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Clin Cancer Res. 2014 Dec 15;20(24):6284-94. doi: 10.1158/1078-0432.CCR-14-0409. Epub 2014 Oct 2.

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

Author information

1
Drug Development Unit, The Royal Marsden/Institute of Cancer Research, Downs Road, Sutton, Surrey, United Kingdom. rhoda.molife@icr.ac.uk.
2
Clinical Trials Unit, University of Manchester, The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom.
3
Drug Development Unit, The Royal Marsden/Institute of Cancer Research, Downs Road, Sutton, Surrey, United Kingdom.
4
Clinical Pharmacology, Eisai Inc., Woodcliff Lake, New Jersey.
5
Biomarkers and Personalized Medicine, Eisai Inc., Andover, Massachusetts.
6
Oncology PCU, Eisai Ltd, Hatfield, United Kingdom.

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 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.

CONCLUSIONS:

Golvatinib at the MTD of 400 mg once daily was well tolerated with pharmacodynamic evidence of c-Met target modulation.

PMID:
25278451
DOI:
10.1158/1078-0432.CCR-14-0409
[Indexed for MEDLINE]
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