Chemoembolization and Bevacizumab in Treating Patients With Liver Cancer That Cannot Be Removed With Surgery

OBJECTIVES:

- Compare neovessel formation at 8 and 14 weeks after hepatic arterial chemoembolization
in patients with unresectable hepatocellular carcinoma treated with bevacizumab versus
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.

All patients receive hepatic artery chemotherapy (chemoembolization) comprising doxorubicin
HCl liposome, cisplatin, and mitomycin on day 8 and possibly on day 92. Patients are then
randomized to 1 of 2 treatment arms.

- 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 in arm II may cross-over receive
bevacizumab as in 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.

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

Inclusion Criteria:

- Age > 18 year old

- Histologically or cytologically documented HCC

- Patients must have bi-dimensional measurable disease by CT or MRI scan that does not
exceed 50% of the liver parenchyma

- Patients must be considered clinical candidates for chemoembolization, with at least
one lesion > 3cm and no lesion > 15cm in its longest diameter

- Patients awaiting cadaveric orthotopic liver transplantation are eligible if they
meet all other criteria. These patients must have a model for end-stage liver disease
priority score < 28 points at entry

- Cirrhosis Child-Pugh class A or B

- Patients with documented grad III varices or prior history of UGI bleeding will
require endoscopic evaluation prior to treatment under this protocol.

- Platelet count equal or greater than 60,000/μL

- Female patients must use effective contraception, be surgically sterile or be
postmenopausal; male patients must be using barrier contraception or be surgically
sterile

- Patients must be willing and able to comply with all study requirements and have
signed the informed consent

Exclusion Criteria:

- Previous history of liver transplantation

- Fibrolamellar histology

- Prior antiangiogenesis therapy

- Presence of extrahepatic disease

- Presence of biliary obstruction defined as biliary dilatation and total bilirubin >
2.5mg/dl

- Thrombosis of the main portal vein

- Absolute contraindications to doxorubicin, mitomycin-C, cisplatin, iodinated contrast
material, Avitene or dexamethasone treatment

- Other active malignancies during the past year (except for non-melanoma skin cancer
or in situ carcinomas)

- ECOG PS> 2 or life expectancy < 12 weeks

- History or evidence upon physical examination of CNS disease

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 0, or anticipation of need for major surgical procedure within 3 months
of study entry; fine needle aspirations within 7 days prior to Day 0

- Current or recent (within the 10 days prior to Day 0) use of full-dose oral or
parenteral anticoagulants (except as required to maintain patency of preexisting,
permanent indwelling IV catheters) or thrombolytic agent (for subjects receiving
warfarin, international normalized ration of < 1.5)

- Chronic, daily treatment with aspirin (> 325mg/day) or nonsteroidal anti-inflammatory
medications

- Positive pregnancy test or lactation

- Proteinuria at baseline or clinically significant impairment of renal function.
Subjects unexpectedly discovered to have > 1+ proteinuria at baseline should undergo
a 24-hour urine collection, which must be an adequate collection and must demonstrate
< 500 mg of protein/24 hr to allow participation in the study

- Serious, nonhealing wound, ulcer, or bone fracture

- Evidence of bleeding diathesis or coagulopathy

- Current or recent (within the 28 days prior to Day 0) participation in another
experimental drug study

- Clinically significant cardiovascular disease, New York Heart Association Grade II or
greater congestive heart failure, serious cardiac arrhythmia requiring medication, or
Grade II or greater peripheral vascular disease within 1 year prior to Day 0

- Prior history of hypertensive crisis of hypertensive encephalopathy

- History of abdominal fistula or gastrointestinal perforation within 6 months prior to
Day 1

- History of hemoptysis within 1 month prior to Day 1

- Significant vascular disease within 6 months prior to Day 1

- Screening clinical laboratory values:

- ANC of < 1500/μL

- INR of > 1.5

- Total bilirubin of > 2.5mg/dL

- AST or ALT > 5 times upper limit of normal

- Serum creatinine of > 2.0 mg/dL or creatinine clearance < 45 mL/min

- Hemoglobin of < 8.5 gm/dL

- History of other disease, metabolic dysfunction, physical examination finding, or
clinical laboratory finding giving reasonable suspicion of a disease or condition
that contraindicates use of an investigational drug or that might affect
interpretation of the results of the study or render the subject at high risk from
treatment complications