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

This study has been completed.
Sponsor:
Information provided by:
National Taiwan University Hospital
ClinicalTrials.gov Identifier:
NCT00464919
First received: April 23, 2007
Last updated: July 6, 2009
Last verified: June 2009
  Purpose

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.


Condition Intervention Phase
Hepatocellular Carcinoma
Drug: Sorafenib
Drug: tegafur/uracil (UFUR®)
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Sorafenib Plus Tegafur/Uracil for the Treatment of Advanced or Metastatic Hepatocellular Carcinoma

Resource links provided by NLM:


Further study details as provided by National Taiwan University Hospital:

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

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

Estimated Enrollment: 50
Study Start Date: April 2007
Study Completion Date: March 2009
Arms Assigned Interventions
Experimental: A Drug: Sorafenib Drug: tegafur/uracil (UFUR®)

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00464919

Locations
Taiwan
National Taiwan University Hospital
Taipei, Taiwan, 100
Sponsors and Collaborators
National Taiwan University Hospital
Investigators
Study Chair: Chih-Hung Hsu, M.D.Ph.D Department of Oncology, National Taiwan University Hospital
  More Information

No publications provided by National Taiwan University Hospital

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Chih-Hung Hsu, Department of Oncology
ClinicalTrials.gov Identifier: NCT00464919     History of Changes
Other Study ID Numbers: 950914
Study First Received: April 23, 2007
Last Updated: July 6, 2009
Health Authority: Taiwan: Department of Health

Keywords provided by National Taiwan University Hospital:
Advance, hepatocellular carcinoma

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Tegafur
Sorafenib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 27, 2014