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

Phase 2

Completed

• Conditions: Hepatocellular Carcinoma
• Interventions: Drug: Sorafenib; Drug: tegafur/uracil (UFUR®)

• Registration Number: NCT00464919
• Lead Sponsor: National Taiwan University Hospital

Brief Summary

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.

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 Timeline

• Study Start: 2007-04
• Study First Submitted: 2007-04-23
• Study First Submitted QC: 2007-04-23
• Study First Posted: 2007-04-24
• Study Completion: 2009-03
• Status Verified: 2009-06
• Last Update Submitted: 2009-07-06
• Last Update Posted: 2009-07-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 50

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
A	Sorafenib	-
A	tegafur/uracil (UFUR®)	-

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan