Sorafenib Tosylate and Chemoembolization With Doxorubicin Hydrochloride and Mitomycin in Treating Patients With Liver Cancer That Cannot Be Removed By Surgery

OBJECTIVES:

Primary

- To determine the safety of sorafenib tosylate when given in combination with
transarterial chemoembolization (TACE) comprising doxorubicin hydrochloride and
mitomycin C in patients with unresectable hepatocellular carcinoma.

Secondary

- To estimate the time to progression (TTP) in patients treated with this regimen.

- To estimate the overall survival (OS) of patients treated with this regimen.

- To explore correlative relationships between measures of serum VEGF in the
peri-procedure TACE period and changes with TACE and sorafenib tosylate as well as
patient outcomes (TTP and OS).

OUTLINE: This is a multicenter study.

Patients receive oral sorafenib tosylate twice daily on days 1-14. Patients then undergo
transarterial chemoembolization (TACE) comprising doxorubicin hydrochloride and mitomycin C
on days 17-19*. Patients then receive oral sorafenib tosylate twice daily beginning after
recovery from TACE and continuing in the absence of disease progression or unacceptable
toxicity.

NOTE: *A second course of TACE may be administered within 8 weeks after the first TACE
procedure.

Blood samples may be collected periodically for biomarker and pharmacokinetic analysis.

After completion of study treatment, patients are followed up at 3-4 weeks and then every 3
months for up to 3 years.

DISEASE CHARACTERISTICS:

- Diagnosis of hepatocellular carcinoma (HCC), as defined by 1 of the following:

- Tissue histology

- Recurrence of previously resected HCC does not require tissue confirmation
if there is clear radiographic recurrence, in the judgment of the
investigator

- AFP > 400 ng/mL with compatible mass on MRI

- Locally advanced disease

- Not eligible for surgical resection or immediate liver transplantation OR have refused
such procedures

- All disease must be amenable to embolization in one or two procedures

- Measurable disease, according to modified HCC RECIST criteria

- Must have radiographically documented measurable disease with at least one site
of disease that is unidimensionally measurable as ≥ 10 mm on MRI

- Lesions previously treated by radiofrequency ablation should not represent the
only site of measurable disease

- Childs-Pugh score ≤ 7

- No complete thrombosis of the main portal vein

- If unilateral portal vein thrombosis is present, must demonstrate radiographic
evidence of adequate flow to the lobe to be embolized

- No evidence of extrahepatic/metastatic disease, such as lymph node metastases, lung or
bone metastases, or peritoneal carcinomatosis

- Evidence of cirrhosis is acceptable as long as the lab parameters are met

- No known brain metastases

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Life expectancy ≥ 12 weeks

- Hemoglobin ≥ 9.0 g/dL

- ANC ≥ 1,500/mm³

- Platelet count ≥ 75,000/mm³

- Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 50 mL/min

- Total bilirubin ≤ 3 mg/dL

- ALT and AST ≤ 5 times ULN

- INR < 1.5

- Negative pregnancy test

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

- No other cancer within the past 3 years except for cervical carcinoma in situ,
previously treated basal cell carcinoma, or superficial bladder tumors (Ta, Tis, or
T1)

- No NYHA class III or IV congestive heart failure

- No unstable angina (anginal symptoms at rest) or new-onset angina within the past 3
months

- No myocardial infarction within the past 6 months

- No cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

- No uncontrolled hypertension (i.e., systolic BP > 150 mm Hg or diastolic BP > 90 mm
Hg, despite optimal medical management)

- No venous thrombotic or arterial embolic events (e.g., cerebrovascular accident,
including transient ischemic attacks or venous thromboembolism) within the past 6
months

- No pulmonary hemorrhage/bleeding event > CTCAE grade 2 within the past 12 weeks

- No other hemorrhage/bleeding event > CTCAE grade 3 within the past 12 weeks

- No variceal bleeding within past 12 weeks

- No known grade 2 or 3 esophageal varices (endoscopic evaluation is not required for
study entry)

- No evidence or history of bleeding diathesis or coagulopathy

- No significant traumatic injury within the past 12 weeks

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

- No significant proteinuria (i.e., proteinuria > 1+ on urine dipstick)

- No HIV positivity (by patient report)

- No active hepatitis B or C, unless patient has been on stable medications for ≥ 2
months

- No active clinically serious infections (> grade 2)

- No active gastrointestinal malabsorption problem

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

- No active drug or alcohol abuse

- No known severe hypersensitivity or suspected allergy to sorafenib tosylate, any of
its excipients, or other drugs used in this study

- No psychological, familial, sociological, or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule

PRIOR CONCURRENT THERAPY:

- No prior systemic therapy, embolic therapy, or radiotherapy for HCC (e.g.,
chemotherapy, transarterial chemoembolization, transarterial embolization, or 90Y
microspheres)

- At least 4 weeks since prior liver resection or ablative therapy and recovered

- No prior Raf/MEK/ERK-targeted therapy or VEGF-targeted therapy

- More than 4 weeks since prior participation in any investigational drug study

- More than 12 weeks since prior major surgery or open biopsy

- Prior core liver biopsy allowed

- No concurrent antiretroviral therapy for HIV

- No concurrent chronic anticoagulation (other than 1 mg of warfarin daily for port
patency)

- No concurrent St. John wort or rifampin

- No other concurrent anticancer therapy, radiotherapy, or investigational therapy