AZD6244 and Sorafenib in Advanced Hepatocellular Carcinoma

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

Eligibility Criteria:
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