Sorafenib Plus Tegafur/Uracil (UFUR®) for Hepatocellular Carcinoma (HCC)
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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 |
- To determine the progression- free survival of sorafenib plus tegafur/uracil (UFUR®) for the treatment of advanced or metastatic HCC. [ Time Frame: 2007~2008 ]
- 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 |
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| Taiwan | |
| National Taiwan University Hospital | |
| Taipei, Taiwan, 100 | |
| 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 May 19, 2013