Summary
Background Tivantinib is a selective, small-molecule inhibitor of the MET receptor tyrosine kinase. Preclinical and phase 1 data suggested a possible role for MET in the pathophysiology of germ cell tumors (GCTs) and a potential clinical benefit from tivantinib in patients with these tumors. Methods Men (≥16 years) with relapsed or refractory, histologically confirmed, non-central nervous system GCTs received oral tivantinib 360 mg twice daily in 28-day cycles until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate in the first 4 cycles, with study termination for <2 responses among the first 21 patients. Secondary endpoints included 12-week progression-free survival (PFS), overall survival (OS), and safety. Results Twenty-seven patients were enrolled in 9 months (median age, 32 years). Most patients had tumors with nonseminoma histology (n = 25), and primary tumor sites were testis (n = 24) and mediastinum (n = 3). Among 25 evaluable patients, no objective responses were observed; accrual was halted when the 21st patient became evaluable. Best response was stable disease (n = 5). Median PFS was 1 month, the 12-week PFS rate was 21 %, and median OS was 6 months. Grade 3 or 4 adverse events considered related to study drug included grade 3 pneumonia and grade 3 syncope (n = 1, each). Conclusions Tivantinib was well tolerated but did not demonstrate single-agent activity in patients with relapsed/refractory GCTs. Rapid accrual to this phase 2 trial was achieved in this rare patient population through multicenter collaboration.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
National Comprehensive Cancer Network (2011) NCCN clinical practice guidelines in oncology, testicular cancer, version 2.2011. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed December 6, 2012
Lail-Trecker M, Gulati R, Peluso JJ (1998) A role for hepatocyte growth factor/scatter factor in regulating normal and neoplastic cells of reproductive tissues. J Soc Gynecol Investig 5:114–121. doi:10.1016/S1071-5576(98)00002-1
Beviglia L, Matsumoto K, Lin CS, Ziober BL, Kramer RH (1997) Expression of the c-Met/HGF receptor in human breast carcinoma: correlation with tumor progression. Int J Cancer 74:301–309. doi:10.1002/(SICI)1097-0215(19970620)74:3<301::AID-IJC12>3.0.CO;2-E
Qiao H, Hung W, Tremblay E et al (2002) Constitutive activation of met kinase in non-small-cell lung carcinomas correlates with anchorage-independent cell survival. J Cell Biochem 86:665–677. doi:10.1002/jcb.10239
Takayama H, LaRochelle WJ, Sharp R et al (1997) Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proc Natl Acad Sci U S A 94:701–706
Takeuchi H, Bilchik A, Saha S et al (2003) c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin Cancer Res 9:1480–1488
Cecchi F, Rabe DC, Bottaro DP (2010) Targeting the HGF/Met signalling pathway in cancer. Eur J Cancer 46:1260–1270. doi:10.1016/j.ejca.2010.02.028
Sattler M, Hasina R, Reddy MM, Gangadhar T, Salgia R (2011) The role of the c-Met pathway in lung cancer and the potential for targeted therapy. Ther Adv Med Oncol 3:171–184. doi:10.1177/1758834011408636
Daiichi Sankyo Inc (2009) Data on file
Munshi N, Jeay S, Li Y et al (2010) ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther 9:1544–1553
Adjei AA, Schwartz B, Garmey E (2011) Early clinical development of ARQ 197, a selective, non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers. Oncologist 16:788–799. doi:10.1634/theoncologist.2010-0380
Rosen LS, Senzer N, Mekhail T et al (2011) A phase I dose-escalation study of tivantinib (ARQ 197) in adult patients with metastatic solid tumors. Clin Cancer Res 17:7754–7764
Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247
Mekhail T, Rich T, Rosen L et al. (2009) Final results: a dose escalation phase I study of ARQ 197, a selective c-MET inhibitor, in patients with metastatic solid tumors. J Clin Oncol 27:Abstract 3548
Daiichi Sankyo Inc (2011) ARQ 197 for subjects with relapsed or refractory germ cell tumors. http://clinicaltrials.gov/ct2/show/NCT01055067. Accessed December 6, 2012
Yap TA, Olmos D, Brunetto AT et al (2011) Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies. J Clin Oncol 29:1271–1279. doi:10.1200/JCO.2010.31.0367
Feldman DR, Patil S, Trinos MJ et al (2012) Progression-free and overall survival in patients with relapsed/refractory germ cell tumors treated with single-agent chemotherapy: endpoints for clinical trial design. Cancer 118:981–986. doi:10.1002/cncr.26375
Detre S, Saclani Jotti G, Dowsett M (1995) A “quickscore” method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas. J Clin Pathol 48:876–878
Einhorn LH, Williams SD, Chamness A, Brames MJ, Perkins SM, Abonour R (2007) High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 357:340–348. doi:10.1056/NEJMoa067749
Kondagunta GV, Bacik J, Sheinfeld J et al (2007) Paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol 25:85–90. doi:10.1200/JCO.2006.06.9401
De Giorgi U, Rosti G, Aieta M et al (2006) Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refractory nonseminomatous germ cell tumor. Eur Urol 50:1032–1038. doi:10.1016/j.eururo.2006.05.011, discussion 1038–1039
Kollmannsberger C, Beyer J, Liersch R et al (2004) Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol 22:108–114. doi:10.1200/JCO.2004.06.068
Pectasides D, Pectasides M, Farmakis D et al (2004) Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study. Ann Oncol 15:493–497
Gherardi E, Birchmeier W, Birchmeier C, Woude GV (2012) Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12:89–103. doi:10.1038/nrc3205
Acknowledgments
Financial support for medical editorial assistance was provided by Daiichi Sankyo, Inc., a member of the Daiichi Sankyo Group, and ArQule, Inc. We thank Bret A. Wing, PhD, ProEd Communications, Inc., for his medical editorial assistance with this manuscript.
Conflicts of interest
DRF, LHE, YL, JKJ, DJV, AF, and JH have no disclosures of interest.
DIQ is an advisory board member for and has received honoraria from Pfizer, Bayer, Dendreon, Novartis, Aveo, Prometheus, Teva, and Medivation.
A-BH and HZ are employees of Daiichi Sankyo, Inc.
RJM has received research funding from ArQule, Inc.
Ethical standards
This study was approved by the institutional review boards of the participating institutions and was conducted according to institutional and federal guidelines. Written informed consent was obtained from all patients before study participation.
Funding sources
Financial support for medical editorial assistance was provided by Daiichi Sankyo, Inc., a member of the Daiichi Sankyo Group, and ArQule, Inc.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Feldman, D.R., Einhorn, L.H., Quinn, D.I. et al. A phase 2 multicenter study of tivantinib (ARQ 197) monotherapy in patients with relapsed or refractory germ cell tumors. Invest New Drugs 31, 1016–1022 (2013). https://doi.org/10.1007/s10637-013-9934-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-013-9934-y