Sorafenib Tosylate With or Without Stereotactic Body Radiation Therapy in Treating Patients With Liver Cancer

PRIMARY OBJECTIVES:

I. To determine if stereotactic body radiation therapy (SBRT) improves overall survival in
hepatocellular carcinoma (HCC) patients treated with sorafenib (sorafenib tosylate).

SECONDARY OBJECTIVES:

I. To determine the difference in time to progression (TTP) and progression-free survival
(PFS) in HCC patients treated with sorafenib compared to SBRT followed by sorafenib.

II. To measure differences in toxicity in HCC patients treated with sorafenib versus SBRT
followed by sorafenib.

III. To measure vascular thrombosis response post sorafenib versus SBRT followed by
sorafenib.

IV. To measure differences in health related quality of life (QOL) and quality-adjusted
survival in HCC patients treated with sorafenib compared to SBRT followed by sorafenib.

V. Collection of biospecimens for future correlative studies to investigate differences in
potential biomarkers in patients treated with sorafenib versus SBRT followed by sorafenib.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM 1: Patients receive sorafenib tosylate orally (PO) twice daily (BID) on days 1-28.
Treatment repeats every 28 days for up to 5 years in the absence of disease progression or
unacceptable toxicity.

ARM 2: Patients undergo SBRT every 24-72 hours for a total of 5 fractions over 5 to 15 days.
Within 1-5 days post-SBRT, patients receive sorafenib tosylate PO BID on days 1-28. Treatment
repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable
toxicity.

Patients are followed weekly during SBRT, monthly during sorafenib tosylate and on the
following schedule as a whole from study entry: every 3 months for 3 years, then every 6
months for 2 years and then annually.

Inclusion Criteria:

- Patients must have a diagnosis of HCC by at least one criterion listed below within
360 days prior to study entry:

- Pathologically (histologically or cytologically) proven diagnosis of
HCC,(biopsies are recommended, and are to be submitted for research evaluation if
patients consent)

- At least one solid liver lesion or vascular tumor thrombosis (involving portal
vein, inferior vena cava [IVC] and/or hepatic vein) > 1 cm with arterial
enhancement and delayed washout on multi-phasic computerized tomography (CT) or
magnetic resonance imaging (MRI) in the setting of cirrhosis or chronic hepatitis
B or C without cirrhosis.

- For patients whose CURRENT disease is vascular only: enhancing vascular
thrombosis (involving portal vein, IVC and/or hepatic vein) demonstrating early
arterial enhancement and delayed washout on multi-phasic CT or MRI in a patient
with known HCC (diagnosed previously <720 days) using the above criteria.

- Measureable hepatic disease and/or presence of vascular tumor thrombosis (involving
portal vein, IVC and/or hepatic vein) which may not be measureable as per Response
Evaluation Criteria in Solid Tumors (RECIST) on liver CT or MRI, within 28 days of
registration

- Appropriate for protocol entry based upon the following minimum diagnostic workup:

- History/physical examination including examination for encephalopathy, ascites,
weight, height, and blood pressure within 14 days prior to study entry

- Assessment by radiation oncologist and medical oncologist or hepatologist who
specializes in treatment of HCC within 28 days prior to study entry

- Pre-randomization Scan (REQUIRED for All Patients): CT scan chest/abdomen/pelvis
or PET CT chest/abdomen/pelvis with multiphasic liver CT or multiphasic liver MR
scan within 28 days prior to study entry. MRI of abdomen and pelvis with contrast
with chest CT is permitted.

