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

Study Overview
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Brief Summary
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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. Drugs used in chemotherapy, such as gemcitabine hydrochloride and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether sorafenib tosylate is more effective when given with or without gemcitabine hydrochloride and oxaliplatin in treating patients with liver cancer. PURPOSE: This randomized phase II trial is studying sorafenib tosylate to see how well it works when given with or without gemcitabine hydrochloride and oxaliplatin in treating patients with locally advanced, unresectable, or metastatic liver cancer.

Detailed Description
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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.

Official Title
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Randomized Phase II Trial Assessing the Combination of Nexavar® (Sorafenib), and Gemcitabine/Oxaliplatin in Patients Treated for Advanced (Unresectable/Metastatic) Hepatocellular Carcinoma.

Conditions
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Liver Cancer

Intervention / Treatment
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* Drug: gemcitabine hydrochloride
* Drug: oxaliplatin
* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Randomized
Intervention Model: Parallel Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Drug: sorafenib tosylate<br>* Given orally.<br>|
| Experimental: Arm II<br>Patients receive oral sorafenib tosylate twice daily on days 1-14. | Drug: gemcitabine hydrochloride<br>* Given IV<br>Drug: oxaliplatin<br>* Given IV<br>Drug: sorafenib tosylate<br>* Given orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response according to RECIST criteria |  | 18 months | 
| Progression-free survival |  | 18 months | 

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