A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors

Investigational New Drugs
Suzanne F JonesGeoffrey I Shapiro

Abstract

VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies. Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state. Forty-six patients were treated across nine dose levels (12.5-750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the ti...Continue Reading

References

May 12, 2000·Nature Cell Biology·D J SiegD D Schlaepfer
Oct 19, 2001·Proceedings of the National Academy of Sciences of the United States of America·S D ZuckerK E Sherman
Feb 7, 2002·Biochemical and Biophysical Research Communications·Katalin JemnitzLászló Vereczkey
Apr 28, 2004·Current Opinion in Genetics & Development·David D Schlaepfer, Satyajit K Mitra
Jul 13, 2004·Biochimica Et Biophysica Acta·David D SchlaepferDusko Ilic
Oct 7, 2004·The American Journal of Pathology·Anil K SoodMary J C Hendrix
Jun 3, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Priscila M F Siesser, Steven K Hanks
Jun 1, 2007·Proceedings of the National Academy of Sciences of the United States of America·Leonard BuckbinderMei Li
Oct 12, 2007·Seminars in Cancer Biology·Robert W Tilghman, J Thomas Parsons
Feb 5, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·J Thomas ParsonsW Gregory Roberts
Mar 15, 2008·Cancer Research·Walter Gregory RobertsFelix Vajdos
Apr 9, 2008·The Journal of Cell Biology·Sara M WeisDavid A Cheresh
Oct 7, 2008·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Claudio ThurneysenEmanuela Felley-Bosco
Aug 20, 2009·Cell Adhesion & Migration·Paolo P Provenzano, Patricia J Keely
Dec 17, 2009·Expert Opinion on Therapeutic Targets·Joerg SchwockDavid W Hedley
Dec 17, 2009·Expert Opinion on Therapeutic Targets·Christopher A Lipinski, Joseph C Loftus
May 15, 2010·Expert Opinion on Investigational Drugs·Alexander Schultze, Walter Fiedler
Dec 2, 2010·Advanced Drug Delivery Reviews·Xiaofeng Zhao, Jun-Lin Guan
Jan 11, 2011·Anti-cancer Agents in Medicinal Chemistry·Vita M Golubovskaya
Apr 13, 2011·International Review of Cell and Molecular Biology·Jessica E HallMichael D Schaller
Mar 29, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jeffrey R InfanteLillian L Siu
Jan 30, 2013·Cancer Discovery·Georgia KonstantinidouPier Paolo Scaglioni
May 23, 2014·Science Translational Medicine·Irina M ShapiroJonathan A Pachter

❮ Previous
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Citations

Nov 22, 2014·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Alexandra S Zimmer, Patricia S Steeg
Jun 1, 2016·Frontiers in Oncology·Fabrizio MarcucciFrançois Lefoulon
Oct 14, 2016·Annals of Oncology : Official Journal of the European Society for Medical Oncology·J C SoriaM Millward
Oct 5, 2016·Expert Opinion on Drug Discovery·Roberta RosaRoberto Bianco
Dec 17, 2016·Cell Communication and Signaling : CCS·Nishant P VisavadiyaTheo Hagg
Jun 14, 2018·PloS One·UNKNOWN Synodos for NF2 ConsortiumWen-Ning Zhao
Feb 20, 2018·Molecular Cancer·Jennifer PasquierCyril Touboul
Jul 23, 2019·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Ken MasudaEriko Satomi
Feb 23, 2020·Chemical Biology & Drug Design·Erik StahlTimothy Marlowe
Mar 18, 2020·Expert Opinion on Investigational Drugs·Atish MohantyErminia Massarelli
Apr 18, 2020·Experimental & Molecular Medicine·So-Yeon Park, Jeong-Seok Nam
Dec 22, 2016·Biological Chemistry·Ellen Dickreuter, Nils Cordes
Feb 21, 2019·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Dean A FennellJoachim G J V Aerts
Mar 8, 2019·Targeted Oncology·Rachael Chang Lee, Hui K Gan
Nov 8, 2017·Expert Review of Anticancer Therapy·Agnieszka WozniakPatrick Schöffski
Feb 2, 2019·Nature Reviews. Clinical Oncology·Yosuke TogashiHiroyoshi Nishikawa
Jun 10, 2020·Experimental & Molecular Medicine·James M MurphySsang-Taek Steve Lim
Sep 22, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Carlos AlvaradoTimothy Marlowe
Aug 15, 2020·Frontiers in Cell and Developmental Biology·Yang ZhangXiuwei H Yang
Jul 5, 2019·International Journal of Molecular Sciences·Livia ManzellaPaolo Vigneri
Dec 4, 2020·International Journal of Molecular Sciences·Janine Wörthmüller, Curzio Rüegg
May 17, 2018·Cancer Research·James W PurcellDebra T Chao
Apr 5, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Burles A JohnsonElizabeth M Jaffee
Apr 4, 2018·Molecular Cancer Therapeutics·Kristin N Taylor, David D Schlaepfer
Jan 14, 2021·Current Treatment Options in Oncology·Eric P Borrelli, Conor G McGladrigan
Nov 19, 2019·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·David E GerberTimothy F Burns

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