AZD6244 and Sorafenib in Advanced Hepatocellular Carcinoma

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