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A Phase II Study of Sorafenib Plus Tegafur/Uracil for the Treatment of Advanced or Metastatic Hepatocellular Carcinoma

Phase 2
18 Years
Not Enrolling
Hepatocellular Carcinoma

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Trial Information

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.

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


- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the progression- free survival of sorafenib plus tegafur/uracil (UFUR®) for the treatment of advanced or metastatic HCC.

Outcome Time Frame:


Principal Investigator

Chih-Hung Hsu, M.D.Ph.D

Investigator Role:

Study Chair

Investigator Affiliation:

Department of Oncology, National Taiwan University Hospital


Taiwan: Department of Health

Study ID:




Start Date:

April 2007

Completion Date:

March 2009

Related Keywords:

  • Hepatocellular Carcinoma
  • Advance, hepatocellular carcinoma
  • Carcinoma
  • Carcinoma, Hepatocellular