Sorafenib Plus Tegafur/Uracil (UFUR®) for Hepatocellular Carcinoma (HCC)
Sorafenib Plus Tegafur/Uracil (UFUR®) for Hepatocellular Carcinoma (HCC)
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.
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.
Inclusion Criteria:

 -  Age > 18 years;

 -  ECOG PS 0-2;

 -  Histologically or cytologically documented unresectable and/or metastatic HCC;

 -  Measurable disease by RECIST criteria;

 -  Previous local therapy completed > 6 weeks;

 -  Any acute toxicity (CTC-AE) < grade 1;

 -  Child-Pugh A;

 -  Liver transaminases ≤ 5 x ULN;

 -  Albumin ≥ 2.8 g/dl;

 -  Serum total bilirubin ≤ 3 mg/dl;

 -  INR ≤ 2.3 or PT ≤ 6 seconds above control;

 -  WBC ≥ 3,000/µl;

 -  ANC ≥ 1,500/µl;

 -  Platelets ≥ 100,000/µl;

 -  Hb ≥ 8.5 g/dl;

 -  Creatinine ≤ 1.5 x ULN; AND

 -  Amylase and lipase < 1.5 x ULN

 Exclusion Criteria:

 -  Metastatic brain/leptomeningeal tumors;

 -  Prior or concomitant systemic anti-cancer treatment for HCC, including:

 -  Systemic chemotherapy (TACE is allowed)

 -  Immunotherapy

 -  Hormonal therapy (hormonal therapy used for supportive used is allowed)

 -  Raf-kinase inhibitors

 -  MEK inhibitors

 -  Farnesyl transferase inhibitors

 -  VEGF/VEGFR- inhibitors or other anti-angiogenesis agents

 -  Investigational anti-cancer agents

 -  Severe and/or uncontrolled medical conditions:

 -  Uncontrolled high blood pressure

 -  History of poor compliance with anti-hypertensive agents

 -  Active or uncontrolled infection

 -  Unstable angina

 -  CHF

 -  MI or CVA < 6 months

 -  GI bleeding < 30 days

 -  Unable to take oral medications

 -  Severe renal impairment which requires dialysis; proteinuria > grade 2;

 -  BMT or stem cell rescue < 4 months; organ transplant;

 -  HIV infection;

 -  Major surgical procedure, open biopsy, or significant traumatic injury < 4 weeks or
 those who receive minor surgical procedures (e.g. core biopsy or fine needle
 aspiration) within 2 weeks;

 -  Receive central venous line placement within 7 days;

 -  Patients who anticipate receiving major surgery during the course of the study;

 -  Use rifampin, St. John's Wort [Hypericum perforatum];

 -  Patients taking narrow therapeutic index medications will be monitored closely. These
 include warfarin, phenytoin, quinidine, carbamazepine, phenobarbital, cyclosporine,
 and digoxin; OR

 -  Patients for whom tegafur is contra-indicated