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

OBJECTIVES:

Primary

- Determine the maximum tolerated dose of bevacizumab in combination with sorafenib
tosylate in patients with locally advanced or metastatic hepatocellular carcinoma.
(Phase I closed to accrual as of 11/03/2010)

- Determine time to progression in these patients. (Phase II)

Secondary

- Determine the safety of this regimen in these patients. (Phase I closed to accrual as
of 11/03/2010)

- Assess tolerability of this regimen in these patients. (Phase I closed to accrual as of
11/03/2010)

- Determine overall survival of these patients. (Phase II)

- Determine tumor response (at 6 months) in patients treated with this regimen. (Phase
II)

- Determine progression-free survival of these patients. (Phase II)

- Determine response rate in patients treated with this regimen. (Phase II)

- Assess the occurrence of adverse events in these patients. (Phase II)

Tertiary

- Determine the relationship between tumor biomarkers and circulating biomarkers of
vascular response and clinical outcome in patients treated with this regimen.

OUTLINE: This is a phase I, dose escalation study followed by a randomized phase II study.

- Phase I (closed to accrual as of 11/03/2010): Patients receive oral sorafenib tosylate
twice daily on days 1-28 and bevacizumab IV on days 1 and 15. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

- Phase II: Patients are stratified according to gender (female vs male), ECOG
performance status (0 vs 1), and Child-Pugh class (A vs B7). Patients are randomized to
1 of 2 treatment arms.

- Arm I: Patients receive oral sorafenib tosylate on days 1-28 twice daily and
bevacizumab IV on days 1 and 15.

- 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.

Blood samples are collected periodically for analysis of circulating endothelial cells and
circulating endothelial progenitor cells and angiogenic proteins in plasma by ELISA.

After completion of study treatment, patients are followed for 3 years.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed hepatocellular carcinoma

- Locally advanced or metastatic disease that is not amenable to treatment with
surgery or to orthotopic liver transplant

- Child Pugh class A or B7 disease

- Measurable disease

- No mixed cholangiocarcinoma/hepatocellular carcinoma

- No current or previously resected brain metastases

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Life expectancy ≥ 3 months

- ANC ≥ 1,200/mm³

- Platelet count ≥ 75,000/mm³

- Hemoglobin ≥ 9.0 g/dL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST ≤ 5 times ULN

- Alkaline phosphatase ≤ 5 times ULN

- Urine protein ≤ 1+ by urine protein:creatinine ratio OR 24-hour urine protein < 1 g

- QTc interval ≤ 500 msec on baseline EKG

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 2 weeks after
sorafenib tosylate and 6 months after bevacizumab

- None of the following risk factors for decreased LVEF:

- Prior treatment with anthracyclines

- History of myocardial infarction within the past 12 months

- No uncontrolled hypertension (defined as systolic blood pressure [BP] > 150 mm Hg or
diastolic BP > 100 mm Hg) despite optimal medical management

- No New York Heart Association class III-IV congestive heart failure

- No cardiac ventricular arrhythmias requiring antiarrhythmic therapy

- No history of hypertensive crisis or hypertensive encephalopathy

- No cardiac ventricular arrhythmia requiring anti-arrhythmic therapy within the past 6
months

- None of the following within the past 6 months:

- Transient ischemic attack

- Cerebrovascular accident

- Unstable angina or angina

- Clinically significant peripheral artery disease (i.e., claudication in less
than one block) or any other arterial thrombotic event

- Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess

- Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or
recent peripheral arterial thrombosis

- No active or recent history of hemoptysis (≥ ½ teaspoon of bright red blood per
episode) within the past 30 days

- No evidence of bleeding diathesis (greater than normal risk of bleeding) or
coagulopathy (in the absence of therapeutic anticoagulation)

- No significant traumatic injury within the past 4 weeks

- No serious or non-healing wound, ulcer, or bone fracture

- No uncontrolled intercurrent illness, including, but not limited to, ongoing or
active infection, or psychiatric illness/social situations that would limit
compliance with study requirements

- No other active malignancy within the past 3 years, except nonmelanotic skin cancer
or carcinoma in situ of the cervix

- No comorbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to bevacizumab or sorafenib tosylate

PRIOR CONCURRENT THERAPY:

- No prior systemic chemotherapy regimens for hepatocellular carcinoma

- No prior external beam radiation to the primary site

- No prior central thoracic radiation therapy (RT), including RT to the heart

- No prior radiation (if given for another malignancy) to ≥ 25% of the bone marrow

- At least 6 weeks since prior chemoembolization, radioembolization, radiofrequency
ablation, or other local ablative therapies

- More than 4 weeks since prior biologic, hormonal, or immune therapy

- More than 4 weeks since prior and no concurrent major surgical procedure or open
biopsy

- More than 7 days since prior core biopsy or other minor surgical procedure (placement
of a vascular access device allowed)

- No concurrent investigational agent which would be considered as a treatment for the
primary neoplasm

- No concurrent anticoagulants, except low-dose warfarin or heparin for deep venous
thrombosis prophylaxis

- No other concurrent treatment for prior malignancy (other than hormonal therapy)