The phase II portion was not conducted due to funding issue.

This will be a phase I/II clinical trial testing the combination of sorafenib and AZD6244 in advanced hepatocellular carcinoma with Childs A liver cirrhosis. The aim of the phase I portion is to determine appropriate dose of this drug combination. The phase 2 study will look at effectiveness and safety of this drug combination

Patients with unresectable BCLC Stage B/C hepatocellular carcinoma that is biopsy-proven ( histology or cytology from prior tumor biopsy specimen is acceptable Patients without prior systemic treatment ( chemotherapy or molecular targeted therapy) except prior adjuvant therapy, if given more than 6 months ago Child-Pugh class A only ECOG performance status 0 or 1

Inclusion Criteria:

• Patients with unresectable BCLC Stage B/C hepatocellular carcinoma that is biopsy-proven ( histology or cytology from prior tumor biopsy specimen is acceptable)
• Patients without prior systemic treatment ( chemotherapy or molecular targeted therapy) except prior adjuvant therapy, if given more than 6 months ago
• Patients who had prior local therapy ( TACE; PEI; RFA) more than 4 weeks prior to study entry
• No radiotherapy within 4 weeks before entry
• Child-Pugh class A only ( Appendix A)
• Age 21 years and older
• ECOG performance status 0 or 1 ( Appendix A)
• Life expectancy > 3 months.
• Patients must have normal organ and marrow function as defined below:

Absolute neutrophil count > 1.5 x 109/L;Platelets> 75 x 109/L; Haemoglobin > 9.0g/dl;Total bilirubin < 51umol/L ( 3 mg /dL); AST(SGOT)/ALT(SGPT) < 5 X institutional ULN; Creatinine 1.5 ULN; INR <1.7 or prothrombin time ( PT) <4 seconds above ULN; Left ventricular ejection fraction (LVEF) >50%

• Measurable disease according to RECIST. A lesion which has previously been locally treated (including TACE or RFA) is eligible as long as there is evidence of disease progression
• Suitable for oral administration of drug
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Prior systemic therapy including sorafenib or a MEK inhibitor or sunitinib or other investigational drugs
• Any prior local therapy ( surgery, radiation therapy, hepatic arterial embolization, or cryoablation) within 4 weeks of study entry.
• Prior liver transplant
• NCI CTCAE grade > 3 hemorrhage within 4 weeks of starting study treatment, or documented variceal hemorrhage of any grade within 12 months of study entry (as documented on endoscopy)
• Presence of esophageal varices (> Grade 2) at risk of bleeding and/or serious or non-healing wound/ulcer ( as documented by endoscopy)
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of study entry
• Patients with underlying inflammatory bowel disease, partial or complete bowel obstruction or chronic diarrhea
• Any of the following within the 12 months prior to study drug administration: severe/unstable angina, myocardial infarction, coronary artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, including transient ischemic attack, or pulmonary embolism.
• History of cardiac disease:
• active congestive heart failure
• cardiac arrythmias of NCI CTCAE grade >2 or requiring pacemaker
• uncontrolled hypertension
• cardiomyopathy
• atrial fibrillation rate >100bpm
• Patients with factors that increase the risk of QT prolongation or arrhythmic events ( hypokalemia, family history of long QT interval syndrome) or QTc interval of > 450ms for males or > 470ms for females on screening