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

Investigational New Drugs

Volumn 33, Issue 5, 2015, Pages 1100-1107

  Jones, Suzanne F ^a   Siu, Lillian L ^b   Bendell, Johanna C ^a   Cleary, James M ^c   Razak, Albiruni R A ^b   Infante, Jeffrey R ^a   Pandya, Shuchi S ^d   Bedard, Philippe L ^b   Pierce, Kristen J ^e   Houk, Brett ^e   Roberts, W Gregory ^e   Shreeve, S Martin ^e   Shapiro, Geoffrey I ^f  

^a SARAH CANNON RESEARCH INSTITUTE   (United States)

^b PRINCESS MARGARET HOSPITAL   (Canada)

^c BRIGHAM AND WOMEN S HOSPITAL   (United States)

^d BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

^e PFIZER INC   (United States)

^f DANA FARBER CANCER INSTITUTE   (United States)

Author keywords

Defactinib; Dose escalation study; Focal adhesion kinase; Proline rich tyrosine kinase 2; VS 6063

Indexed keywords

DEFACTINIB; ANTINEOPLASTIC AGENT; ORGANIC COMPOUND; VS-6063;

ADULT; ADVANCED CANCER; AGED; ANTINEOPLASTIC ACTIVITY; ANUS TUMOR; AREA UNDER THE CURVE; ARTICLE; BILE DUCT TUMOR; BREAST TUMOR; CANCER CHEMOTHERAPY; CLINICAL ARTICLE; COHORT ANALYSIS; COLORECTAL TUMOR; DECREASED APPETITE; DIARRHEA; DIET RESTRICTION; DRUG ABSORPTION; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; FATIGUE; FEMALE; FOOD; GASTROINTESTINAL STROMAL TUMOR; GILBERT DISEASE; HEADACHE; HUMAN; KIDNEY CARCINOMA; LARYNX TUMOR; LEIOMYOSARCOMA; LUNG TUMOR; MALE; MAXIMUM PLASMA CONCENTRATION; MULTIPLE CYCLE TREATMENT; NAUSEA; OVARY TUMOR; PANCREAS TUMOR; PHASE 1 CLINICAL TRIAL; POSTPRANDIAL STATE; PRIORITY JOURNAL; RECOMMENDED DRUG DOSE; SKIN TUMOR; SOLID TUMOR; STEADY STATE; SYNOVIAL SARCOMA; THYROID TUMOR; TIME TO MAXIMUM PLASMA CONCENTRATION; VOMITING; CLINICAL TRIAL; DOSE RESPONSE; DRUG ADMINISTRATION; FOOD DRUG INTERACTION; HALF LIFE TIME; MAXIMUM TOLERATED DOSE; MIDDLE AGED; NEOPLASMS;

ADULT; AGED; ANTINEOPLASTIC AGENTS; AREA UNDER CURVE; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG ADMINISTRATION SCHEDULE; FEMALE; FOOD-DRUG INTERACTIONS; HALF-LIFE; HUMANS; MALE; MAXIMUM TOLERATED DOSE; MIDDLE AGED; NEOPLASMS; ORGANIC CHEMICALS;

EID: 84942194205     PISSN: 01676997     EISSN: 15730646     Source Type: Journal    
DOI: 10.1007/s10637-015-0282-y     Document Type: Article

References (37)

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
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
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
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
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
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
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
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
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
10. Golubovskaya VM (2010) Focal adhesion kinase as a cancer therapy target. Anti Cancer Agents Med Chem 10:735-741
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
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
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
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
15. Provenzano PP, Keely PJ (2009) The role of focal adhesion kinase in tumor initiation and progression. Cell Adhes Migr 3:347-350
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
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
18. Lipinski CA, Loftus JC (2010) Targeting Pyk2 for therapeutic intervention. Expert Opin Ther Targets 14:95-108. doi: 10.1517/14728220903473194
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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