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