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 language | English |
|---|---|
| Pages (from-to) | 611-617 |
| Number of pages | 7 |
| Journal | Cancer Science |
| Volume | 106 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 1 2015 |
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Keywords
- C-Met inhibitor
- CYP2C19 polymorphisms
- Hepatocellular carcinoma
- Phase I study
- Tivantinib
ASJC Scopus subject areas
- Cancer Research
- Oncology
- Medicine(all)
Cite this
Phase I study of tivantinib in Japanese patients with advanced hepatocellular carcinoma : Distinctive pharmacokinetic profiles from other solid tumors. / Okusaka, Takuji; Aramaki, Takeshi; Inaba, Yoshitaka; Nakamura, Shinichiro; Morimoto, Manabu; Moriguchi, Michihisa; Sato, Takashi; Ikawa, Yuta; Ikeda, Masafumi; Furuse, Junji.
In: Cancer Science, Vol. 106, No. 5, 01.05.2015, p. 611-617.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phase I study of tivantinib in Japanese patients with advanced hepatocellular carcinoma
T2 - Distinctive pharmacokinetic profiles from other solid tumors
AU - Okusaka, Takuji
AU - Aramaki, Takeshi
AU - Inaba, Yoshitaka
AU - Nakamura, Shinichiro
AU - Morimoto, Manabu
AU - Moriguchi, Michihisa
AU - Sato, Takashi
AU - Ikawa, Yuta
AU - Ikeda, Masafumi
AU - Furuse, Junji
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
KW - C-Met inhibitor
KW - CYP2C19 polymorphisms
KW - Hepatocellular carcinoma
KW - Phase I study
KW - Tivantinib
UR - http://www.scopus.com/inward/record.url?scp=84929705265&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929705265&partnerID=8YFLogxK
U2 - 10.1111/cas.12644
DO - 10.1111/cas.12644
M3 - Article
C2 - 25711511
AN - SCOPUS:84929705265
VL - 106
SP - 611
EP - 617
JO - Cancer Science
JF - Cancer Science
SN - 1347-9032
IS - 5
ER -