Sorafenib With or Without Gemcitabine and Oxaliplatin in Treating Patients With Locally Advanced, Unresectable, or Metastatic Liver Cancer

OBJECTIVES:

Primary

• Assess progression-free survival (RECIST) in patients with locally advanced, unresectable or metastatic hepatocellular carcinoma treated with sorafenib tosylate with vs without gemcitabine hydrochloride and oxaliplatin.

Secondary

• Evaluate the tolerability of these regimens in these patients.
• Determine the objective response rate (RECIST) in patients treated with these regimens.
• Assess the overall survival of patients treated with these regimens.
• Evaluate the pharmacokinetics of sorafenib tosylate.
• Assess biomarkers (e.g., pERK levels) associated with treatment response.
• Assess angiogenic response by functional imaging.

OUTLINE: This is a multicenter study. Patients are stratified according to performance status and CLIP score. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral sorafenib tosylate as in arm I. Patients also receive gemcitabine hydrochloride IV over 100 minutes on day 1 and oxaliplatin IV over 2 hours on day 2. Treatment with gemcitabine hydrochloride and oxaliplatin repeats every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oral sorafenib tosylate twice daily on days 1-14. In both arms, courses with sorafenib tosylate repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Blood samples and/ or tumor tissue samples may be collected for further analysis.

After completion of study therapy, patients are followed every 2 months until disease progression and then every 6 months thereafter.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed hepatocellular carcinoma not amenable to liver transplantation

• Locally advanced, unresectable, or metastatic disease
• At least 1 lesion accurately measured in ≥ 1 dimension according to RECIST criteria AND has not been previously treated with local therapy (e.g., intra-arterial chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation)

• No presence of bone metastasis only
• No known brain metastasis

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• Life expectancy > 12 weeks
• ANC > 1,500/mm^3
• WBC > 3,000/mm^3
• Platelet count ≥ 90,000/mm^3
• Hemoglobin > 10 g/dL
• Total protein ≥ 40%
• ALT or AST ≤ 1.5 times upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 times ULN
• Amylase and lipase < 1.5 times ULN
• Creatinine < 1.5 times ULN
• Creatinine clearance ≥ 60 mL/min
• Albumin ≥ 2.8 mg/dL
• INR ≤ 2.3
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during study and for up to 4 months for females and 6 months for males after completion of study treatment
• CLIP score 0-3
• No Child Pugh score B or C cirrhosis
• No known HIV positivity
• No other prior malignancy, except adequately treated or curative basal cell skin cancer or carcinoma in situ of the cervix
• No known or suspected allergy to the investigational agent or any agent given in association with this study
• No cardiovascular disease, including any of the following:

• Cardiac arrhythmia requiring antiarrhythmic therapy, except beta-blockers or digoxin for chronic atrial fibrillation
• Active coronary artery disease or ischemia
• Myocardial infarction within the past 6 months
• NYHA class II-IV congestive heart failure
• No uncontrolled hypertension
• No severe active bacterial or fungal infection > CTCAE v3.0 grade 2
• No peripheral neuropathy ≥ grade 2
• No condition that could affect the absorption of study drug, including any of the following:

• Malabsorption syndrome
• Disease significantly affecting gastrointestinal function
• Bowel obstruction or sub-obstruction
• No dysphagia or inability to swallow tablets
• No history of seizures requiring long-term antiepileptic treatment
• No unstable condition that would jeopardize safety or compliance with study including any of the following :

• Medical, psychological, or social conditions
• Substance abuse
• Legal incapacity or limited legal capacity
• No psychological, familial, social, or geographic reasons that would preclude clinical follow-up
• Must be registered in a social security program

PRIOR CONCURRENT THERAPY:

• No prior organ transplantation with immunosuppressive treatment
• No prior systemic chemotherapy or systemic antiangiogenic treatment for hepatocellular carcinoma
• No prior major resection of the stomach or proximal small bowel
• Prior anticoagulation therapy (e.g., warfarin or heparin) allowed with INR parameters within normal limit range
• At least 4 weeks since prior local therapy to lesions and treated lesions may not be selected as target lesions
• No concurrent or prior long-term treatment with CYP3A4 inducers (e.g., rifampin, hypericum perforatum, phenytoin, carbamazepine, phenobarbital, and dexamethasone)
• No concurrent antitumoral treatment, including tamoxifen, interferon, or somatostatin analogues
• No other concurrent experimental drugs or anticancer therapy