Phase I study of tivantinib in Japanese patients with advanced hepatocellular carcinoma: Distinctive pharmacokinetic profiles from other solid tumors |
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| Authors: | Takuji Okusaka Takeshi Aramaki Yoshitaka Inaba Shinichiro Nakamura Manabu Morimoto Michihisa Moriguchi Takashi Sato Yuta Ikawa Masafumi Ikeda Junji Furuse |
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| Affiliation: | 1. Division of Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo‐ku, Japan;2. Division of Interventional Radiology, Shizuoka Cancer Center, Shunto‐gun, Japan;3. Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Japan;4. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan;5. Division of Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan;6. R&D Division, Kyowa Hakko Kirin Co., Ltd., Chiyoda‐ku, Japan;7. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan;8. Department of Medical Oncology, Kyorin University School of Medicine, Mitaka, Japan |
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| 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. |
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| Keywords: | c‐Met inhibitor CYP2C19 polymorphisms hepatocellular carcinoma phase I study tivantinib |
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