Sorafenib Tosylate in Treating Patients With Liver Cancer That Can Be Removed by Surgery

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Sorafenib tosylate 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 II trial is studying how well sorafenib tosylate works in treating patients with liver cancer that can be removed by surgery.

Detailed Description
-----------------
OBJECTIVES: Primary To assess anti-tumor activity of neoadjuvant sorafenib tosylate in tumor samples from patients with resectable hepatocellular carcinoma (HCC). Secondary To characterize pathologic findings in sorafenib tosylate pre-treated patients undergoing surgical resection for HCC: 1-2 core tumor biopsies will be performed prior to treatment and at day 35. To evaluate the number of R0 resections in these patients. To correlate pathological biomarker changes in resected tumors after 4-week treatment with sorafenib tosylate in comparison with biopsies obtained prior to treatment in these patients. To evaluate plasma biomarkers, including PIGF, VEGF-A, VEGF-C, sVEGFR2, sVEGFR3, sKIT, IL-6, Ang2, IL-8, bFGF, AFP, collagen 4, endostatin, thrombospondin, TSP-1 and angiostatin, and CXCL12 at baseline, day 28, and the day before surgery. To identify potential biomarkers of sensitivity and/or resistance on biological and pathological samples of these patients (exploratory). To characterize the safety profile of sorafenib tosylate in these patients. To assess the tolerance of liver resection after sorafenib tosylate treatment of these patients. OUTLINE: This is a multicenter study. Patients receive oral sorafenib tosylate twice daily on days 1-28 in the absence of unacceptable toxicity. Approximately 7 days after completion of sorafenib tosylate therapy, patients undergo liver resection. Blood and tissue specimens are collected periodically for laboratory and biomarker assessments. Biomarkers include both molecular markers investigating the direct antitumor effects of sorafenib tosylate against cancer cells vs the effects of the drug on angiogenesis. After completion of study treatment, patients are followed up on day 50 and at 3 months after surgery.

Official Title
-----------------
Proof-of-Concept Phase II Study to Evaluate the Anti-Tumor Activity of Sorafenib Along With Pathological and Molecular Changes in Tumor Samples From Patients With Resectable Hepatocellular Carcinoma

Conditions
-----------------
Liver Cancer

Intervention / Treatment
-----------------
* Drug: sorafenib tosylate
* Other: laboratory biomarker analysis
* Procedure: neoadjuvant therapy
* Procedure: therapeutic conventional surgery


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed hepatocellular carcinoma (HCC) Fibrolamellar or mixed histology allowed No cholangiocarcinoma or other tubal disease Must be eligible for conservative hepatic resection or liver resection with curative intent No cirrhosis with Child-Pugh score > 7 Chronic liver disease without liver insufficiency and without portal liver hypertension allowed No known history or presence of metastatic brain or meningeal tumors PATIENT CHARACTERISTICS: ECOG performance status 0-1 Life expectancy ≥ 3 months WBC > 3,000/µL ANC > 1,500/µL Platelet count ≥ 100,000/µL Hemoglobin ≥ 9 g/dL Bilirubin < 1.5 times upper normal limit (ULN) AST and ALT ≤ 5 times UNL Alkaline phosphatase ≤ 5 times ULN Serum creatinine < 2 times ULN PT/INR/PTT < 1.5 times UNL Amylase and lipase < 1.5 times ULN Negative pregnancy test Fertile patients must use effective contraception Body mass index 18.5-30 kg/m^2 (WHO normal range: 18.5-25 kg/m^2) Able to swallow oral compound No criterion for unresectability or medical condition that contraindicates surgical resection No serious concurrent systemic disorder incompatible with the study, including any of the following: Uncontrolled hypertension (i.e., BP > 150/100 mm Hg despite optimal therapy) Active uncontrolled infection Active alcoholism No prior medical disorder, including any of the following: Cardiac arrhythmias requiring anti-arrhythmics (excluding beta-blockers or digoxin for chronic atrial fibrillation) Active coronary artery disease or ischemia Myocardial infarction within the past 6 months NYHA class III-IV congestive heart failure Pulmonary embolism within the past 6 months Gastrointestinal bleeding within the past 6 months No other prior malignancy within the past 5 years, except basal cell or squamous cell skin carcinoma or cured in situ cervical carcinoma No history or concurrent seizure disorder requiring medications (e.g., antiepileptic drugs) No history of HIV infection, or chronic hepatitis B or C No active clinically serious bacterial or fungal infection (i.e., grade 2 CTCAE v. 3) No condition that is unstable or could jeopardize the safety of the patient and his/her compliance with the study No substance abuse or medical, psychological, or social condition that could interfere with adherence to the study No known or suspected allergy to the investigational agent or to any agent given concurrently No presence of asthenia or rash > CTC grade 1 at enrollment Must be registered in a national health-care system PRIOR CONCURRENT THERAPY: No prior orthotopic liver transplantation Not a candidate for orthotopic liver transplantation No prior systemic or loco-regional treatment for HCC No prior organ allograft No treatment with any other investigational medicinal product within the past 28 days No concurrent treatment with full-dose anticoagulants Deep-vein or catheter-associated thrombosis prophylaxis allowed Warfarin or heparin therapy allowed if the coagulation parameters were within the acceptable ranges prior to initiation of anticoagulant therapy No concurrent or chronic co-administration of CYP3A4 inducers (e.g., rifampin, Hypericum perforatum, phenytoin, carbamazepine, phenobarbital, or dexamethasone)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: sorafenib tosylate|nan|
|Other: laboratory biomarker analysis|nan|
|Procedure: neoadjuvant therapy|nan|
|Procedure: therapeutic conventional surgery|nan|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antiangiogenic effects of sorafenib tosylate |  |  | 
| Significant pathological changes |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic findings in sorafenib tosylate pre-treated patients undergoing surgical resection for hepatocellular carcinoma |  |  | 
| Number of R0 resections |  |  | 
| Correlations between baseline patient characteristics, cancer biomarkers, and outcome variables and resected tumors |  |  | 
| Plasma biomarkers at baseline, day 28, and the day before surgery |  |  | 
| Safety profile of sorafenib tosylate |  |  | 
| Tolerance of liver resection after sorafenib tosylate treatment |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult primary hepatocellular carcinoma, localized resectable adult primary liver cancer