Sorafenib and Vorinostat in Treating Patients With Advanced Liver Cancer

Outline: This is a dose-escalation study of vorinostat. The purpose of this research study is
to test the safety and effectiveness of a combination of two cancer drugs, sorafenib
(Nexavar) and vorinostat (Zolinza), in advanced liver cancer (hepatocellular carcinoma).
Advanced means that the cancer has spread too far to consider surgery. Approximately 19
people will take part in this study.

After enrollment of 6 patients at sorafenib 400 mg orally twice a day and vorinostat 300 mg
orally, only 2 of the 6 patients were evaluable for DLT (no DLTs). The other 4 patients were
not evaluable for DLT because of required dose modifications. Because of this dose
modification need, Cohort A has been modified to include 2 dose levels: Dose level A-1a
(sorafenib 400 mg orally twice a day and vorinostat 200 mg orally once a day) and dose level
A1 (sorafenib 400 mg orally twice a day with vorinostat 100 mg orally once a day). The
starting dose upon reopening after approval of this version will be dose level A-1a. Dose
level A1 will only be used if dose level A-1a is not tolerable.

Inclusion Criteria:

- Diagnosis of HCC by biopsy-proven pathologic diagnosis or by clinical criteria as
defined below:

* Clinical criteria to be met if patient has a history of cirrhosis or chronic
hepatitis B infection:

- Imaging abnormalities > 1 cm in size with classic enhancement by magnetic
resonance imaging (MRI) or triple-phase computed tomography (CT) scan

- Alpha-fetoprotein (AFP) of any value

- Performance status Eastern Cooperative Oncology Group (ECOG) =< 1

- If cirrhosis, Child-Pugh classification A or B

- Total bilirubin =< 3.0 mg/dL

- Creatinine =< 1.5 x upper limit of normal for the laboratory

- International normalized ratio (INR) =< 1.7 (if not due to anticoagulants)

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Platelets >= 80,000/mm^3

- Hemoglobin (Hgb) >= 8.5 g/dL (transfusion or erythropoietin-like substances not
permitted prior to baseline evaluation)

- Any prior therapies such as surgery, chemoembolization, radiofrequency ablation, and
alcohol injection are allowed as long as toxicity from such prior therapy is =< grade
1

- Prior sorafenib is allowed as long as toxicity from ongoing is ≤ grade 2 and prior
intolerance of 400 mg sorafenib PO daily is felt amenable, by the principal
investigator, to supportive care measures or dose modifications.

- Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) criteria version (v) 1.1 mRECIST or elevated AFP

- Ability to understand and willingness to sign a written informed consent; a signed
informed consent must be obtained prior to any study specific procedures

- Women of childbearing potential must have a negative pregnancy test performed within 2
weeks prior to the start of treatment

- Women of childbearing potential and men must agree to use a medically accepted form of
birth control for the duration of study participation and for 4 months following
completion of study treatment

Exclusion Criteria:

- Candidate for curative therapy including surgical resection or orthotopic liver
transplantation

- Known central nervous system metastasis

- Any investigational agent within 4 weeks of first dose of study treatment

- Known intolerance of vorinostat

- Unable to swallow medication

- Unable to swallow medication; suspected malabsorption

- Active alcohol abuse

- Contraindication to antiangiogenic agents, including:

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

- Any other hemorrhage/bleeding event >= grade 3 within 4 weeks of first dose of
study treatment

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

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months; hepatic portal vein thrombus is not
considered an exclusion criterion

- Major cardiac dysfunction, such as uncontrolled angina, congestive heart failure with
New York Heart Association (NYHA) class III or higher, known left ventricular ejection
fraction less than 40%

- Systolic blood pressure > 160 mmHg or diastolic pressure > 90 mmHg despite optimal
medical management

- Significant lung disease (oxygen [O2] saturation less than 88% in room air)

- Serious uncontrolled infection; known human immunodeficiency virus
(HIV)-seropositivity requiring retroviral therapy, or diagnosis of acquired immune
deficiency syndrome (AIDS); diagnosis of chronic hepatitis B or C allowed

- Medical, psychological, or social conditions that, in the opinion of the investigator,
may increase the patient's risk or interfere with the patient's participation in the
study or hinder evaluation of the study results