Sorafenib With Capecitabine for Patients With Measurable Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC), also known as primary liver cancer, is the most common form
of liver cancer and is responsible for 80 percent of the primary malignant liver tumors in
adults. It is the fifth most common cancer in the world. HCC disproportionately affects men,
with four times as many men developing the disease as women. In 2002, approximately 626,000
cases of HCC were reported worldwide (15,000 in the United States and 53,600 in Europe), and
more than 600,000 deaths (about 13,000 Americans and 57,000 Europeans) due to HCC were
reported. The five-year relative survival rate is about seven percent.

The Gem-Ox regimen has been used in the treatment of pancreatic cancer with encouraging
results. Preliminary results of the Gem-Ox combination have been encouraging as well.Based
on these observations the possibility of adding bevacizumab, a monoclonal antibody against
VEGF, is being studied by other investigators. However, the combination of GEM-OX with
bevacizumab is unlikely to be tolerated by HCC patients with Child-Pugh class B and C liver
cirrhosis especially those with significant thrombocytopenia.It would seem therefore that
the agents that could be tolerated by cirrhotic patients with advanced HCC would include
capecitabine, erlotinib and sorafenib. We propose this phase II trial of sorafenib +
capecitabine combination in patients with HCC and advanced liver cirrhosis who have a
platelet count of ≥ 40,000 and a Child-Pugh (C-P) class A-and B liver cirrhosis with a life
expectancy of ≥16 weeks.

Inclusion Criteria:

Histologic diagnosis of hepatocellular carcinoma The lesion or lesions are not resectable
with curative intent. Prior loco-regional treatment (resection, RFA, chemoembolization) is
allowed.

Adequate bone marrow function:

- Absolute neutrophil count (AGC) >1500/µL

- Platelet count >60,000 /µL

Renal function:

- Serum creatinine < 2.0 mg/dl, and a calculated CCT of > 30 mL/min. Hepatic
function:(Patients with a Child-Pugh (C-P) class A-B)

- Bilirubin < 2.8 mg/dl (provided the Child-Pugh class of liver cirrhosis is A or B (7)
(ie. The Child-Pugh score is only 7 points)

- ALT and AST ≤ 5.0 times the ULN • Hemoglobin > 8.5 g/dl

ECOG/Zubrod/SWOG Performance Status = 0>1 Life expectancy > 16 weeks Male or female' age
>18 years Patients of childbearing potential must be using an effective means of
contraception.

INR < 1.5 or a PT/PTT within normal limits.

Exclusion Criteria:

- Any prior systemic therapy including chemotherapy of targeted agents

- Uncontrolled ascites defined as not easily controlled by stable doses of diuretics.

- Pregnant or lactating females

- Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have
unstable angina (anginal symptoms at rest) or new onset angina (began within the last
3 months) or myocardial infarction within the past 6 months.

- Uncontrolled' clinically significant dysrhythmia

- History of prior malignancy within the prior 3 years, with the exception of
non-melanoma carcinomas of the skin, carcinoma in situ of the cervix or breast, Rai
Stage I chronic lymphocytic leukemia and superficial bladder cancer.

- Prior radiotherapy to an indicator lesion unless there is objective evidence of tumor
growth in that lesion

- Uncontrolled metastatic disease of the central nervous system

- Radiotherapy within the 2 weeks before Cycle 1' Day 1

- Surgery within the 2 weeks before Cycle 1' Day 1

- Any co morbid condition that' in the view of the attending physician' renders the
patient at high risk from treatment complications.

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

- Known human immunodeficiency virus (HIV) infection.

- Patients with chronic Hepatitis B or C infections are eligible.

- Active clinically serious infection > CTCAE Grade 2.

- 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.

- Evidence or history of bleeding diathesis or coagulopathy.

- Use of St. John's Wort or rifampin (rifampicin).

- Known or suspected allergy to sorafenib or any agent given in the course of this
trial.

- Any condition that impairs patient's ability to swallow whole pills.

- Any malabsorption problem.