Bevacizumab in Treating Patients With Unresectable Nonmetastatic Liver Cancer

Study Overview
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Brief Summary
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This phase II trial is to see if bevacizumab works in treating patients who have unresectable nonmetastatic liver cancer that has not spread to the main portal vein. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or deliver cancer-killing substances to them.

Detailed Description
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OBJECTIVES: I. Determine the efficacy of bevacizumab, in terms of progression-free survival and disease stability and response, in patients with unresectable nonmetastatic hepatocellular cancer (HCC) without main portal vein invasion. II. Determine the safety of this drug in these patients. III. Assess tumor vascular perfusion kinetics, by dynamic gadolinium-enhanced MRI, in patients before and after treatment with this regimen. IV. Determine the effect of vascular endothelial growth factor (VEGF)-inhibition by this drug on circulating levels of VEGF and related cytokines that also contribute to HCC pathogenesis (including bFGF, TGF-alpha, and IGF-II) and on potential alterations of these levels on prognostic variables in these patients. V. Determine the effect of VEGF-inhibition by this drug on hepatic function and hepatitis viral activity in cirrhosis in these patients. OUTLINE: This is a multicenter, pilot study. Patients receive bevacizumab IV over 30-90 minutes on day 1. Treatment continues every 2 weeks in the absence of disease progression or unacceptable toxicity. PROJECTED ACCRUAL: A total of 18-46 patients will be accrued for this study.

Official Title
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Bevacizumab (RhuMAB-VEGF) In Hepatocellular Cancer For Patients With Unresectable Tumor (Without Invasion Of The Main Portal Vein Or Metastatic Disease) A Phase II Study

Conditions
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Adult Primary Hepatocellular Carcinoma, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

Intervention / Treatment
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* Biological: bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed hepatocellular carcinoma Confirmed by needle aspirate, biopsy, or prior surgical resection specimen Clinically confirmed hepatocellular carcinoma defined as follows: Cirrhosis or chronic hepatitis B or C virus infection, with 1 or more hypervascular liver masses more than 2 cm Alpha-fetoprotein (AFP) greater than 400 ng/mL OR greater than 3 times normal and doubling in value during the past 3 months Deemed unresectable Prior surgical resection allowed Recurrence after hepatic resection or other procedure allowed Tumor that extends into branches of the portal or hepatic veins allowed No tumor invading the main portal vein (portal trunk) or inferior vena cava No tumor occupying more than 50% of the liver volume Enlargement/involvement of regional lymph nodes allowed At least 1 unidimensionally measurable lesion at least 20 mm No poorly defined lesions No vague hypervascular patches Child-Pugh class A or compensated Child-Pugh class B liver dysfunction No Child-Pugh class C or uncompensated class B indicated by active encephalopathy, persistent ascites, or prothrombin time greater than 1.5 times normal Prior ascites allowed if manageable with diuretics alone No repeated paracentesis (more than 1 per month) No extrahepatic metastasis No documented brain metastases No history or clinical evidence of CNS disease (e.g., primary brain tumor, seizures uncontrolled with standard medical therapy, or history of stroke) Performance status - ECOG 0-2 Absolute neutrophil count greater than 1,500/mm^3 Hemoglobin at least 8 g/dL Platelet count at least 75,000/mm^3 No prior serious bleeding event (unrelated to liver disease) No bleeding diathesis No coagulopathy Bilirubin no greater than 3 mg/dL Transaminases less than 5 times upper limit of normal (ULN) Albumin at least 2.5 mg/dL PTT less than 4 seconds above ULN INR less than 1.5 (for patients receiving warfarin) Creatinine less than 1.5 g/dL Urine protein less than 500 mg/24hrs* Exclusion criteria: No thromboembolic event within the past 12 months No clinically significant cardiovascular disease Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No active infection requiring parenteral antibiotics No serious non-healing wound/ulcer or bone fracture No variceal bleeding within the past 6 months No malignancy within the past 5 years except localized nonmelanoma skin cancer No ongoing psychiatric or social situation that would preclude study compliance No known hypersensitivity to Chinese hamster ovary cell products No known hypersensitivity to other recombinant human antibodies No more than 1 prior biologic therapy No concurrent interferon No concurrent interleukin-2 No more than 1 prior antineoplastic chemotherapy At least 4 weeks since prior invasive surgery, including open biopsy At least 2 weeks since prior needle biopsy (core or fine-needle aspirate) No concurrent hepatic transplant At least 4 weeks since prior anticancer therapy No concurrent platelet-stimulating factors (e.g., oprelvekin) No concurrent full-dose anticoagulants or thrombolytic agents (except as required to maintain patency of pre-existing, permanent indwelling IV catheters) No chronic daily antiplatelet drugs (e.g., aspirin doses of 325 mg/day or higher or non-steroidal anti-inflammatory drugs)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (bevacizumab)<br>Patients receive bevacizumab IV over 30-90 minutes on day 1. Treatment continues every 2 weeks in the absence of disease progression or unacceptable toxicity. | Biological: bevacizumab<br>* Given orally<br>* Other names: rhuMAb VEGF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival |  | At 6 months | 
| Disease Response | MRI scan is required at weeks 8, 16 and then every 12 weeks until disease progression. Per Response Evaluation Criteria in Solid Tumors (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | MRI is required at weeks 8, 16 and then every 12 weeks until disease progression | 
| Mean Arterial Enhancement, Per Lesion, as Determined by Dynamic Gadolinium-enhanced Magnetic Resonance Imaging (MRI), Before and Following Bevacizumab Therapy. |  | Baseline and 8 weeks after bevacizumab therapy | 
| Assessment on Circulating Levels of VEGF Which Also Contribute to HCC Pathogenesis and on Potential Alterations of These Levels in the Setting of VEGF-inhibition |  | During treatment | 
| To Collect Information on Hepatic Function and Hepatitis Viral Activity in Cirrhosis and Upon Potential Alterations in the Setting of VEGF-inhibition |  | During and after treatment |