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

  • PHASE I STUDIES
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Summary

Objective 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. Methods 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. Results 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 time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d. Conclusions VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.

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Notes

  1. Preclinical and early clinical development of PF-04554878 was conducted by Pfizer Oncology; the drug was out-licensed to Verastem Inc. in 2012 and renamed VS-6063 or defactinib.

References

  1. Schwock J, Dhani N, Hedley DW (2010) Targeting focal adhesion kinase signaling in tumor growth and metastasis. Expert Opin Ther Targets 14:77–94. doi:10.1517/14728220903460340

    Article  CAS  PubMed  Google Scholar 

  2. Schultze A, Fiedler W (2010) Therapeutic potential and limitations of new FAK inhibitors in the treatment of cancer. Expert Opin Investig Drugs 19:777–788. doi:10.1517/13543784.2010.489548

    Article  CAS  PubMed  Google Scholar 

  3. Schlaepfer DD, Mitra SK, Ilic D (2004) Control of motile and invasive cell phenotypes by focal adhesion kinase. Biochim Biophys Acta 1692:77–102. doi:10.1016/j.bbamcr.2004.04.008

    Article  CAS  PubMed  Google Scholar 

  4. Hao H, Naomoto Y, Bao X et al (2009) Focal adhesion kinase as potential target for cancer therapy (Review). Oncol Rep 22:973–979

    Article  CAS  PubMed  Google Scholar 

  5. Tilghman RW, Parsons JT (2008) Focal adhesion kinase as a regulator of cell tension in the progression of cancer. Semin Cancer Biol 18:45–52. doi:10.1016/j.semcancer.2007.08.002

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH, Schlaepfer DD (2000) FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol 2:249–256. doi:10.1038/35010517

    Article  CAS  PubMed  Google Scholar 

  7. Zhao X, Guan JL (2011) Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. Adv Drug Deliv Rev 63:610–615. doi:10.1016/j.addr.2010.11.001

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Schlaepfer DD, Mitra SK (2004) Multiple connections link FAK to cell motility and invasion. Curr Opin Genet Dev 14:92–101. doi:10.1016/j.gde.2003.12.002

    Article  CAS  PubMed  Google Scholar 

  9. Siesser PM, Hanks SK (2006) The signaling and biological implications of FAK overexpression in cancer. Clin Cancer Res 12:3233–3237. doi:10.1158/1078-0432.CCR-06-0456

    Article  CAS  PubMed  Google Scholar 

  10. Golubovskaya VM (2010) Focal adhesion kinase as a cancer therapy target. Anti Cancer Agents Med Chem 10:735–741

    Article  CAS  Google Scholar 

  11. Smith CS, Golubovskaya VM, Peck E, Xu LH, Monia BP, Yang X, Cance WG (2005) Effect of focal adhesion kinase (FAK) downregulation with FAK antisense oligonucleotides and 5-fluorouracil on the viability of melanoma cell lines. Melanoma Res 15:357–362

    Article  CAS  PubMed  Google Scholar 

  12. Wu ZM, Yuan XH, Jiang PC, Li ZQ, Wu T (2006) Antisense oligonucleodes targeting the focal adhesion kinase inhibit proliferation, induce apoptosis and cooperate with cytotoxic drugs in human glioma cells. J Neurooncol 77:117–123. doi:10.1007/s11060-005-9025-9

    Article  CAS  PubMed  Google Scholar 

  13. Shen TL, Park AY, Alcaraz A, Peng X, Jang I, Koni P, Flavell RA, Gu H, Guan JL (2005) Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis. J Cell Biol 169:941–952. doi:10.1083/jcb.200411155

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Golubovskaya VM, Huang G, Ho B, Yemma M, Morrison CD, Lee J, Eliceiri BP, Cance WG (2013) Pharmacologic blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide. Mol Cancer Ther 12:162–172. doi:10.1158/1535-7163.MCT-12-0701

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Provenzano PP, Keely PJ (2009) The role of focal adhesion kinase in tumor initiation and progression. Cell Adhes Migr 3:347–350

    Article  Google Scholar 

  16. Parsons JT, Slack-Davis J, Tilghman R, Roberts WG (2008) Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention. Clin Cancer Res 14:627–632. doi:10.1158/1078-0432.CCR-07-2220

    Article  CAS  PubMed  Google Scholar 

  17. Roberts WG, Ung E, Whalen P et al (2008) Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res 68:1935–1944. doi:10.1158/0008-5472.CAN-07-5155

    Article  CAS  PubMed  Google Scholar 

  18. Lipinski CA, Loftus JC (2010) Targeting Pyk2 for therapeutic intervention. Expert Opin Ther Targets 14:95–108. doi:10.1517/14728220903473194

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Hall JE, Fu W, Schaller MD (2011) Focal adhesion kinase: exploring Fak structure to gain insight into function. Int Rev Cell Mol Biol 288:185–225. doi:10.1016/B978-0-12-386041-5.00005-4

    Article  CAS  PubMed  Google Scholar 

  20. Buckbinder L, Crawford DT, Qi H et al (2007) Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis. Proc Natl Acad Sci U S A 104:10619–10624. doi:10.1073/pnas.0701421104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Schaller MD (2010) Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. J Cell Sci 123:1007–1013. doi:10.1242/jcs.045112

    Article  CAS  PubMed  Google Scholar 

  22. Weis SM, Lim ST, Lutu-Fuga KM et al (2008) Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK. J Cell Biol 181:43–50. doi:10.1083/jcb.200710038

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Fan H, Guan JL (2011) Compensatory function of Pyk2 protein in the promotion of focal adhesion kinase (FAK)-null mammary cancer stem cell tumorigenicity and metastatic activity. J Biol Chem 286:18573–18582. doi:10.1074/jbc.M110.200717

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Infante JR, Camidge DR, Mileshkin LR et al (2012) Safety, pharmacokinetic, and pharmacodynamic phase I dose-escalation trial of PF-00562271, an inhibitor of focal adhesion kinase, in advanced solid tumors. J Clin Oncol 30:1527–1533. doi:10.1200/JCO.2011.38.9346

    Article  CAS  PubMed  Google Scholar 

  25. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  CAS  PubMed  Google Scholar 

  26. Jemnitz K, Lengyel G, Vereczkey L (2002) In vitro induction of bilirubin conjugation in primary rat hepatocyte culture. Biochem Biophys Res Commun 291:29–33. doi:10.1006/bbrc.2002.6400

    Article  CAS  PubMed  Google Scholar 

  27. Zucker SD, Qin X, Rouster SD, Yu F, Green RM, Keshavan P, Feinberg J, Sherman KE (2001) Mechanism of indinavir-induced hyperbilirubinemia. Proc Natl Acad Sci U S A 98:12671–12676. doi:10.1073/pnas.231140698

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG (2005) In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos 33:1729–1739. doi:10.1124/dmd.105.005447

    Article  CAS  PubMed  Google Scholar 

  29. Soria JC, Gan HK, Arkenau HT (2012) Phase I clinical and pharmacologic study of the focal adhesion kinase (FAK) inhibitor GSK2256098 in pts with advanced solid tumors. J Clin Oncol 30(Suppl):Abst. 3000

  30. Konstantinidou G, Ramadori G, Torti F et al (2013) RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. Cancer Discov 3:444–457. doi:10.1158/2159-8290.CD-12-0388

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Poulikakos PI, Xiao GH, Gallagher R, Jablonski S, Jhanwar SC, Testa JR (2006) Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Oncogene 25:5960–5968. doi:10.1038/sj.onc.1209587

    Article  CAS  PubMed  Google Scholar 

  32. Thurneysen C, Opitz I, Kurtz S, Weder W, Stahel RA, Felley-Bosco E (2009) Functional inactivation of NF2/merlin in human mesothelioma. Lung Cancer 64:140–147. doi:10.1016/j.lungcan.2008.08.014

