Treatment of Non-Metastatic Hepatocellular Carcinoma in Humans by Increasing Gabaergic Activity: A Pilot Study

This study has suspended participant recruitment.
(The study have been stoped because the protocol is going to be modify.)
Sponsor:
Information provided by:
University of Manitoba
ClinicalTrials.gov Identifier:
NCT00493428
First received: June 27, 2007
Last updated: March 2, 2009
Last verified: June 2007
  Purpose

Recent studies indicate that liver cancer cells possess a receptor called the GABA-B receptor that when activated, inhibits the spread of cancer cells in test tubes. One of the drugs that activate these receptors is Baclofen, an agent that was originally developed to treat patients with various neurologic disorders. In this study, patients with recently identified liver cancer will be treated with Baclofen in an attempt to prevent or delay spread of the cancer beyond the liver. The time it takes for liver cancer to spread in the patients will be compared to the results obtained from patients enrolled in previous studies where Baclofen was not used.


Condition Intervention Phase
Hepatocellular Carcinoma
Drug: Baclofen
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: Treatment of Non-Metastatic Hepatocellular Carcinoma in Humans by Increasing Gabaergic Activity: A Pilot Study

Resource links provided by NLM:


Further study details as provided by University of Manitoba:

Primary Outcome Measures:
  • Document and Compare the effects of the GABAb receptor agonist Baclofen on the time to develop tumor metastasis in patients with non-metastatic HCC at diagnosis who subsequently undergo surgical resection, ablation or chemoembolization. [ Time Frame: 6 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Document and compare the effects of the GABAb receptor agonist Baclofen on changes in serum tumor markers ( alpha-fetoprotein andd CA19-9 levels) in patients with no-metastatic HCC at diagnosis. [ Time Frame: 6 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 47
Study Start Date: July 2007
Estimated Study Completion Date: July 2013
Estimated Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Baclofen
    Patients will receive an initial dose of: 5 mg tid to be increased as tolerated to a maximum dose of 20 mg qid. This dose range and schedule reflects that suggested for the drug's muscle relaxant properties in human.
    Other Name: Lioresal,Nu-Baclo
Detailed Description:

A total of 47 consecutive patients with radiologic or histologic evidence of non metastatic liver cancer will be enrolled over a 2-4 year period. Subjects will receive oral Baclofen at the manufacturer's suggested maximal dose. Clinical, hematologic, biochemical, and radiologic features of liver function, tumor metastasis and recurrence will be monitored at regular time intervals over a 2 year treatment period. The primary study end point will be the event of interest (time to metastasis or recurrence). Secondary end points will include time to metastasis following recurrence, objective tumor responses (complete, partial and non response), response duration, survival and safety. It is hoped the results of this study will permit liver cancer patients to remain candidates for surgical resection and transplantation longer than would otherwise have been the case.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • A diagnosis of HCC and no evidence of extra-hepatic metastases on CT/MRI scan of the abdomen, CT of the chest and brain and a negative bone scan.
  • Patients undergoing local therapy (resection, ablation or chemoembolization) and those listed for liver transplantation will not be excluded from participating in the study.
  • Patients with multiple space occupying lesions within the liver (but no evidence of extra-hepatic metastases) will continue to be eligible (the distinction between regenerative nodules and multi-focal HCC versus intra-hepatic metastases can not be made with certainty by presently available techniques).
  • Karnofsky Performance Status (KPS) ≥ 60 %.
  • Age 18 years or greater.
  • Life expectancy of at least 12 weeks.
  • Concomitant Medications
  • Patients should be on stable doses of other medications (no change in dose for two weeks prior to study initiation) when entered into the study.
  • Patient consent must be obtained from all patients prior to entry into the trial.
  • Patients must be accessible for treatment and follow-up i.e. residing within reasonable geographical limits of the study site.

Exclusion Criteria:

  • Any investigational agent within a minimum of 6 weeks prior to study treatment.
  • Pregnant or lactating women; women or men of childbearing potential unless using effective contraception. Patients capable of reproduction must agree to use appropriate methods of contraception during the study and for six months afterwards. Female patients of childbearing potential must have a negative urine pregnancy test within 14 days of study enrollment.
  • Patients whose partners are pregnant.
  • Other serious illness or medical conditions which would not permit the patient to be managed according to the protocol including:

    • History of a psychiatric disorder which would impair the ability to obtain consent or follow-up tumor imaging.
    • Active uncontrolled infection.
  • Any known defect in GABA metabolism or hypersensitivity to Baclofen.
  • Patients with previous organ allograft or taking immunomodulatory drugs.
  • Renal failure not being managed by dialysis.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00493428

Locations
Canada, Manitoba
Liver Unit, Section of Hepatology, Department of Medicine,Health Sciences Centre
Winnipeg, Manitoba, Canada, R3E 3P4
Liver Unit, health sciences Centre
Winnipeg, Manitoba, Canada
Sponsors and Collaborators
University of Manitoba
Investigators
Principal Investigator: Minuk Y Minuk, MD, FRCPC University of Manitoba
  More Information

