A phase I/II multicenter study of single-agent foretinib as first-line therapy in patients with advanced hepatocellular carcinoma

Thomas C.C. Yau, Riccardo Lencioni, Wattana Sukeepaisarnjaroen, Yee Chao, Chia Jui Yen, Wirote Lausoontornsiri, Pei Jer Chen, Theeranun Sanpajit, Aaron Camp, Donna S. Cox, Robert C. Gagnon, Yuan Liu, Kristen E. Raffensperger, Diptee A. Kulkarni, Howard Kallender, Lone Harild Ottesen, Ronnie T.P. Poon, Donald P. Bottaro

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Abstract

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.

Original languageEnglish
Pages (from-to)2405-2413
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number10
DOIs
Publication statusPublished - 2017 May 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Yau, T. C. C., Lencioni, R., Sukeepaisarnjaroen, W., Chao, Y., Yen, C. J., Lausoontornsiri, W., Chen, P. J., Sanpajit, T., Camp, A., Cox, D. S., Gagnon, R. C., Liu, Y., Raffensperger, K. E., Kulkarni, D. A., Kallender, H., Ottesen, L. H., Poon, R. T. P., & Bottaro, D. P. (2017). A phase I/II multicenter study of single-agent foretinib as first-line therapy in patients with advanced hepatocellular carcinoma. Clinical Cancer Research, 23(10), 2405-2413. https://doi.org/10.1158/1078-0432.CCR-16-1789