Effectiveness and Safety Study of TACE Plus Oral Sorafenib for Unresectable HCC

The proposed study will make an important contribution to understanding not only the safety
and efficacy of sorafenib in addition to TACE in patients diagnosed with unresectable HCC,
but this will also be the first clinical trial with sorafenib to assess the effects of this
novel therapy on HRQL. Understanding the effects of sorafenib on HRQL is critical in the
treatment of HCC secondary to the modest benefits in survival that have been reported with
conventional therapies. Our team has one of the largest experiences in evaluating HRQL in
patients diagnosed with unresectable hepatocellular carcinoma. We have previously reported
on alternative methods of evaluating HRQL, solutions for missing data in clinical trials as
well as tested statistical and clinically meaningful differences, within and between
treatment groups, in clinical trials with patients diagnosed with hepatobiliary carcinoma.

Inclusion Criteria:

- Adult patients with HCC seen at UPMC will be enrolled in this study if they meet the
following eligibility criteria:

- Adults patients (≥ 18 years of age) with a diagnosis of HCC which is not amenable to
surgical resection or local ablative therapy

- Histological confirmed HCC or clinical/laboratory diagnosis of HCC or nodules larger
than 2 cm with typical vascular features or AFP > 200

- Patient must have quantifiable disease limited to the liver

- Patients must have at least one tumor lesion that meets both of the following
criteria:

- The lesion can be accurately measured in at least one dimension according to
RECIST criteria

- The lesion has not been previously treated with surgery, radiation therapy,
radiofrequency ablation, percutaneous ethanol or acetic acid injection, or
cryoablation.

- ECOG performance status (PS) <2

- No prior targeted antiangiogenic therapy. Metronomic chemotherapies are allowed. At
least 4 weeks since prior systemic chemotherapy

- At least 4 weeks since prior TACE

- At least 4 weeks since prior interferon

- Not pregnant

- No significant baseline liver dysfunction. Cirrhotic status of Child-Pugh class A
only

- No significant renal impairment (creatinine clearance < 30 mL/minute) or patients on
dialysis

- No current infections requiring antibiotic therapy

- Not on anticoagulation or suffering from a known bleeding disorder

- No unstable coronary artery disease or recent MI

- The following laboratory parameters:

- Platelet count ≥ 60,000/µL

- Hemoglobin ≥ 8.5 g/dL

- Total bilirubin ≤ 1.5 mg/dL

- ASL and AST ≤ 5 x upper limit of normal

- Serum creatinine ≤ 1.5 x upper limit of normal

- INR ≤ 1.5 or a Pt/PTT within normal limits

- Absolute neutrophil count (ANC) > 1,500/mm3

- Ability to understand the protocol and to agree to and sign a written informed
consent document

Exclusion Criteria:

- Previous or concurrent cancer that is distinct in primary site or histology from HCC
except cervical carcinoma in situ, treated basal-cell carcinoma of the skin,
superficial bladder tumors (Ta, Tis & T1), and any cancer curatively treated > 3
years prior to entry is permitted

- Renal failure requiring hemo- or peritoneal dialysis

- Child-Pugh B & C hepatic impairment

- History of cardiac disease: > NY Heart Association (NYHA) class 2 congestive heart
failure, active coronary artery disease, cardiac arrhythmias requiring
anti-arrhythmic therapy other than beta blockers or digoxin, and uncontrolled
hypertension. Myocardial infarction more than 6 months prior to study entry is
permitted.

- Active clinically serious infections (> CTCAEv3 grade 2)

- Known history of HIV

- Known central nervous system tumors including metastatic brain disease

- History of organ allograft

- Substance abuse (current), psychological, or social conditions that may interfere
with the patient's participation in the study or evaluation of the study results.

- Known or suspected allergy to the investigational agents or any agent given in
association with this trial.

- Patients unable to swallow oral medications.

- Pregnant or breast-feeding patients. Women of childbearing potential must have a
negative pregnancy test performed within seven days prior to the start of the study
drug. Both men and women enrolled in this trial must use adequate barrier birth
control measures during the course of the trial.

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic
blood pressure > 90 mmHg, despite optimal medical management

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months

- Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of
study drug

- Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of
study drug

- Serious non-healing wound, ulcer, or bone fracture

Excluded therapies and medications, previous and concomitant:

- Prior use of Raf-kinase inhibitors (RKI), VEGF inhibitors, MEK inhibitors, or
farnesyl transferase inhibitors

- Major surgery within 6 weeks of start of study drug

- Radiotherapy during study or within 3 weeks prior to start of study drug.

- Use of biologic response modifiers such as granulocyte colony-stimulating factor
(G-CSF) within 3 weeks prior to study entry.

- Autologous bone marrow transplant or stem cell rescue within four months of study
drug initiation

- Concomitant treatment with rifampin or St. John's wort.