TY - JOUR
T1 - A phase I/II multicenter study of single-agent foretinib as first-line therapy in patients with advanced hepatocellular carcinoma
AU - Yau, Thomas C.C.
AU - Lencioni, Riccardo
AU - Sukeepaisarnjaroen, Wattana
AU - Chao, Yee
AU - Yen, Chia Jui
AU - Lausoontornsiri, Wirote
AU - Chen, Pei Jer
AU - Sanpajit, Theeranun
AU - Camp, Aaron
AU - Cox, Donna S.
AU - Gagnon, Robert C.
AU - Liu, Yuan
AU - Raffensperger, Kristen E.
AU - Kulkarni, Diptee A.
AU - Kallender, Howard
AU - Ottesen, Lone Harild
AU - Poon, Ronnie T.P.
AU - Bottaro, Donald P.
N1 - Publisher Copyright:
©2016 AACR.
PY - 2017/5/15
Y1 - 2017/5/15
N2 - Purpose: This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma patients. Experimental Design: In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30-60 mg) every day using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival. Results: The MTD of foretinib was established as 30 mg every day. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg every day in the first-line setting, foretinib demonstrated promising antitumor activity. According to the modified mRECIST, the objective response rate was 22.9%, the disease stabilization rate 82.9%, and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS. Conclusions: Foretinib demonstrated promising antitumor activity and good tolerability in the first-line setting in Asian advanced hepatocellular carcinoma patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib.
AB - Purpose: This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma patients. Experimental Design: In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30-60 mg) every day using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival. Results: The MTD of foretinib was established as 30 mg every day. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg every day in the first-line setting, foretinib demonstrated promising antitumor activity. According to the modified mRECIST, the objective response rate was 22.9%, the disease stabilization rate 82.9%, and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS. Conclusions: Foretinib demonstrated promising antitumor activity and good tolerability in the first-line setting in Asian advanced hepatocellular carcinoma patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib.
UR - http://www.scopus.com/inward/record.url?scp=85020386314&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020386314&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-16-1789
DO - 10.1158/1078-0432.CCR-16-1789
M3 - Article
C2 - 27821605
AN - SCOPUS:85020386314
SN - 1078-0432
VL - 23
SP - 2405
EP - 2413
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -