Randomized Phase I/II of RAD001 in Advanced Hepatocellular Carcinoma (HCC)

Summary

The mTOR has been examined in hepatocellular carcinomas as well. This pathway is up-regulated in a proportion of hepatocellular carcinoma (HCC) and that rapamycin inhibits cell proliferation and blocks S6K phosphorylation. Inhibition of mTOR had been shown to suppress substantially the liver tumor growth. Nevertheless, inhibition of mTOR was demonstrated to have a clinical response in some cancer types. These reports imply that inhibition of mTOR could be a promising therapeutic strategy in the treatment of HCC. Therefore, we hypothesize that RAD001, a rapamycin analog, can inhibit the mTOR, and subsequently suppress the liver tumor in the treatment of HCC patients. This study is aimed to investigate the safety, efficacy, pharmacokinetics, pharmacogenetics and feasibility of RAD001 in advanced HCC patients. This study will be a randomized phase I study with dose escalation and subsequently a phase II study of intent to treat, as well as pharmacokinetic, pharmacogenetic and surrogate marker study of RAD001.

Timeline

Start

2006-10

Primary completion

2010-06

Completion

2011-06

Publications

• Background Chan S. Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br J Cancer. 2004 Oct 18;91(8):1420-4. doi: 10.1038/sj.bjc.6602162.
• Background Meric-Bernstam F, Mills GB. Mammalian target of rapamycin. Semin Oncol. 2004 Dec;31(6 Suppl 16):10-7; discussion 33. doi: 10.1053/j.seminoncol.2004.10.013.
• Background Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004 May;4(5):335-48. doi: 10.1038/nrc1362. No abstract available.
• Results Yee KW, Zeng Z, Konopleva M, Verstovsek S, Ravandi F, Ferrajoli A, Thomas D, Wierda W, Apostolidou E, Albitar M, O'Brien S, Andreeff M, Giles FJ. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2006 Sep 1;12(17):5165-73. doi: 10.1158/1078-0432.CCR-06-0764.
• Results Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res. 2004 Dec 15;10(24):8421-5. doi: 10.1158/1078-0432.CCR-04-0941.
• Results Rizell M, Lindner P. Inhibition of mTOR suppresses experimental liver tumours. Anticancer Res. 2005 Mar-Apr;25(2A):789-93.
• Shiah HS, Chen CY, Dai CY, Hsiao CF, Lin YJ, Su WC, Chang JY, Whang-Peng J, Lin PW, Huang JD, Chen LT. Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma. Aliment Pharmacol Ther. 2013 Jan;37(1):62-73. doi: 10.1111/apt.12132. Epub 2012 Nov 8.
• Treiber G. mTOR inhibitors for hepatocellular cancer: a forward-moving target. Expert Rev Anticancer Ther. 2009 Feb;9(2):247-61. doi: 10.1586/14737140.9.2.247.

Drugs

Indications