Publications:
1. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001; 94:153-156. 2. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 2004; 127:S27-S34. 3. Takano S, Yokosuka O, Imazeki F, Tagawa M, Omata M. Incidence of hepatocellular carcinoma in chronic hepatitis B and C: a prospective study of 251 patients. Hepatology 1995; 21:650-655. 4. Kaplan DE, Reddy KR. Rising incidence of hepatocellular carcinoma: the role of hepatitis B and C; the impact on transplantation and outcomes. Clin Liver Dis 2003; 7:683-714. 5. Sherman M, Klein A. AASLD single-topic research conference on hepatocellular carcinoma: conference proceedings. Hepatology 2004; 40:1465-1473. 6. Befeler AS, Di Bisceglie AM. Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 2002: 122:1609-1619. 7. Di Bisceglie AM, Carithers RL, Gores GJ. Hepatocellular carcinoma. Hepatology 1998; 28:1161-1165. 8. Minuk GY. GABAergic mechanisms and their functional importance in the liver. In: GABAergic Mechanism in the Mammalian Periphery, edited by: S.L. Erdo and N.G. Bowery, pp 325-337, Raven Press, New York. 9. Seiler N. On the role of GABA in vertebrate polyamine metabolism. Physiol Chem Physics 1980; 12:411-429. 10. Enna SJ, Karbon EW. GABA receptors: An overview. Benzodiazepine/GABA Receptors and Chloride Channels: Structural and Functional Properties 1986; 41-56. 11. Stephenson FA. The GABAA receptors. Biochem J 1995; 319:1-9. 12. Ong J, Kerr DI. Recent advances in GABAB receptors: from pharmacology to molecular biology. Acta Pharmacol Sin 2000; 21:111-123. 13. Guastella J, Nelson N, Nelson H, Czyzyk L, Keynan S, Miedel MC, Davidson N, Lester HA, Kanner BI. Cloning and expression of rat brain GABA transporter. Science 1990; 249:1303-1306. 14. Minuk GY, Vergalla J, Ferenci P, Jones EA. Identification of an acceptor system for gamma-aminobutyric acid on isolated rat hepatocytes. Hepatology 1984; 4:180-185. 15. Erlitzki R, Gong Y, Zhang M, Minuk GY. Identification of g-aminobutyric acid receptor subunit types in human and rat liver. Am J Physiol Gastrointest Liver Physiol 2000; 279:G733-G739. 16. Gong Y, Zhang M, Cui L, Minuk GY. Sequence and chromosomal assignment of a human novel cDNA: similarity to gamma-aminobutyric acid transporter. Can J Physiol Pharmacol 2001; 79:977-984. 17. Minuk GY, Bear CE, Sarjeant EJ. Sodium-independent, bicuculline-sensitive [3H] GABA binding to isolated rat hepatocytes. Am J Physiol 1987; 252:G642-G647. 18. Minuk GY, MacCannell KL. Is the hypotension of cirrhosis a GABA-mediated process? Hepatology 1988; 8:73-77. 19. Minuk GY, Sarjeant EJ. Gamma aminobutyric acid (GABA) and hepatic bile flow in the adult rat. Clinical and Investigative Medicine 1984; 7:193-197. 20. Minuk GY, Sarjeant EJ. Insulin and glucagon secretion by the dog pancreas during intravenous and oral administration of gamma aminobutyric acid (GABA). Horm Metabol Res 1985; 17: 313-314. 21. Minuk GY, Gauthier T. The effect of gamma aminobutyric acid (GABA) on hepatic regeneration activity following partial hepatectomy in rats. Gastroenterology 1993; 104:217-221. 22. Minuk GY, Kaita K, Gauthier T, Dembinski T, Murphy LJ. Effect of exogenous g-aminobutyric acid (GABA) on hepatic insulin-like growth factor 1 (IGF-1) and IGF-1 binding protein (IGFBP-1) mRNA abundance following partial hepatectomy in rats. Can J Physiol Pharmacol 19995; 73:1546-1551. 23. Kaita KDE, Assy N, Gauthier T, Zhang M, Meyers AFA, Minuk GY. The beneficial effects of ciprofloxacin on survival and hepatic regenerative activity in a rat model of fulminant hepatic failure. Hepatology 1998; 27:533-536. 24. Minuk GY, Kren BT, Xu R, Zhang X, Burczynski F, Mulrooney NP, Fan G, Gong Y, Steer CJ. The effect of changes in hepatocyte membrane potential on immediate-early proto-oncogene expression following partial hepatectomy in rats. Hepatology 1997; 25:1123-1127. 25. Sun D, Gong Y, Kojima H, Wang G, Ravinsky E, Zhang M, Minuk GY. Increasing cell membrane potential and GABAergic activity inhibits malignant hepatocyte growth. Am J Physiol Gastrointest Liver Physiol 2003; 285:G12-G19. 26. Zhang M, Gong Y, Assy N, Minuk GY. Increased GABAergic activity inhibits a-fetoprotein mRNA expression and the proliferative activity of the HepG2 human hepatocellular carcinoma cell line. J Hepatol 2000; 32:85-91. 27. Fava G, Marucci L, Glaser S, Francis H, De Morrow S, Benedetti A, Alvaro D, Venter J, Meininger C, Patel, T, Taffetani S, Marzioni M, Summers R, Reichenbach R, Alpini G. Gamma-Aminobutyric acid inhibits cholangiocarcinoma growth by cyclic AMP-dependent regulation of the protein kinase A/extracellular signal-regulated kinase ½ pathway. Cancer Res. 2005 Dec 15; 65(24):11437-46.

Responsible Party: Minuk Gerald, Liver Unit, Health Sciences Centre
ClinicalTrials.gov Identifier: NCT00493428     History of Changes
Other Study ID Numbers: B2006:156
Study First Received: June 27, 2007
Last Updated: March 2, 2009
Health Authority: Canada: Health Canada

Keywords provided by University of Manitoba:
Hepatocellular Carcinoma
GABAergic Activity
Baclofen

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
Baclofen
GABA-B Receptor Agonists
GABA Agonists
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Muscle Relaxants, Central
Neuromuscular Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 17, 2014