Bevacizumab and Erlotinib or Sorafenib as First-Line Therapy in Treating Patients With Advanced Liver Cancer

OBJECTIVES:

Primary

• To estimate the overall survival in patients with advanced hepatocellular carcinoma treated with bevacizumab and erlotinib hydrochloride vs sorafenib tosylate.

Secondary

• To estimate the event-free survival and tumor response rate of these patients.
• To evaluate the safety and tolerability of these regimens in these patients.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral erlotinib hydrochloride once daily on days 1-28.
• Arm II: Patients receive oral sorafenib tosylate twice daily on days 1-28. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 30 days and then every 3 months for 1 year.

DISEASE CHARACTERISTICS:

• Pathologically confirmed advanced hepatocellular carcinoma (HCC)

• Childs-Pugh class A
• CLIP score ≤ 5
• Not a candidate for curative surgical resection or loco-regional therapy
• Measurable disease as per RECIST 1.1 criteria, defined as ≥ 1 previously unirradiated, bidimensionally measurable lesion ≥ 20 mm by CT scan or MRI (triphasic spiral CT scan or MRI employing a "liver protocol" image capture technique required)

• Bone lesions, ascites, and pleural effusions are not considered measurable lesions
• No fibrolamellar HCC
• No known brain metastases
• No prior organ transplantation

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 75,000/mm³
• Hemoglobin ≥ 9 g/dL
• Transaminases ≤ 5 times upper limit of normal (ULN)
• Total bilirubin ≤ 2.0 times ULN
• PT ≤ 1.8 times ULN

• Prolonged INR allowed for patients who require full dose anticoagulation
• Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 45 mL/min
• Urine protein < 2+ by urine dipstick OR urine protein ≤ 1 g by 24-hour urine collection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 12 weeks after completion of study treatment
• Able to take and absorb oral medication
• No active infection requiring parenteral therapy
• No known HIV or AIDS
• No uncontrolled blood pressure (BP), defined as systolic BP ≥ 150 mm Hg and/or diastolic BP ≥ 100 mm Hg
• No uncontrolled or significant cardiovascular disease, including any of the following:

• Myocardial infarction within the past 6 months
• Uncontrolled angina within the past 6 months
• New York Heart Association class II-IV congestive heart failure
• Grade 3 cardiac valve dysfunction
• Cardiac arrhythmia not controlled by medication
• Stroke or transient ischemic attack within the past 6 months
• Arterial thrombotic event of any type within the past 6 months
• No significant or symptomatic vascular disease (e.g., aortic aneurysm, aortic dissection, or peripheral vascular disease) within the past 6 months
• No decompensated liver disease as evidenced by clinically significant ascites refractory to diuretic therapy, hepatic encephalopathy, or coagulopathy not corrected by conservative measures
• No grade 3 bleeding esophageal or gastric varices within the past 2 months

• Prior variceal bleeding allowed provided patient has undergone banding or sclerotherapy and there has been no evidence of bleeding for 2 months
• No gastric varices ≥ grade 2
• No hemoptysis (i.e., ≥ ½ teaspoon of bright red blood per episode) within the past month
• No evidence of bleeding diathesis or coagulopathy
• No concurrent uncontrolled illness, including, but not limited to, a history of or current evidence of unexplained nephrotic syndrome or other severe illness/disease that would preclude study participation
• No history of hypertensive crisis or hypertensive encephalopathy
• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
• No serious, non-healing wound, active ulcer, or untreated bone fracture
• No significant traumatic injury within the past 28 days
• No history of allergy to bevacizumab, erlotinib hydrochloride, sorafenib tosylate, or related compounds
• No other primary malignancy within the past 5 years, except carcinoma in situ of the cervix or urinary bladder or nonmelanoma skin cancer
• No mental incapacitation or psychiatric illness that would preclude study participation
• Not incarcerated or compulsorily detained (i.e., involuntarily incarcerated) for treatment of either a psychiatric or physical illness (e.g., infectious disease)

PRIOR CONCURRENT THERAPY:

• Prior surgery, local ablation, trans-arterial hepatic artery embolization, or trans-arterial chemoembolization are allowed provided the lesion(s) have progressed since treatment OR there are additional measurable, untreated lesions present
• No prior systemic therapy for HCC
• No prior organ transplantation
• More than 7 days since prior minor surgical procedures, fine needle aspirations, or core biopsies (excluding placement of a vascular access device)
• More than 28 days since any prior therapy
• More than 28 days since prior and no concurrent major surgical procedure or open biopsy
• More than 28 days since prior and no concurrent participation in another experimental drug study
• No other concurrent anticancer or antitumor therapy, including chemotherapy, radiotherapy, immunotherapy, or hormonal anticancer therapy
• No other concurrent investigational agents
• No concurrent warfarin (other types of anticoagulation allowed)