Sorafenib Tosylate Before and After Hepatic Arterial Chemoembolization With Doxorubicin Hydrochloride and Mitomycin C in Treating Patients With Localized Liver Cancer That Cannot Be Removed by Surgery

OBJECTIVES:

Primary

- To evaluate the safety and tolerability of sorafenib tosylate therapy when administered
before and after doxorubicin hydrochloride-based hepatic arterial chemoembolization
(HACE) as assessed by NCI CTCAE v3.0 in patients with localized unresectable
hepatocellular carcinoma.

Secondary

- To determine if sorafenib tosylate decreases the number of HACE treatments required to
achieve radiologic tumor kill.

- To assess improvement in progression-free survival.

- To assess changes in monthly AFP levels in patients with AFP-producing tumors.

- To measure VEGF levels.

OUTLINE: Patients receive oral sorafenib tosylate twice daily on days 1-14. Beginning ≥ 3
days later, patients undergo hepatic arterial chemoembolization (HACE)* with doxorubicin
hydrochloride and mitomycin C. Beginning ≥ 3 days after the completion of HACE and/or once
liver function returns to baseline, patients resume sorafenib tosylate twice daily for up to
6 months in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients may undergo more than one HACE treatment.

Blood samples are collected periodically for further laboratory analysis.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed hepatocellular carcinoma (HCC)

- Single lesion > 6.5 cm; > 3 tumors, any tumor with a diameter > 4.5 cm; or a
cumulative tumor diameter > 8.0 cm

- Stage B (intermediate) disease according to the Barcelona Clinic Liver Cancer
(BCLC) classification system

- Unresectable, multinodular asymptomatic tumor

- No vascular invasion (including segmental portal invasion)

- No extrahepatic spread

- Stage C disease (according to the BCLC classification system) with portal vein
invasion that is limited to a sub-segmental branch of either the right or left
portal vein (i.e., sub-segmental portal vein invasion)

- Being considered for hepatic arterial embolization

- Must have ≥ 1 tumor lesion that can be accurately measured in ≥ 1 dimension according
to RECIST criteria

- The measurable lesion must not have been previously treated with local therapy
(e.g., surgery, radiotherapy, radiofrequency ablation, PEI, or cryoablation)

- Child Pugh class A-B7 liver function

- No diffuse HCC

- No unstable ascites

- No known brain metastasis or CNS disease

- Patients with neurological symptoms must undergo a CT scan/MRI of the brain to
exclude brain metastasis

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Life expectancy ≥ 12 weeks

- ANC ≥ 1,500/mm³

- Platelet count ≥ 75,000/mm³

- Hemoglobin ≥ 9.0 g/dL

- Total bilirubin ≤ 2 mg/dL

- ALT and AST ≤ 2.5 times upper limit of normal (ULN) (≤ 5 times ULN for patients with
liver involvement)

- Creatinine ≤ 1.5 mg/dL

- INR < 1.5 or PT/PTT normal

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 3 months after
completion of study treatment

- No cardiac disease, including any of the following:

- NYHA class III-IV congestive heart failure

- Unstable angina (anginal symptoms at rest) or new onset angina (within the past
3 months)

- Myocardial infarction within the past 6 months

- No cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

- No uncontrolled hypertension, defined as systolic BP > 150 mm Hg or diastolic BP > 90
mm Hg, despite optimal medical management

- No known HIV infection

- No active clinically serious infection > CTCAE grade 2, except hepatitis B or C

- No thrombolic or embolic event (e.g., cerebrovascular accident, including transient
ischemic attacks) within the past 6 months

- No pulmonary hemorrhage or bleeding event ≥ CTCAE grade 2 within the past 4 weeks

- No other hemorrhage or bleeding event ≥ CTCAE grade 3 within the past 4 weeks

- No clinically significant gastrointestinal bleeding within the past 30 days

- No serious non-healing wound, ulcer, or bone fracture

- No evidence or history of bleeding diathesis or coagulopathy

- No significant traumatic injury within the past 4 weeks

- No known or suspected allergy to sorafenib tosylate or any agent given in the course
of this study

- No condition that would impair the ability to swallow whole pills

- No malabsorption problem

- No porto-systemic shunt

- No renal failure

- No severe atheromatosis

- No encephalopathy ≥ grade 1

- No contraindication for any of the following:

- Arterial procedure (e.g., impaired clotting tests [e.g., platelet count <
50,000/mm³ or prothrombin activity < 50%])

- Systemic chemotherapy administration (e.g., serum bilirubin > 5 mg/dL, leukocyte
count < 3,000/mm³)

- Sorafenib tosylate administration

- No substance abuse or medical, psychological, or social condition that would
interfere with study participation or evaluation of study results

- No other prior or concurrent cancer, except cervical carcinoma in situ, treated basal
cell carcinoma, superficial bladder tumor (Ta, Tis, or T1), or cancer that was
curatively treated > 3 years ago

PRIOR CONCURRENT THERAPY:

- More than 4 weeks since prior surgery or open biopsy

- No prior systemic chemotherapy or targeted agents

- No concurrent St. John's wort or rifampin

- No concurrent therapy for hepatitis A, B, or C

- Concurrent anti-coagulation with warfarin or heparin allowed