    Article  PubMed  Google Scholar 

  33. Shapiro IM, Kolev VN, Vidal CM et al (2014) Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci Transl Med 6:237–268. doi:10.1126/scitranslmed.3008639

    Google Scholar 

  34. Soria JC, Plummer R, Ranson M, Gan H, Arkenau HT, Zalcman G, Blagden S (2012) Loss of the tumor suppressor Merlin as a potential predictive biomarker of clinical activity for the oral, focal adhesion kinase (FAK) inhibitor GSK2256098 in pts with recurrent mesothelioma. Eur J Cancer 48(Suppl 6):188, Abst. 610

    Article  Google Scholar 

  35. Xu Q, Kolev VN, Vidal CM, Shapiro IM, Ring JE, Padval MV, Keegan M, Pachter JA (2012) FAK inhibitor VS-4718 attenuates breast cancer stem cell function and inhibitors tumor growth in vivo. Eur J Cancer 48(Suppl 6):122, Abst. 400

    Article  Google Scholar 

  36. Sood AK, Coffin JE, Schneider GB, Fletcher MS, DeYoung BR, Gruman LM, Gershenson DM, Schaller MD, Hendrix MJ (2004) Biological significance of focal adhesion kinase in ovarian cancer: role in migration and invasion. Am J Pathol 165:1087–1095. doi:10.1016/S0002-9440(10)63370-6

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Patel MR, Infante JR, Moore KN, Keegan M, Poli A, Padval M, Jones SF, Horobin J, Burris HA (2014) Phase 1/1b study of the FAK inhibitor defactinib (VS-6063) in combination with weekly paclitaxel for advanced ovarian cancer. J Clin Oncol 32(15 Supplement), Abstract 5521

    Google Scholar 

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Acknowledgments

This study was sponsored by Pfizer Inc. Medical writing support was provided by Andrew Fitton, PhD, of Engage Scientific Solutions, and was funded by Pfizer Inc.

Source of funding

Drs. K. Pierce, B. Houk, and W.G. Roberts are full-time employees of Pfizer Inc. At the time the study was conducted, Dr. S.M. Shreeve was an employee of Pfizer Inc.; currently he is an employee of Janssen Pharmaceutical Companies of Johnson and Johnson. At the time the study was conducted, Dr. S. Pandya was an employee of Beth Israel Deaconess Medical Center; currently she is an employee of Acceleron Pharma. Dr. L. Siu receives research funding for clinical trial support from Pfizer Inc.

Conflict of interest

Dr. G. Shapiro, Dr P. Bedard, Dr J. Infante, Dr A Razak, Dr S. Jones, and Dr J. Cleary have no financial conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Sarah Cannon Research Institute, 250 25th Avenue North, Suite 200, Nashville, TN, 37203, USA

    Suzanne F. Jones, Johanna C. Bendell & Jeffrey R. Infante

  2. Princess Margaret Cancer Centre, Toronto, ON, Canada

    Lillian L. Siu, Albiruni R. A. Razak & Philippe L. Bedard

  3. Brigham and Women’s Hospital, Boston, MA, USA

    James M. Cleary

  4. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Shuchi S. Pandya

  5. Pfizer Oncology, Groton, CT, USA

    Kristen J. Pierce & W. Gregory Roberts

  6. Pfizer Oncology, La Jolla, CA, USA

    Brett Houk & S. Martin Shreeve

  7. Dana-Farber Cancer Institute, Boston, MA, USA

    Geoffrey I. Shapiro

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  1. Suzanne F. Jones
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Corresponding author

Correspondence to Suzanne F. Jones.

Additional information

Previously presented at the 2011 ASCO Annual Meeting. Jones SF, et al. J Clin Oncol 2011; 29 (15 Suppl): Abst. 3002

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Jones, S.F., Siu, L.L., Bendell, J.C. et al. A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors. Invest New Drugs 33, 1100–1107 (2015). https://doi.org/10.1007/s10637-015-0282-y

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