Sorafenib Plus Tegafur/Uracil (UFUR®) for Hepatocellular Carcinoma (HCC)

July 6, 2009 updated by: National Taiwan University Hospital

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

50

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Taiwan
      • Taipei, Taiwan, 100
        • National Taiwan University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: A
Drug: Sorafenib
Drug: tegafur/uracil (UFUR®)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To determine the progression- free survival of sorafenib plus tegafur/uracil (UFUR®) for the treatment of advanced or metastatic HCC.
Time Frame: 2007~2008
2007~2008

Secondary Outcome Measures

Outcome Measure
Time Frame
The 6-month progression-free survival rate.
Time Frame: 2007~2008
2007~2008
The objective tumor response rate.
Time Frame: 2007~2008
2007~2008
The disease stabilization rate (complete response + partial response + stable disease for at least 2 months).
Time Frame: 2007~2008
2007~2008
The overall survival.
Time Frame: 2007~2008
2007~2008
The safety profile.
Time Frame: 2007~2008
2007~2008
To evaluate the changes of circulating biomarkers indicating the angiogenesis activity and their correlation with objective tumor response.
Time Frame: 2007~2008
2007~2008

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Taiwan University Hospital

Investigators

  • Study Chair: Chih-Hung Hsu, M.D.Ph.D, Department of Oncology, National Taiwan University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2007

Study Completion (Actual)

March 1, 2009

Study Registration Dates

First Submitted

April 23, 2007

First Submitted That Met QC Criteria

April 23, 2007

First Posted (Estimate)

April 24, 2007

Study Record Updates

Last Update Posted (Estimate)

July 7, 2009

Last Update Submitted That Met QC Criteria

July 6, 2009

Last Verified

June 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 950914

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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