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Trial record 2 of 8 for:    "Liver Cirrhosis" | "Sorafenib"

Sorafenib in Treating Patients With Locally Advanced or Metastatic Liver Cancer and Cirrhosis

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ClinicalTrials.gov Identifier: NCT00767468
Recruitment Status : Terminated (Funding unavailable)
First Posted : October 7, 2008
Last Update Posted : May 23, 2012
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Brief Summary:

RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PURPOSE: This phase I trial is studying the side effects and best dose of sorafenib in treating patients with locally advanced or metastatic liver cancer and cirrhosis.


Condition or disease Intervention/treatment Phase
Liver Cancer Drug: sorafenib tosylate Phase 1

Detailed Description:

OBJECTIVES:

Primary

  • To evaluate the pharmacokinetic parameters of sorafenib tosylate in patients with locally advanced or metastatic hepatocellular carcinoma and Child-Pugh B cirrhosis.
  • To correlate the pharmacokinetic parameters of sorfenib tosylate with hepatic retention and clearance of technetium Tc 99m mebrofenin (MEB) and technetium Tc 99m sestamibi (MIBI).

Secondary

  • To establish a tolerable dose of sorafenib tosylate based on degree of liver dysfunction (bilirubin ≤ 3 times upper limit of normal [ULN] or bilirubin > 3 times but ≤ 6 times ULN).
  • To correlate the pharmacokinetics MEB and MIBI with the dose-limiting toxicity of sorafenib tosylate.
  • To explore whether increase in bilirubin consists primarily of conjugated or unconjugated bilirubin in response to sorafenib tosylate.
  • To explore whether there is a correlation between increased bilirubin and decreased clearance of MEB and/or MIBI.
  • To explore whether there is a correlation between survival and MRI characteristics associated with high tumor VEGF levels.
  • To assess VEGF levels directly in available biopsy samples using IHC.
  • To determine expression levels of hepatic transport proteins (i.e., OATPs, Pgp, or MRPs) that may correlate with clearance of sorafenib tosylate.
  • To explore whether there is a correlation between survival and activation of the RAF/MEK/ERK pathway at baseline.
  • To estimate median overall survival.

OUTLINE: This is a multicenter study. Patients are stratified according to degree of hepatic dysfunction (moderate [bilirubin ≤ 3 times upper limit of normal (ULN)] vs severe [bilirubin > 3 times but ≤ 6 times ULN]).

Patients receive oral sorafenib tosylate twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo hepatic scintigraphy with technetium Tc 99m mebrofinin (MEB) and technetium Tc 99m sestamibi (MIBI) at baseline. Blood and urine samples are collected periodically for pharmacokinetic studies.

After completion of study therapy, patients are followed at 3-4 weeks and then every 3 months thereafter.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase IB Study of Sorafenib for Patient With Locally Advanced or Metastatic Hepatocellular Carcinoma and Child's B Cirrhosis
Study Start Date : October 2008
Actual Primary Completion Date : February 2010
Actual Study Completion Date : November 2010


Arm Intervention/treatment
Experimental: Bilirubin Normal to 3x Upper Limit of Normal Drug: sorafenib tosylate
Sorafenib 400mg BID until disease progression or patient withdrawal.
Other Names:
  • Sorafenib
  • Nexavar

Experimental: Bilirubin >3x to 6x Upper Limit of Normal Drug: sorafenib tosylate
Sorafenib 400mg BID until disease progression or patient withdrawal.
Other Names:
  • Sorafenib
  • Nexavar




Primary Outcome Measures :
  1. Correlation between hepatic retention and clearance of technetium Tc 99m mebrofenin (MEB) and technetium Tc 99m sestamibi (MIBI) and clearance (and other pharmacokinetic parameters) of sorafenib tosylate [ Time Frame: 4 years ]

Secondary Outcome Measures :
  1. Tolerable dose of sorafenib tosylate [ Time Frame: 4 years ]
  2. Correlation between the pharmacokinetics of MEB and MIBI and the dose-limiting toxicity of sorafenib tosylate [ Time Frame: 4 years ]
  3. Conjugated or unconjugated bilirubin increase in response to sorafenib tosylate [ Time Frame: 4 years ]
  4. Correlation between increased bilirubin and decreased clearance of MEB and/or MIBI [ Time Frame: 4 years ]
  5. Correlation between survival and MRI characteristics associated with high tumor VEGF levels [ Time Frame: 4 years ]
  6. Correlation between clearance of sorafenib tosylate and expression levels of hepatic transport proteins [ Time Frame: 4 years ]
  7. Correlation between survival and activation of the RAF/MEK/ERK pathway at baseline [ Time Frame: 7 years ]
  8. Median overall survival [ Time Frame: 7 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of hepatocellular carcinoma (HCC) according to tissue histology* NOTE: *Recurrence of previously resected HCC does not require tissue confirmation if there is clear radiographic recurrence, in the opinion of the investigator
  • Locally advanced or metastatic disease OR not eligible for surgical resection or immediate liver transplantation
  • Child-Pugh class B cirrhosis

