The effect of CYP2C19 polymorphism on the safety, tolerability, and pharmacokinetics of tivantinib (ARQ 197): results from a phase I trial in advanced solid tumors

Abstract

BackgroundTivantinib (formerly ARQ 197) is a selective inhibitor of c-Met mainly metabolized by CYP2C19. CYP2C19 is known for genetic polymorphisms, and ∼20% of Asians are poor metabolizers (PMs), while others are extensive metabolizers (EMs). In this study, we examined the safety, pharmacokinetics (PK), and preliminary efficacy of tivantinib as a single agent to determine recommended phase II doses (RPIIDs). Patients and methodsForty-seven patients (EMs, 33; PMs, 14) with solid tumors were orally treated with tivantinib, from 70 to 360 mg bid in a 3 + 3 dose-escalation scheme. EMs and PMs were separately enrolled at the doses >120 mg bid. ResultsTivantinib was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. Neutropenia, leukopenia, anemia, fatigue, and anorexia were the frequent adverse events related to tivantinib and were commonly observed in both EMs and PMs. PMs had 1.9-fold higher AUC0–12 compared with EMs at 240 mg bid. Regardless of CYP2C19 phenotype, Gr.4 neutropenia occurred in patients with relatively high exposure to tivantinib. A confirmed partial response was achieved in two non-small-cell lung cancer (NSCLC) patients. ConclusionTwo different settings of RPIIDs, 360 mg bid for EMs and 240 mg bid for PMs, were determined.