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

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

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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 ]

Eligibility Criteria

• 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

Contacts and Locations

Locations

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

• Principal Investigator: Bert H. O'Neil, MD; UNC Lineberger Comprehensive Cancer Center

More Information

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT00767468
• 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
• 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:

Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Liver Diseases; Sorafenib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action