UFUR Plus Thalidomide for Advanced Hepatocellular Carcinoma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Taiwan University Hospital
ClinicalTrials.gov Identifier:
NCT00519688
First received: August 22, 2007
Last updated: October 13, 2011
Last verified: October 2011
  Purpose

We hypothesize that combination of tegafur/uracil(UFUR) and thalidomide, both of which have been shown to be active in some HCC patients,may be a highly useful regimen for the treatment of advanced HCC. There are several rationales underlying this combination. First, anti-angiogenesis therapy may improve the efficacy of chemotherapy by normalizing the abnormal vasculature in tumors, and thus improving the delivery of chemotherapeutic agents to the tumor cells. Second, chemotherapeutic drugs given in a low-dose, un interrupted, and protracted way can induce anti-tumor effect through the anti-angiogenesis activity (so-called"metronomic chemotherapy"). The efficacy of metronomic chemotherapy can be suppressed by VEGF/VEGFR signaling pathways and thus can bo further potentiated by agents blocking those survival signals of endothelial cell. In this regard, tegafur/uracil appears to be a good candidate for metronomic chemotherapy because tegafur/uracil and its metabolites bave already been shown to inhibit angiogenesis in several pre-clinical models.


Condition Intervention Phase
Hepatocellular Carcinoma
Drug: Thalidomide
Drug: Tegafur/Uracil
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Tegafur/Uracil(UFUR) Plus Thalidomide for the Treatment of Advanced or Metastatic Hepatocellular Carcinoma (HCC)

Resource links provided by NLM:


Further study details as provided by National Taiwan University Hospital:

Primary Outcome Measures:
  • To evaluate the overall response rate of UFUR and thalidomide in the treatment of advanced HCC by RECIST criteria [ Time Frame: Confirmed response within 4 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To determine the disease stabilization rate. [ Time Frame: 2 to 3 months ] [ Designated as safety issue: No ]
  • To assess the progression- free survival and overall survival. [ Time Frame: 2 to 3 years ] [ Designated as safety issue: No ]
  • To establish the safety profile. [ Time Frame: Additional 4 months after stopping the investigational drugs ] [ Designated as safety issue: No ]
    Toxicity criteria based on CTC-AE version 3


Enrollment: 44
Study Start Date: July 2006
Study Completion Date: August 2010
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Thalidomide plus Tegafur/Uracil1
Thalidomide plus Tegafur/Uracil
Drug: Thalidomide
100 mg, BID
Other Name: Thado
Drug: Tegafur/Uracil
125 mg/m2, based on tegafur, BID
Other Name: UFUR

Detailed Description:

Thalidomide, a glutamic acid derivative first developed in 1950s, was marketed as a sedative, tranquilizer, and antiemetic for morning sickness. It was withdrawn from the European and Canadian markets in early 1960s because of its teratogenic effects. In recent years, thalidomide is emerging as a novel treatment for cancer because of its anti-angiogenic properties. The clinical efficacy has been demonstrated in various types of human cancers, including HCC.

Tegafur and uracil is a composite drug, which has been marketed as UFT® in Japan and marketed as UFUR® in Taiwan. Tegafur, a prodrug of 5-FU, is easily absorbed though the gastrointestinal tract slowly metabolized to 5-FU mainly in liver. Uracil is an inhibitor of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of 5-FU degradation. Therefore, tegafur/uracil is expected to maintain a stably high concentration in liver and in circulation. Tegafur/uracil has been approved for the indications of advanced gastric cancer and colorectal cancer. In several phase II studies conducted in Japan, tegafur/uracil induced a response rate of 0 to 17% in advanced HCC patients.

We hypothesize that combination of tegafur/uracil and thalidomide, both of which have been shown to be active in some HCC patients, may be a highly useful regimen for the treatment of advanced HCC. There are several rationales underlying this combination. First, anti-angiogenesis therapy may improve the efficacy of chemotherapy by normalizing the abnormal vasculature in tumors, and thus improving the delivery of chemotherapeutic agents to the tumor cells. Second, chemotherapeutic drugs given in a low-dose, un-interrupted, and protracted way can induce anti-neoplasm effect through the anti-angiogenesis activity. What so-called "metronomic chemotherapy" is based on direct targeting of the activation, growth, and proliferation of vascular endothelial cells by cytotoxic chemotherapeutic agents. The anti-angiogenesis effect of metronomic chemotherapy is suppressed by VEGF/VEGFR signaling pathways and thus can be further potentiated by agents blocking those survival signals of endothelial cells. In this regard, tegafur/uracil appears to be a good candidate for metronomic chemotherapy because tegafur/uracil and its metabolites have already been shown to inhibit angiogenesis in several pre-clinical models.

The combination of tegafur/uracil and thalidomide has clinical advantages for patients with HCC. Both drugs are orally active, thus are convenient to be given on an out-patient basis. More importantly, the low and non-overlapping toxicity profiles of the two drugs make the combination relatively safe in patients of HCC.

  Eligibility

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

Inclusion Criteria:

  • Histologically confirmed HCC or HBC/HCV carrier with hepatic tumor of α-FP>400 Stage IV dis. By AJCC KPS>70% Age>18 Liver function reserves:Child-Pugh Class A, ALT<5xUNL, Bil-T<1.5xUNL WBC>4000 or ANC>1500, PLT>75K, Cr<1.5xUNL Previous local therapy completed 6wks

Exclusion Criteria:

  • Concurrent corticosteroids Previous exposure to C/T, Thalidomide CNS metastasis Concomitant illness: active infection, >NCIG2 neuropathy, Hx of seizures Organ transplantation
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00519688

Locations
Taiwan
Department of Oncology , National Taiwan University Hospital
Taipei, Taiwan
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

Responsible Party: National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT00519688     History of Changes
Other Study ID Numbers: 940813, TTY-TU0510
Study First Received: August 22, 2007
Last Updated: October 13, 2011
Health Authority: Taiwan: Department of Health

Keywords provided by National Taiwan University Hospital:
tegafur
thalidomide
advanced 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
Thalidomide
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on August 01, 2014