title: Phase I study of tivantinib in Japanese patients with advanced hepatocellular carcinoma: Distinctive pharmacokinetic profiles from other solid tumors.
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.
authors.affiliation: Division of Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.affiliation: Division of Interventional Radiology, Shizuoka Cancer Center, Shunto-gun, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aramaki
authors.affiliation: Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Inaba
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Division of Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Morimoto
authors.affiliation: Division of Interventional Radiology, Shizuoka Cancer Center, Shunto-gun, Japan.
authors.forename: Michihisa
authors.initials: M
authors.lastname: Moriguchi
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co., Ltd., Chiyoda-ku, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co., Ltd., Chiyoda-ku, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Ikawa
authors.affiliation: Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Medical Oncology, Kyorin University School of Medicine, Mitaka, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Furuse
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D044466:Asian People; D002214:Capsules; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013607:Tablets; D016896:Treatment Outcome
chemical_list: C551661:ARQ 197; D000970:Antineoplastic Agents; D002214:Capsules; D011760:Pyrrolidinones; D011804:Quinolines; D013607:Tablets; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019859:Proto-Oncogene Proteins c-met
keywords: CYP2C19 polymorphisms; c-Met inhibitor; hepatocellular carcinoma; phase I study; tivantinib