Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma

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 eligible 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.