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Tivantinib

Description of Tivantinib: Tivantinib (ARQ-197) is an orally bioavailable small molecule inhibitor of c-Met with potential antineoplastic activity. c-Met inhibitor ARQ 197 binds to the c-Met protein and disrupts c-Met signal transduction pathways, which may induce cell death in tumor cells overexpressing c-Met protein or expressing consitutively activated c-Met protein. c-Met protein, the product of the proto-oncogene c-Met, is a receptor tyrosine kinase also known as hepatocyte growth factor receptor (HGFR); this protein is overexpressed or mutated in many tumor cell types and plays key roles in tumor cell proliferation, survival, invasion, and metastasis, and tumor angiogenesis. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Current developer:  ArQule, Inc

Phase I study of Tivantinib:  A total of 79 patients with advanced solid tumors were enrolled. A maximum tolerated dose was not determined. Tivantinib was well tolerated, with mild to moderate toxicities. Two patients discontinued the study drug due to treatment-emergent adverse events. Dose-limiting grade of 3 or more toxicities including leukopenia, neutropenia, thrombocytopenia, vomiting, and dehydration, were observed in 2 patients treated with tivantinib 360 mg twice a day. The rate of absorption of tivantinib peaked approximately 2 to 4 hours after initial dosing, followed by a linear decrease in plasma concentrations. Increases in tivantinib exposure were not dose proportional. There was significant interpatient pharmacokinetic variability; however the clinical safety of tivantinib seemed unaffected. Three patients (3.8%) achieved a partial response and 40 patients (50.6%) maintained stable disease for a median of 19.9 weeks.  CONCLUSIONS:  Tivantinib 360 mg twice a day was well tolerated in patients with refractory advanced solid tumors. The results of this trial warrant further clinical investigation. (source: Clin Cancer Res; 17(24); 7754-64.)

1: Previdi S, Abbadessa G, Dalò F, France DS, Broggini M. Breast Cancer-Derived Bone Metastasis Can Be Effectively Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown. Mol Cancer Ther. 2012 Jan;11(1):214-23. Epub 2011 Oct 25. PubMed PMID: 22027690.

2: Rosen LS, Senzer N, Mekhail T, Ganapathi R, Chai F, Savage RE, Waghorne C, Abbadessa G, Schwartz B, Dreicer R. A phase I dose-escalation study of Tivantinib (ARQ 197) in adult patients with metastatic solid tumors. Clin Cancer Res. 2011 Dec 15;17(24):7754-64. Epub 2011 Oct 5. PubMed PMID: 21976535.

3: Adjei AA, Schwartz B, Garmey E. Early clinical development of ARQ 197, a selective, non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers. Oncologist. 2011;16(6):788-99. Epub 2011 May 31. PubMed PMID: 21632449.

4: Eathiraj S, Palma R, Volckova E, Hirschi M, France DS, Ashwell MA, Chan TC. Discovery of a novel mode of protein kinase inhibition characterized by the mechanism of inhibition of human mesenchymal-epithelial transition factor (c-Met) protein autophosphorylation by ARQ 197. J Biol Chem. 2011 Jun 10;286(23):20666-76. Epub 2011 Mar 24. PubMed PMID: 21454604; PubMed Central PMCID: PMC3121448.

5: Yap TA, Olmos D, Brunetto AT, Tunariu N, Barriuso J, Riisnaes R, Pope L, Clark J, Futreal A, Germuska M, Collins D, deSouza NM, Leach MO, Savage RE, Waghorne C, Chai F, Garmey E, Schwartz B, Kaye SB, de Bono JS. Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies. J Clin Oncol. 2011 Apr 1;29(10):1271-9. Epub 2011 Mar 7. PubMed PMID: 21383285.

6: Bagai R, Fan W, Ma PC. ARQ-197, an oral small-molecule inhibitor of c-Met for the treatment of solid tumors. IDrugs. 2010 Jun;13(6):404-14. PubMed PMID: 20506063.

7: Munshi N, Jeay S, Li Y, Chen CR, France DS, Ashwell MA, Hill J, Moussa MM, Leggett DS, Li CJ. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther. 2010 Jun;9(6):1544-53. Epub 2010 May 18. PubMed PMID: 20484018.