A Phase II Study of Sorafenib Plus Tegafur/Uracil for the Treatment of Advanced or Metastatic Hepatocellular Carcinoma
The prognosis for patients with metastatic or locally advanced hepatocellular carcinoma
(HCC) is poor. The role of conventional systemic chemotherapy has been very limited because
most chemotherapeutic agents are in-effective and relative toxic to HCC patients who tend to
have poor organ function reserves due to liver cirrhosis. The molecular-targeted therapy,
which aims at deranged signaling pathways of cancer cells or their microenvironment, holds
promise for HCC.
Sorafenib (BAY 43-9006), a novel bi-aryl urea, is a potent inhibitor of VEGFR2 and Raf
kinase. The clinical activity of sorafenib in HCC has been tested in a phase II study
(Bayer study 10874), which enrolled a total of 137 advanced HCC patients. There were 4% of
documented partial response, 5% of minor response, and 55% of stable disease. The 6- month
progression -free for the cohort was 40%. Currently, there are two on-going large-scale
randomized trials of sorafenib in advanced HCC patients worldwide.In this study proposal, we
propose to combine sorafenib with metronomic chemotherapy in the treatment of advanced HCC
patients. It has been recently demonstrated that cytotoxic chemotherapy, when given in a
low-dose, continuous, and uninterrupted way (i.e. the "metronomic" chemotherapy), inhibits
tumor angiogenesis. The anti-angiogenesis effect of metronomic chemotherapy can be
potentiated by combining the inhibitors of VEGF/VEGFR pathway. UFUR®, a composite drug
composed of tegafur and uracil, is an orally active 5-fluorouracil (5-FU) preparation. The
activity of tegafur/uracil in HCC has been tested in two relatively small-scale phase II
studies, with objective tumor response rates ranging from 0~18%. Interestingly, tegafur and
its metabolites, including γ-hydroxybutyric acid and γ-butyrolactone, have been shown to be
potent inhibitors of angiogenesis in several preclinical models. Therefore, tegafur/uracil
(UFUR®), which has potential anti-HCC activity and interesting anti-angiogenesis activity,
is an ideal candidate drug to improve the efficacy of sorafenib in HCC.
Interventional
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the progression- free survival of sorafenib plus tegafur/uracil (UFUR®) for the treatment of advanced or metastatic HCC.
2007~2008
Chih-Hung Hsu, M.D.Ph.D
Study Chair
Department of Oncology, National Taiwan University Hospital
Taiwan: Department of Health
950914
NCT00464919
April 2007
March 2009
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