A Phase I Dose-Escalation Study of Tivantinib (ARQ 197) in Adult Patients with Metastatic Solid Tumors Article

Industry Collaboration

cited authors

  • Rosen, Lee S., Senzer, Neil, Mekhail, Tarek, Ganapathi, Ram, Chai, Feng, Savage, Ronald E., Waghorne, Carol, Abbadessa, Giovanni, Schwartz, Brian, Dreicer, Robert

funding text

  • L.S. Rosen: other commercial research support, ArQule, Inc. R. Ganapathi: commercial research grant. F. Chai: employment, ArQule, Inc. (Director of Drug Safety); ownership interest, ArQule, Inc. stocks. R. E. Savage: employment (Director, Pre-Clinical development and clinical pharmacology); ownership interest, ArQule, Inc. stock options. C. Waghorne: employment, ArQule, Inc. (Lead Investigator). G. Abbadessa: employment, ArQule, Inc. (Senior Medical Director); ownership interest, ArQule, Inc. stock options. B. Schwartz: employment, ArQule, Inc. (Chief Medical Officer); ownership interest, ArQule, Inc. stocks. R. Dreicer: honoraria from speakers bureau, Centecor Ortho Biotech; consultant/advisory board, GTX, Sanofi Aventis, Novartis and Millenium.

abstract

  • Background: Tivantinib, an oral, non-ATP competitive, selective c-MET inhibitor, exhibited antitumor activity in preclinical models. This open-label, phase I, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of tivantinib in patients with advanced or metastatic solid tumors refractory to standard therapy. Methods: Thirteen dose levels of tivantinib ranging from 10 to 360 mg twice a day were administered to patient cohorts in 21-day cycles (14 days on/7 days off); three active pharmaceutical ingredient forms of tivantinib (amorphous, crystalline A, and crystalline B) were also investigated. Treatment was continued until the occurrence of unacceptable toxicity, tumor progression, patient withdrawal, or death. Results: 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. Clin Cancer Res; 17(24); 7754-64. (C) 2011 AACR.

authors

Publication Date

  • December 15, 2011

webpage

published in

category

start page

  • 7754

end page

  • 7764

volume

  • 17

issue

  • 24

WoS Citations

  • 72

WoS References

  • 42