RATIONALE: Drugs used in chemotherapy, such as liposomal doxorubicin, cisplatin, and mitomycin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. Chemoembolization kills tumor cells by blocking the blood flow to the tumor and keeping chemotherapy drugs near the tumor. Monoclonal antibodies, such as bevacizumab, can kill any tumor cells that are left after chemoembolization by blocking their ability to grow and spread.

PURPOSE: This randomized phase II trial is studying to see if chemoembolization followed by bevacizumab works better than chemoembolization alone in treating patients who have liver cancer that cannot be removed with surgery.

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

Further Study Details: 

OBJECTIVES:

• Compare neovessel formation at 8 and 14 weeks after hepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma treated with bevacizumab vs no bevacizumab (observation after chemoembolization only).
• Compare time to progression, objective response rate, and tumor marker progression in patients treated with these regimens.
• Determine the pharmacokinetics of bevacizumab in patients with liver function impairment.
• Determine the toxic effects of this drug in these patients.
• Compare the cancer biomarker pattern of peripheral blood cells and plasma before and after chemoembolization in patients treated with these regimens.

OUTLINE: This is a randomized, open-label study. Patients are randomized to 1 of 2 treatment arms.

• Chemoembolization: All patients receive hepatic artery chemotherapy comprising doxorubicin HCl liposome, cisplatin, and mitomycin on day 8 and possibly on day 92.
• Arm I: Patients receive bevacizumab IV over 30-90 minutes once every 2 weeks beginning 1 week prior to the first chemoembolization. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients do not receive bevacizumab. Patients may cross-over to arm I if recurrent tumor is evident at week 14 by CT scan or MRI or a 50% or greater increase in AFP level has occurred since day 8 chemoembolization. Patients then receive bevacizumab as in arm I.

PROJECTED ACCRUAL: A total of 30 patients (15 per treatment arm) will be accrued for this study.

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

Criteria

DISEASE CHARACTERISTICS:

• Histologically, cytologically, or serologically confirmed hepatocellular carcinoma
• 1-4 lesions
• Involvement of 1 or both liver lobes
• Measurable disease by CT scan or MRI that does not exceed 50% of the liver parenchyma
• Clinical candidate for chemoembolization with at least 1 lesion 3 cm or more in longest diameter
• Unresectable disease due to any of the following:
• Multifocality
• Advanced cirrhosis
• Comorbidity
• Refusal of surgery
• Prior liver-directed therapy such as chemoembolization, radiofrequency ablation, cryoablation, or ethanol injection is allowed if the following criteria are met:
• Treated lesion remains inactive by CT scan or MRI
• New lesions are distinct from the previously treated lesion
• Patients awaiting cadaveric or orthotopic liver transplantation are eligible, but must have a model for end-stage liver disease priority score of less than 20 points
• Child-Pugh class A or B cirrhosis
• No fibrolamellar histology
• No extrahepatic disease
• No thrombosis of the main portal vein
• No prior or concurrent CNS disease (e.g., primary brain tumor or brain metastases)

PATIENT CHARACTERISTICS: Age

• Adult

Performance status

• ECOG 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• No bleeding diathesis or coagulopathy
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 60,000/mm^3
• Hemoglobin at least 8.5 g/dL (transfusion allowed)

Hepatic

• See Disease Characteristics
• INR no greater than 1.5
• Bilirubin no greater than 2.5 mg/dL
• AST or ALT no greater than 5 times upper limit of normal

Renal

• No proteinuria
• No clinically significant impairment of renal function
• Creatinine no greater than 2 mg/dL OR
• Creatinine clearance at least 45 mL/min

Cardiovascular

• No prior stroke
• No clinically significant cardiovascular disease
• No uncontrolled hypertension
• No prior myocardial infarction
• No unstable angina
• No New York Heart Association class II-IV congestive heart failure
• No serious cardiac arrhythmia requiring medication
• No grade II or greater peripheral vascular disease within the past year

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No absolute contraindications to doxorubicin, mitomycin, cisplatin, iodinated contrast material, microfibrillar collagen hemostat, or dexamethasone
• No other active malignancies within the past year except nonmelanoma skin cancer or carcinoma in situ
• No uncontrolled seizures
• No significant traumatic injury within the past 4 weeks
• No serious nonhealing wound, ulcer, or bone fracture
• No other disease, metabolic dysfunction, physical exam finding, or clinical laboratory finding that would preclude study participation

PRIOR CONCURRENT THERAPY: Biologic therapy

• Prior immunotherapy allowed
• No prior antiangiogenesis therapy
• No other concurrent immunotherapy

Chemotherapy

• See Disease Characteristics
• Prior systemic chemotherapy allowed
• No other concurrent chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No concurrent radiotherapy

Surgery

• At least 4 weeks since prior major surgical procedure or open biopsy
• At least 1 week since prior fine needle aspiration
• Prior liver resection allowed
• No prior liver transplantation
• No anticipated need for major surgery within 3 months of study

Other

• At least 10 days since prior full-dose oral or parenteral anticoagulants (except as required to maintain patency of pre-existing, permanent indwelling IV catheters) or thrombolytic agents
• At least 4 weeks since prior participation in another experimental drug study
• No concurrent warfarin or thrombolytic agents
• No chronic, daily treatment with aspirin (greater than 325 mg/day) or nonsteroidal anti-inflammatory medications (of the kind known to inhibit platelet function at doses used to treat chronic inflammatory diseases)
• No concurrent participation in another experimental drug study
• No other concurrent investigational agents

California
      Jonsson Comprehensive Cancer Center, UCLA, Los Angeles,  California,  90095-1781,  United States; Recruiting

Study chairs or principal investigators

Carolyn Britten, MD,  Principal Investigator,  Jonsson Comprehensive Cancer Center   

Study ID Numbers:  CDR0000258045; UCLA-0206060; NCI-G02-2124; NCT00049322
Record last reviewed:  February 2005
Last Updated:  March 3, 2005
Record first received:  November 12, 2002
ClinicalTrials.gov Identifier:  NCT00049322
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08