.handle.net/10541/333869
    DOI
    10.1158/1078-0432.CCR-14-0409
    PubMed ID
    25278451
    Type
    Article
    Language
    en
    ISSN
    1078-0432
    ae974a485f413a2113503eed53cd6c53
    10.1158/1078-0432.CCR-14-0409
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