Phase II Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma

INCLUSION CRITERIA

• Patients must have histologically diagnosed American Joint Committee on Cancer (AJCC) stage II, III, or IV hepatocellular carcinoma (HCC) not eligible for curative resection, transplantation, or ablative therapies
• Radiographically measurable disease by RECIST version 1.1 in at least one site not previously treated with chemoembolization, radioembolization, or other local ablative procedures (i.e. must have at least one measurable target lesion, either within the liver or in a measurable metastatic site); a new area of tumor progression within or adjacent to a previously-treated lesion, if clearly measurable by a Radiologist, is acceptable
• No prior systemic cytotoxic chemotherapy or targeted therapy (including sorafenib) for HCC
• Prior chemoembolization, local ablative therapies, or hepatic resection permitted if completed ≥ 4 weeks prior to study enrollment if patient has recovered with ≤ grade 1 toxicity and if measurable disease (criterion 2) 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.
• Age ≥ 18 years.
• Child-Pugh score of A or B with ≤ 7 points and meeting laboratory eligibility for all parameters
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy greater than 3 months
• Treatment with appropriate antiviral therapy for patients with active hepatitis B Virus (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 ≤ 150 mm Hg, diastolic ≤ 90 mm Hg)
• Baseline cholesterol must be = 1, 000/microliter (mcL) platelets ≥ 75,000/mcL hemoglobin ≥ 8.5 g/dL

Adequate hepatic function:

total bilirubin ≤ 2 mg/dL or ≤ 1.5 times ULN aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) & alanine aminotransferase (ALT) / serum glutamic-pyruvic transaminase (SGPT) ≤ 5 X upper limit of normal (ULN) International Normalized Ratio (INR) 150/90 mmHg).

• Uncontrolled hyperlipidemia (total cholesterol > 350 or triglycerides > 300).
• 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.
• Major surgical procedure less than 4 weeks from start of protocol treatment.
• 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. (Patients with history of malignancy are not considered to have a "currently active" malignancy if they have completed therapy and are now considered by their physician to be at less than 30% risk for relapse.)
• Uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, uncontrolled peripheral vascular disease, myocardial infarction within preceding 12 months, cerebrovascular accident within preceding 12 months, pulmonary disease impairing functional status or requiring oxygen, impairment in gastrointestinal function that may affect or alter absorption of oral medications (such as malabsorption or history of gastrectomy or bowel resection).
• Patients will be excluded if the