This phase II trial is studying how well giving bevacizumab together with erlotinib works in treating patients with advanced liver cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and erlotinib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving bevacizumab together with erlotinib may kill more tumor cells

PRIMARY OBJECTIVES:

I. Evaluate the objective response rate in patients with advanced hepatocellular carcinoma treated with bevacizumab and erlotinib.

SECONDARY OBJECTIVES:

I. Evaluate the time to progression in patients treated with this regimen. II. Evaluate the overall and progression-free survival of patients treated with this regimen.

III. Evaluate the adverse events in patients treated with this regimen.

TERTIARY OBJECTIVES:

I. Determine the presence of epidermal growth factor receptor (EGFR) mutations in tumor tissue and correlate this with response rate, progression, and survival in patients treated with this regimen.

II. Evaluate the expression of molecules involved in EGFR signal transduction, including EGFR, phosphorylated-EGFR, Akt, phosphorylated-Akt, mitogen-activated protein kinase (MAPK), phosphorylated-MAPK, and HER2/neu by immunohistochemistry (from tumor tissue) and correlate these with patient outcome measures.

III. Determine the levels of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor tissue as well as baseline plasma VEGF levels and correlate these with patient outcome measures.

OUTLINE: This is a multicenter study.

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral erlotinib hydrochloride once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo laboratory studies to determine epidermal growth factor receptor (EGFR) and phosphorylated-EGFR protein levels using initial diagnostic biopsy specimens by immunohistochemistry (IHC) for correlation with clinical outcome. Levels of proteins through which EGFR signals, including Akt, phosphorylated-Akt, mitogen-activated protein kinase (MAPK), and phosphorylated-MAPK, are also determined using initial diagnostic biopsy specimens by IHC and correlated with clinical outcome. Total and free serum vascular endothelial growth factor levels are determined at the start of study and prior to course 3 by enzyme-linked immunosorbent assays (ELISA).

After completion of study treatment, patients are followed periodically for up to 3 years.

Inclusion Criteria:

• Absolute neutrophil count >= 1,500/mm^3
• Creatinine =< 2 mg/dL
• Albumin >= 2.5 g/dL
• Total bilirubin =< upper limit of normal (ULN)
• aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times ULN
• Alkaline phosphatase =< 5 times ULN
• Urine protein:creatinine ratio < 1.0 OR 24-hour urine protein < 1,000 mg
• Not pregnant or nursing:

No nursing for >= 6 months after completion of study treatment

• Negative pregnancy test
• Fertile patients must use effective contraception during study and for >= 6 months after completion of study treatment
• No history of allergic reactions attributed to compounds of similar chemical or biological composition to bevacizumab or erlotinib hydrochloride
• No abnormalities of the cornea, including any of the following:

History of dry eye syndrome or Sjögren's syndrome; Congenital abnormality (e.g., Fuch's dystrophy); Abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal-Rose); Abnormal corneal sensitivity test (e.g., Schirmer test or similar tear production test)

• No stroke or transient ischemic attack within the past 6 months
• No uncontrolled high blood pressure, history of labile hypertension, or history of poor compliance with an antihypertensive regimen
• No unstable angina pectoris within the past 6 months
• No symptomatic congestive heart failure
• No myocardial infarction within the past 6 months
• No serious uncontrolled cardiac arrhythmias
• No uncontrolled diabetes mellitus
• No active or uncontrolled infection
• No impaired GI function or disease that may significantly alter the absorption of erlotinib hydrochloride (e.g., ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or bowel obstruction)
• Able to swallow tablets
• No psychiatric illness or social situation that would limit compliance with study requirements
• No history of nephrotic-range protein
• No history of bleeding diathesis
• No encephalopathy
• No serious nonhealing wounds, skin ulcers, or bone fractures
• No clinically significant peripheral vascular disease
• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• No history of a GI bleed that required procedural intervention (e.g., variceal banding, surgical shunt, transvenous intrahepatic porto-systemic shunt [TIPS]) within the past 3 months
• No significant traumatic injury within the past 28 days
• No other prior malignancy within the past 5 years except for the following:

Adequately treated basal cell or squamous cell skin cancer; Adequately treated in situ cervical cancer; Stage I or II cancer from which the patient is currently in complete remission; Stage I chronic lymphocytic leukemia

• Recovered from all therapy-related toxicities
• No more than 1 prior systemic or liver directed drug therapy including transarterial chemoembolization (TACE) (multiple TACEs will count as 1 prior regimen irrespective of their total numbers) that were used for HCC
• No chemotherapy for HCC within the past 4 weeks (6 weeks for nitrosoureas or mitomycin C)
• No biological therapy or immunotherapy for HCC within the past 4 weeks
• Prior surgery, regional therapy (e.g., transarterial embolization), liver transplantation, or other liver-directed ablative therapies of discrete lesions allowed provided any related progressive or recurrent disease is documented
• No cryotherapy, radiofrequency ablation, ethanol injection, or photodynamic therapy within the past 6 weeks:

Indicator lesions must be outside the area of prior treatment OR if the lesion is inside the area of prior treatment, there must be clear evidence of disease progression associated with that lesion

• No core biopsy within the past 7 days
• No radiotherapy within the past 4 weeks
• No prior antiangiogenesis agent or antiepidermal growth factor receptor drug
• No prior treatment with hepatic arterial infusion with chemotherapy or yttrium Y 90-labeled microspheres
• No other concurrent investigational agents
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent anticancer therapy
• Concurrent full-dose anticoagulants (e.g., warfarin) with international normalized ratio (INR) > 1.2 allowed provided the following criteria are met:

An in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant (or on a stable dose of low molecular weight heparin)

• AND (continued from above) No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels, gastrointestinal [GI] ulceration, or known varices)

• No concurrent major surgical procedures

• Histologically confirmed hepatocellular carcinoma (HCC):

  • No fibrolamellar subtype HCC
  • Advanced disease

• Not a candidate for surgical resection or liver transplantation

• Measurable disease:

  • Edges of the indicator lesion must be clearly distinct on CT scan
  • Lesions that measure at least 1 cm but less than 2 cm only must use spiral CT imaging for both pre- and post-treatment tumor assessments

• Child's Pugh classification A or B

• No primary brain tumor, brain metastasis, or other central nervous system (CNS) diseases

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Platelet count >= 75,000/mm^3

• No major surgery (e.g., laparotomy), open biopsy, or minor surgery (e.g., insertion of a vascular access device) within the past 4 weeks

• No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung

• No abdominal fistula, GI perforation, or intra-abdominal abscess within the past 28 days

• No concurrent prophylactic hematopoietic colony-stimulating factors