    • Moderate hepatic dysfunction (bilirubin ≤ 3 times upper limit of normal [ULN]) OR severe hepatic dysfunction (bilirubin > 3 times but ≤ 6 times ULN)
  • No known brain metastasis unless the metastasis has been stable for > 3 months

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-1
  • Life expectancy > 12 weeks
  • Hemoglobin > 9.0 g/dL
  • ANC > 1,000/mm^3
  • Platelet count > 45,000/mm^3
  • ALT and AST < 7 times ULN
  • INR < 2.0
  • Creatinine < 1.7 times ULN OR creatinine clearance > 50 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for ≥ 2 weeks after completion of study treatment
  • No history of uncontrolled seizures, CNS disorders, or psychiatric disability that, in the opinion of the investigator, is clinically significant, precludes giving informed consent, or interferes with compliance of oral drug intake
  • No other concurrent active malignancy
  • No active clinically serious infection > CTCAE grade 2
  • No known hypersensitivity to sorafenib tosylate or to any of the excipients
  • No known or suspected allergy to sorafenib tosylate or to any agent given in the course of this study
  • No NYHA class III or IV congestive heart failure
  • No unstable angina
  • No new onset angina (i.e., within the past 3 months)
  • No myocardial infarction within the past 6 months
  • No cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
  • No uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg, despite optimal medical management
  • No thrombolic or embolic events (e.g., cerebrovascular accident, including transient ischemic attacks) within the past 6 months
  • No pulmonary hemorrhage/bleeding event > CTCAE grade 2 within the past 4 weeks
  • No other hemorrhage/bleeding event > CTCAE grade 3 within the past 4 weeks
  • No variceal bleeding within the past 90 days
  • No known grade 2 or 3 esophageal varices
  • No evidence or history of bleeding diathesis or coagulopathy
  • No significant traumatic injury within the past 4 weeks
  • No serious non-healing wound, ulcer, or bone fracture
  • No other serious uncontrolled medical condition (e.g., uncontrolled ascites or encephalopathy) that, in the opinion of the investigator, may compromise study participation
  • No condition that would impair the patient's ability to swallow whole pills
  • No malabsorption problem
  • No active drug or alcohol abuse

PRIOR CONCURRENT THERAPY:

  • No more than one prior therapy including, but not limited to, any of the following:

    • Systemic chemotherapy
    • Hepatic artery infusion of chemotherapy
    • Chemoembolization
    • Radioembolization
    • Ablation
  • At least 4 weeks since prior embolization, resection, or ablation
  • No prior RAF/MEK/ERK-targeting therapy or VEGF-targeting therapy
  • More than 4 weeks since prior participation in an investigational drug study
  • More than 4 weeks since prior major surgery or open biopsy
  • No concurrent chronic anticoagulation other than 1 mg of warfarin per day for central venous catheter patency
  • No concurrent St. John's wort or rifampin

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00767468


Locations
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United States, North Carolina
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, United States, 27599-7295
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Bert H. O'Neil, MD UNC Lineberger Comprehensive Cancer Center

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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00767468     History of Changes
Other Study ID Numbers: LCCC 0717
P30CA016086 ( U.S. NIH Grant/Contract )
CDR0000615311 ( Other Identifier: PDQ number )
BAYER-UNC-LCCC-0717
First Posted: October 7, 2008    Key Record Dates
Last Update Posted: May 23, 2012
Last Verified: May 2012
Keywords provided by UNC Lineberger Comprehensive Cancer Center:
adult primary hepatocellular carcinoma
advanced adult primary liver cancer
localized unresectable adult primary liver cancer
recurrent adult primary liver cancer
Additional relevant MeSH terms:
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Sorafenib
Liver Neoplasms
Liver Diseases
Digestive System Diseases
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Bilirubin
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antioxidants
Protective Agents
Physiological Effects of Drugs