Inclusion Criteria

• Histologically or clinically* diagnosed AJCC stage III or IV HCC not amenable to curative resection and with no prior systemic cytotoxic or molecularly-targeted therapies. *Clinical diagnosis is acceptable if tumor meets radiographic criteria.
• Age ≥ 18 years.
• Child-Pugh score A or score of B with 7 points only and bilirubin ≤ 2 mg/dL.
• ECOG performance status ≤ 2.
• Radiographically measurable disease in at least one site not previously treated with chemoembolization, radioembolization, or other local ablative procedures.
• Prior chemoembolization, local ablative therapies, or hepatic resection permitted if completed ≥ 6 weeks prior to study enrollment and if criterion 6 is present.
• Prior radiation for bone or brain metastases is permitted if patient is now asymptomatic and has completed all radiation and steroid therapy (if applicable) for brain or bone metastases ≥ 2 weeks prior to study enrollment.
• Treatment with appropriate antiviral therapy for patients with active HBV infection is required.
• Treatment for clinically-significant hyperglycemia, hyperlipidemia, or hypertension that develops on study is required.
• Baseline blood pressure must be adequately controlled with or without antihypertensive medications prior to enrollment (systolic < 140 mm Hg, diastolic < 90 mm Hg).
• Baseline cholesterol must be < 350 mg/dL and triglycerides < 300 mg/dL (with or without the use of antihyperlipidemic medications).
• Baseline fasting blood glucose must be ≤ 140 mg/dL and hemoglobin A1c less than 7% (with or without the use of anti-diabetic medications).
• Adequate baseline organ and marrow function as defined below:
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 75,000/mcL
• Hemoglobin ≥ 8.5 g/dL
• Total bilirubin ≤ 2 mg/dL or ≤ 1.5 times ULN
• AST(SGOT)/ALT(SGPT) ≤ 5 times ULN
• INR ≤ 1.5 times ULN
• Albumin ≥ 2.8 g/dL
• Creatinine ≤ 1.5 times ULN
• Able to tolerate oral therapy.
• Ability to give written informed consent and willingness to comply with the requirements of the protocol.
• Effective means of contraception are required in fertile, sexually-active patients.

Exclusion Criteria

• Mixed tumor histology or fibrolamellar variant tumors are excluded.
• Prior antiangiogenic therapy (including thalidomide, sorafenib, sunitinib, or bevacizumab).
• Prior treatment with mTOR inhibitor or other molecularly targeted therapy.
• Prior systemic cytotoxic therapies for HCC (chemoembolization is permitted if inclusion criteria are met).
• Treatment with other investigational agents.
• Immunosuppressive medications including systemic corticosteroids unless used for adrenal replacement, appetite stimulation, acute therapy for asthma or bronchitis exacerbation (≤ 2 weeks), or antiemesis.
• Patients with known HIV infection are excluded.
• Patients who have undergone liver transplantation are excluded.
• Symptomatic brain or bone metastases; prior radiation and/or steroid therapy for brain or bone metastases (if applicable) must be completed ≥ 2 weeks prior to study enrollment.
• History of seizure disorder requiring antiepileptic medication or brain metastases with seizures.
• Serious non-healing wound, ulcer, bone fracture, or abscess.
• Patients requiring chronic anticoagulation with warfarin are excluded. Patients treated with low molecular weight heparin or unfractionated heparin are eligibile if on a stable dose without evidence of clinically significant bleeding for at least 2 weeks prior to enrollment.
• Active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ.
• Uncontrolled intercurrent illness.
• No required concomitant medications with potential for significant interaction with study drugs.
• Any other condition that compromises compliance with the objectives and procedures of this protocol, as judged by the Study Chair, is also grounds for exclusion.