RATIONALE: 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.

PURPOSE: 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.

Condition	Treatment or Intervention	Phase
adult primary hepatocellular carcinoma recurrent adult primary liver cancer localized unresectable adult primary liver cancer	Drug: bevacizumab  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: antibody therapy  Procedure: biological response modifier therapy  Procedure: growth factor antagonist therapy  Procedure: monoclonal antibody therapy	Phase II

Further Study Details: 

OBJECTIVES:

• 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.
• Determine the safety of this drug in these patients.
• Assess tumor vascular perfusion kinetics, by dynamic gadolinium-enhanced MRI, in patients before and after treatment with this regimen.
• 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.
• 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.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed hepatocellular carcinoma
• Confirmed by needle aspirate, biopsy, or prior surgical resection specimen OR
• 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 (porta-hepatis) 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)

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• 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

Hepatic

• 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)

Renal

• Creatinine less than 1.5 g/dL
• Urine protein less than 500 mg/24hrs* NOTE: *If initial urinalysis indicates 0 protein, 24-hour urine protein evaluation is not required

Cardiovascular

• No thromboembolic event within the past 12 months including the following:
• Stroke
• Myocardial infarction
• Transient ischemic attack
• Angina
• No clinically significant cardiovascular disease including the following:
• Uncontrolled hypertension
• Unstable angina
• Congestive heart failure (New York Heart Association grade II-IV)
• Serious cardiac arrhythmia requiring medication
• Grade II or greater peripheral vascular disease within the past year
• No deep vein thrombosis within the past year

Pulmonary

• No pulmonary embolus within the past year

Other

• 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
• Prior esophageal varices allowed provided the following criteria are met:
• Specific therapy (i.e., banding or sclerotherapy) has been received
• No bleeding within the past 6 months
• Varices remaining obliterated, minimal, or grade 1 (involving less than 33% of lumenal diameter)* by re-endoscopy within the past 4 weeks NOTE: *Varices greater than grade 1 must undergo additional banding and will be considered eligible upon obliteration of all varices
• 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

PRIOR CONCURRENT THERAPY: Biologic therapy

• No more than 1 prior biologic therapy
• No concurrent interferon
• No concurrent interleukin-2

Chemotherapy

• No more than 1 prior antineoplastic chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• See Disease Characteristics
• 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

Other

• 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)

New York
      Albert Einstein Cancer Center at Albert Einstein College of Medicine, Bronx,  New York,  10467,  United States; Recruiting
      Herbert Irving Comprehensive Cancer Center at Columbia University, New York,  New York,  10032,  United States; Recruiting
      Mount Sinai Medical Center, New York,  New York,  10029,  United States; Recruiting
      New York Weill Cornell Cancer Center at Cornell University, New York,  New York,  10021,  United States; Recruiting
      North Shore University Hospital, Manhasset,  New York,  11030,  United States; Recruiting
      NYU Cancer Institute at New York University Medical Center, New York,  New York,  10016,  United States; Recruiting

Study chairs or principal investigators

Jonathan Schwartz, MD,  Study Chair,  Mount Sinai Medical Center   

Study ID Numbers:  CDR0000270798; MTS-NCI-5611; NCI-5611; NCT00055692
Record last reviewed:  October 2004
Last Updated:  April 4, 2005
Record first received:  March 6, 2003
ClinicalTrials.gov Identifier:  NCT00055692
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08