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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase IB Study of Sorafenib for Patient With Locally Advanced or Metastatic Hepatocellular Carcinoma and Child's B Cirrhosis

Conditions
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Liver Cancer

Intervention / Treatment
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* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bilirubin Normal to 3x Upper Limit of Normal<br> | Drug: sorafenib tosylate<br>* Sorafenib 400mg BID until disease progression or patient withdrawal.<br>* Other names: Nexavar;|
| Experimental: Bilirubin >3x to 6x Upper Limit of Normal<br> | Drug: sorafenib tosylate<br>* Sorafenib 400mg BID until disease progression or patient withdrawal.<br>* Other names: Nexavar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerable dose of sorafenib tosylate |  | 4 years | 
| Correlation between the pharmacokinetics of MEB and MIBI and the dose-limiting toxicity of sorafenib tosylate |  | 4 years | 
| Conjugated or unconjugated bilirubin increase in response to sorafenib tosylate |  | 4 years | 
| Correlation between increased bilirubin and decreased clearance of MEB and/or MIBI |  | 4 years | 
| Correlation between survival and MRI characteristics associated with high tumor VEGF levels |  | 4 years | 
| Correlation between clearance of sorafenib tosylate and expression levels of hepatic transport proteins |  | 4 years | 
| Correlation between survival and activation of the RAF/MEK/ERK pathway at baseline |  | 7 years | 
| Median overall survival |  | 7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult primary hepatocellular carcinoma, advanced adult primary liver cancer, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer