A Phase I Dose Esclation Study of Tivantinib (ARQ 197) in Adult Pts w Metastatic Solid Tumors
Mené sur 79 patients atteints d'une tumeur solide de stade avancé ou métastatique réfractaire à un traitement standard, cet essai de phase I évalue un nouvel inhibiteur de c-MET par voie orale, le tivantinib
Background: Tivantinib, an oral, non-ATP competitive, selective c-MET inhibitor, exhibited antitumor activitiy 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 mg to 360 mg BID were administered to patient cohorts in 21-day cycles (14 days on/7 days off); 3 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 ≥ 3 toxicities including leukopenia, neutropenia, thrombocytopenia, vomiting, and dehydration, were observed in2 patients treated with tivantinib 360 mg BID. The rate of absorption of tivantinib peaked approximately 2-4 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 appeared 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 BID was well tolerated in patients with refractory advanced solid tumors. The results of this trial warrant further clinical investigation.