A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

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. In the phase I part, advanced hepatoc...

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Published in:	Clinical cancer research Vol. 23; no. 10; pp. 2405 - 2413
Main Authors:	Yau, Thomas C C, Lencioni, Riccardo, Sukeepaisarnjaroen, Wattana, Chao, Yee, Yen, Chia-Jui, Lausoontornsiri, Wirote, Chen, Pei-Jer, Sanpajit, Theeranun, Camp, Aaron, Cox, Donna S, Gagnon, Robert C, Liu, Yuan, Raffensperger, Kristen E, Kulkarni, Diptee A, Kallender, Howard, Ottesen, Lone Harild, Poon, Ronnie T P, Bottaro, Donald P
Format:	Journal Article
Language:	English
Published:	United States American Association for Cancer Research Inc 15-05-2017
Subjects:	Adult Aged Anilides - administration & dosage Anilides - pharmacokinetics Anticancer properties Antitumor activity Appetite loss Ascites Axl protein Biomarkers Biomarkers, Pharmacological - blood Carcinoma, Hepatocellular - blood Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - pathology Design standards Experimental design Female Fever Hepatocellular carcinoma Humans Hypertension Interleukin 6 Interleukin 8 Interleukin-6 - blood Interleukin-8 - blood Liver cancer Liver Neoplasms - blood Liver Neoplasms - drug therapy Liver Neoplasms - pathology Male Maximum Tolerated Dose Middle Aged Patients Pharmacodynamics Pharmacokinetics Pharmacology Plasma levels Protein-Tyrosine Kinases - antagonists & inhibitors Proto-Oncogene Proteins - antagonists & inhibitors Proto-Oncogene Proteins c-met - antagonists & inhibitors Quinolines - administration & dosage Quinolines - pharmacokinetics Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor, TIE-2 - antagonists & inhibitors Ron protein Safety Survival Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
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Summary:	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. 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. 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. 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. .
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Robert C. Gagnon, Ph.D., Bristol-Myers Squibb Company, Princeton, NJ USA 08540 Yuan Liu, Ph.D., Translational Oncology, Global Product Development Oncology, Pfizer, Inc., 10555 Science Center Drive, San Diego, CA USA 92121 Current Affiliations Howard Kallender, Ph.D., Incyte Corporation, Wilmington, DE USA 19803 Riccardo Lencioni, MD, FSIR, EBIR, Department of Interventional Radiology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, 1475 NW 12th Avenue, Suite C-080, Miami, FL USA 34146 Donna S. Cox, Ph.D., Clinical Pharmacology, Teva Pharmaceuticals, Malvern, PA USA 19355
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-16-1789