title: A phase I, dose-escalation study of the multitargeted receptor tyrosine kinase inhibitor, golvatinib, in patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Drug Development Unit, The Royal Marsden/Institute of Cancer Research, Downs Road, Sutton, Surrey, United Kingdom. rhoda.molife@icr.ac.uk.
authors.forename: L Rhoda
authors.initials: LR
authors.lastname: Molife
authors.affiliation: Clinical Trials Unit, University of Manchester, The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Emma Jane
authors.initials: EJ
authors.lastname: Dean
authors.affiliation: Drug Development Unit, The Royal Marsden/Institute of Cancer Research, Downs Road, Sutton, Surrey, United Kingdom.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Blanco-Codesido
authors.affiliation: Clinical Trials Unit, University of Manchester, The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Krebs
authors.affiliation: Drug Development Unit, The Royal Marsden/Institute of Cancer Research, Downs Road, Sutton, Surrey, United Kingdom.
authors.forename: Andre T
authors.initials: AT
authors.lastname: Brunetto
authors.affiliation: Clinical Trials Unit, University of Manchester, The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Alastair Peter
authors.initials: AP
authors.lastname: Greystoke
authors.affiliation: Drug Development Unit, The Royal Marsden/Institute of Cancer Research, Downs Road, Sutton, Surrey, United Kingdom.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Daniele
authors.affiliation: Clinical Pharmacology, Eisai Inc., Woodcliff Lake, New Jersey.
authors.forename: Lucy
authors.initials: L
authors.lastname: Lee
authors.affiliation: Biomarkers and Personalized Medicine, Eisai Inc., Andover, Massachusetts.
authors.forename: Galina
authors.initials: G
authors.lastname: Kuznetsov
authors.affiliation: Biomarkers and Personalized Medicine, Eisai Inc., Andover, Massachusetts.
authors.forename: Khin Than
authors.initials: KT
authors.lastname: Myint
authors.affiliation: Oncology PCU, Eisai Ltd, Hatfield, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Wood
authors.affiliation: Oncology PCU, Eisai Ltd, Hatfield, United Kingdom.
authors.forename: Begoña
authors.initials: B
authors.lastname: de Las Heras
authors.affiliation: Clinical Trials Unit, University of Manchester, The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Malcolm Richard
authors.initials: MR
authors.lastname: Ranson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000631:Aminopyridines; D015415:Biomarkers; C548173:N-(2-fluoro-4-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)carbonylaminopyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide; D010879:Piperazines; D047428:Protein Kinase Inhibitors