- Zubrod performance status 0-2 within 28 days prior to study entry

- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

- Platelets >= 60,000 cells/mm^3

- Hemoglobin >= 8.0 g/dl (note: the use of transfusion or other intervention to achieve
hemoglobin [Hgb] >= 8.0 g/dl is acceptable)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 6 times upper
limit of normal (ULN)

- Serum creatinine =< 2 x ULN or creatinine clearance >= 60 mL/min

- Barcelona Clinic Liver Cancer (BCLC) stage: intermediate (B) or advanced (C) within 28
days prior to study entry

- Child-Pugh score A within 14 days prior to study entry

- Women of childbearing potential and male participants must agree to practice adequate
contraception while on study and for at least 6 months following the last dose of
radiation therapy (RT) and for at least 28 days following the last dose of sorafenib
(whichever is later)

- Unsuitable for resection or transplant or radiofrequency ablation (RFA)

- Unsuitable for or refractory to transarterial hepatic chemo-embolization (TACE) or
drug eluting beads (DEB) for any of the following reasons, as described by Raoul et al
(2011):

- Technical contraindications: arteriovenous fistula, including, surgical
portosystemic shunt or spontaneous portosystemic shunt

- Severe reduction in portal vein flow: due to tumor portal vein, IVC or atrial
invasion or bland portal vein occlusion

- Medical contraindications including congestive heart failure, angina, severe
peripheral vascular disease

- Presence of extrahepatic disease

- No response post TACE (or DEB) or progressive HCC despite TACE; prior TACE or DEB
is allowed but must be > 28 days from study entry

- Serious toxicity following prior TACE (or DEB); prior TACE or DEB must be > 28
days from study entry

- Other medical comorbidities making TACE (or DEB) unsafe and/or risky (e.g.
combination of relative contraindications including age > 80 years, tumor > 10
cm, > 50% replacement of the liver by HCC, extensive multinodular bilobar HCC,
biliary drainage)

- Patients treated with prior surgery are eligible for this study if they otherwise meet
eligibility criteria

- Patient must be able to provide study-specific informed consent prior to study entry

Exclusion Criteria:

- Prior invasive malignancy (except non-melanomatous skin cancer and T1 renal cell
carcinoma) unless disease free for a minimum of 2 years (note that carcinoma in situ
of the breast, oral cavity, or cervix are all permissible)

- Prior sorafenib use > 60 days and/or grade 3 or 4 sorafenib related toxicity. Note
that prior chemotherapy for HCC or a different cancer is allowable

- Prior radiotherapy to the region of the liver that would result in overlap of
radiation therapy fields

- Prior selective internal radiotherapy/hepatic arterial yttrium therapy, at any time

- Severe, active co-morbidity, defined as follows:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months PRIOR TO registration

- Transmural myocardial infarction within the last 6 months prior to study entry

- Unstable ventricular arrhythmia within the last 6 months prior to study entry

- Acute bacterial or fungal infection requiring intravenous antibiotics within 28
days prior to study entry

- Hepatic insufficiency resulting in clinical jaundice, encephalopathy and/or
variceal bleed within 28 days prior to study entry

- Bleeding within 28 days prior to study entry due to any cause, requiring
transfusion

- Thrombolytic therapy within 28 days prior to study entry. Subcutaneous heparin is
permitted.

- Known bleeding or clotting disorder

- Uncontrolled psychotic disorder

- Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is
necessary because the treatment involved in this study may be significantly
teratogenic

- Maximal diameter of any one hepatocellular carcinoma > 15 cm

- Total sum of maximum diameters of each definite parenchymal hepatocellular carcinoma
within the liver or maximum diameter of a single conglomerate HCC > 20 cm

- More than 5 discrete intrahepatic parenchymal foci of HCC

- Direct tumor extension into the stomach, duodenum, small bowel or large bowel

- Measureable common or main branch biliary duct involvement with HCC

- Extrahepatic metastases or malignant nodes (that enhance with typical features of HCC)
> 3.0 cm, in sum of maximal diameters (e.g. presence of one 3.4 cm metastatic lymph
node or two 2 cm lung lesions); note that benign non-enhancing periportal
lymphadenopathy is not unusual in the presence of hepatitis and is permitted, even if
the sum of enlarged nodes is > 2.0 cm

- Prior liver transplant

- HIV positive with CD4 count < (350) cells/microliter. Note that patients who are HIV
positive are eligible, provided they are under treatment with highly active
antiretroviral therapy (HAART) and have a CD4 count ≥ (350) cells/microliter, and no
known detectable viral load, at the time of study entry. Note also that HIV testing is
not required for eligibility for this protocol