Phase I study of tivantinib in Japanese patients with advanced hepatocellular carcinoma: Distinctive pharmacokinetic profiles from other solid tumors

Takuji Okusaka, Takeshi Aramaki, Yoshitaka Inaba, Shinichiro Nakamura, Manabu Morimoto, Michihisa Moriguchi, Takashi Sato, Yuta Ikawa, Masafumi Ikeda, Junji Furuse

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

A c-Met inhibitor tivantinib is a candidate anticancer agent for patients with hepatocellular carcinoma (HCC), and CYP2C19 is the key metabolic enzyme for tivantinib. Previous Japanese phase I studies in patients with solid tumors (except HCC) recommend 360 mg twice daily (BID) and 240 mg BID for CYP2C19 extensive metabolizers (EM) and poor metabolizers (PM), respectively. In this study, Japanese patients with HCC in whom sorafenib treatment has failed were enrolled to evaluate the safety, tolerability and pharmacokinetics of oral tivantinib as a single agent. The dose was escalated separately in EM and PM, from 120 mg BID to 240 mg BID, in both capsule and tablet formulations. A total of 28 patients (EM: 21, PM: 7) received tivantinib. At a dose of 120 mg BID, dose-limiting toxicities (DLT) did not develop in 12 EM (capsule: 6, tablet: 6) and 7 PM (capsule: 4, tablet: 3) during the DLT-observation period (for 29 days after first dosing). At this dose, the pharmacokinetic profiles of tivantinib (AUC0-12 and Cmax) did not remarkably differ between EM and PM. When treated with 240 mg BID, 5 of 9 EM (capsule: 4 of 6, tablet: 1 of 3) developed neutropenia-related DLT accompanying plasma tivantinib concentration higher than expected from the previous studies. Consequently, PM did not receive 240 mg BID. In conclusion, 120 mg BID of tivantinib is recommended among Japanese patients with HCC regardless of CYP2C19 phenotype.

Original languageEnglish
Pages (from-to)611-617
Number of pages7
JournalCancer Science
Volume106
Issue number5
DOIs
Publication statusPublished - May 1 2015

Keywords

  • C-Met inhibitor
  • CYP2C19 polymorphisms
  • Hepatocellular carcinoma
  • Phase I study
  • Tivantinib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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