Radiation Therapy With Sorafenib for TACE-Resistant Hepatocellular Carcinoma

In patients with unresectable hepatocellular carcinoma (HCC), transarterial
chemoembolization (TACE) is first line therapy. Non-responders to TACE (i.e. stable or
progressive disease) represent a poor prognosis population with limited options. Sorafenib
is indicated for first line salvage therapy, however it only improves survival 2-3 months
and just has a 2-3% response rate. Thus, sorafenib is merely a cytostatic agent that delays
progression and does not cytoreduce disease.

Radiation therapy (RT) is a non-invasive treatment that can cytoreduce HCC with minimal
morbidity using modern techniques. A meta-analysis and multiple retrospective series suggest
TACE + RT improve survival when compared to TACE alone. Higher RT doses are similarly
associated with increased survival due to improved local control. Paradoxically, some series
suggest that RT can induce vascular endothelial growth factor (VEGF) expression which may
stimulate HCC.

Pre-clinical data suggest that combining RT with concurrent sorafenib (a VEGF inhibitor)
improves tumor control. However, clinical data is limited to case reports and safety has not
been well characterized. Prior to determining if this combination can improve control of HCC
in this poor prognosis population, the optimal radiation dose with concurrent sorafenib must
be determined by a phase I dose escalation trial.

Inclusion Criteria:

- Radiographic or histologic diagnosis of hepatocellular carcinoma (HCC).

- Maximum of 3 HCC lesions within the liver.

- No evidence of lymphadenopathy or metastatic disease per either CT or PET.

- Prior transarterial chemo-embolization (TACE) at least 28 days prior to initiation of
protocol therapy.

- Evidence of either progressive disease or stable disease following TACE.

- Child Pugh Class A (score 5-6) or B (score 7).

- ECOG Performance Status ≤1 (or Karnofsky ≥70%).

- Normal organ and marrow function (platelets >60,000/mc; hemoglobin ≥8.5 g/dL; INR
≤2.3; albumin ≥2.8 g/dL; total bilirubin ≤3 mg/dL; AST/ALT <5x upper limit of normal;
creatinine ≤1.5x upper limit of normal).

- Negative human immunodeficiency virus serology.

- Negative pregnancy test for women of child bearing age.

- Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

- Less than 800 cc of normal liver.

- Child Pugh Class B (score 8-9) or C (score 10-15).

- Acute/active hepatitis B infection.

- Prior systemic chemotherapy or abdominal radiation therapy.

- Portal venous (main, primary right, or primary left trunks) or inferior vena cava
thrombosis.

- Prior malignancy within 5 years of enrollment except for non-melanoma skin cancer.

- Prior history of myocardial infarction, cerebrovascular accident, or esophageal
variceal bleed in the last 6 months.

- Pre-existing heart failure with either a clinical classification of New York Heart
Association Class III or IV or cardiac ejection fraction of <45%.

- Systolic blood pressure > 160 mmHg or diastolic pressure > 100 mmHg despite optimal
medical management.

- Pulmonary hemorrhage or other serious bleeding event (grade 2+) within 4 weeks
initiation of protocol therapy.

- Prior history of scleroderma or active systemic lupus erythematosus.