A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma.
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.Clin Cancer Res; 23(10); 2405-13. ©2016 AACR.
Department of Medicine, The University of Hong Kong, Hong Kong, China.
Thomas C C
TCC
Yau
Division of Diagnostic Imaging and Intervention, University of Pisa, Pisa, Italy.
Riccardo
R
Lencioni
Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Wattana
W
Sukeepaisarnjaroen
Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan.
Yee
Y
Chao
Internal Medicine, National Cheng University Hospital, Tainan, Taiwan.
Chia-Jui
CJ
Yen
Clinical Cancer Research Center, National Cancer Institute of Thailand, Bangkok, Thailand.
Wirote
W
Lausoontornsiri
Graduate Institute of Clinical Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Pei-Jer
PJ
Chen
Division of Digestive and Liver Diseases, Phramongkutklao Hospital, Bangkok, Thailand.
Theeranun
T
Sanpajit
PPD, Inc., Austin, Texas.
Aaron
A
Camp
GlaxoSmithKline, King of Prussia, Pennsylvania.
Donna S
DS
Cox
GlaxoSmithKline, Collegeville, Pennsylvania.
Robert C
RC
Gagnon
GlaxoSmithKline, Collegeville, Pennsylvania.
Yuan
Y
Liu
Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
Kristen E
KE
Raffensperger
GlaxoSmithKline, King of Prussia, Pennsylvania.
Diptee A
DA
Kulkarni
GlaxoSmithKline, Collegeville, Pennsylvania.
Howard
H
Kallender
GlaxoSmithKline, Uxbridge, United Kingdom.
Lone Harild
LH
Ottesen
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Ronnie T P
RTP
Poon
Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland. dbottaro@helix.nih.gov.
Donald P
DP
Bottaro
D000328:Adult; D000368:Aged; D000813:Anilides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D054316:Biomarkers, Pharmacological / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D016209:Interleukin-8 / Q000097:blood*; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D000094963:Axl Receptor Tyrosine Kinase
D000813:Anilides; D054316:Biomarkers, Pharmacological; C508606:CXCL8 protein, human; C544831:GSK 1363089; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D011518:Proto-Oncogene Proteins; D011804:Quinolines; C000588866:KDR protein, human; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human