NCT01730937.

Trial name or title	Sorafenib tosylate with or without stereotactic body radiation therapy in treating patients with liver cancer
Methods	Phase III trial
Participants	People with hepatocellular carcinoma unsuitable for resection, radiofrequency ablation, or transarterial chemoembolisation (TACE)
Interventions	Experimental: Arm 1 (sorafenib tosylate): Sorafenib tosylate given orally twice a day on days 1 to 28. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity. Experimental: Arm 2 (stereotactic body radiotherapy and sorafenib tosylate): stereotactic body radiotherapy administered every 24 to 72 hours for a total of 5 fractions over 5 to 15 days. Within 1 to 5 days post‐stereotactic body radiotherapy, treatment with sorafenib tosylate commences, given orally twice a day on days 1 to 28. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Outcomes	Primary outcome measures: Overall survival Secondary outcome measures: Time to progression Progression‐free survival Health‐related quality of life assessments measured by FACT‐Hep
Starting date	April 2013
Contact information	Christopher M Iannuzzi; twhite@stvincents.org
Notes	Inclusion criteria: Patients must have a diagnosis of hepatocellular carcinoma by at least 1 of the following criteria within 360 days prior to study entry: pathologically (histologically or cytologically) proven diagnosis of hepatocellular carcinoma (biopsies are recommended, and are to be submitted for research evaluation if patients consent); at least 1 solid liver lesion or vascular tumor thrombosis (involving portal vein, inferior vena cava, and/or hepatic vein) > 1 cm with arterial enhancement and delayed washout on multiphasic computed tomography or 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, inferior vena cava, and/or hepatic vein) demonstrating early arterial enhancement and delayed washout on multiphasic computed tomography (CT) or MRI in a patient with known hepatocellular carcinoma (diagnosed previously < 720 days) using the above criteria. Measurable hepatic disease or presence of vascular tumour thrombosis (involving portal vein, inferior vena cava, and/or hepatic vein), or both, which may not be measurable as per 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 specialises in treatment of hepatocellular carcinoma within 28 days prior to study entry; pre‐randomisation scan (required for all patients): CT scan chest/abdomen/pelvis with multiphasic liver CT scan or multiphasic liver MRI scan within 28 days prior to study entry. MRI of abdomen with contrast and pelvis is permitted. Zubrod performance status 0 to 2 within 28 days prior to study entry. Absolute neutrophil count >= 1500 cells/mm3. Platelets >= 70,000 cells/mm3. Haemoglobin >= 8.0 g/dL (note: the use of transfusion or other intervention to achieve haemoglobin >= 8.0 g/dL is acceptable). Total bilirubin < 2 mg/dL. International normalised ratio < 1.7. Albumin >= 28 g/L. Aspartate aminotransferase and alanine aminotransferase < 6 times upper limit of normal. Serum creatinine =< 1.5 x upper limit of normal or creatinine clearance >= 60 mL/min. Barcelona Clinic Liver Cancer stage: intermediate (B) or advanced (C) within 14 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 and for at least 28 days following the last dose of sorafenib (whichever is later). Unsuitable for resection or transplant or radiofrequency ablation. Unsuitable for or refractory to TACE or drug‐eluting beads for any of the following reasons: Technical contraindications: arteriovenous fistula, including surgical portosystemic shunt or spontaneous portosystemic shunt. Severe reduction in portal vein flow due to tumour portal vein, inferior vena cava, 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 drug‐eluting beads) or progressive hepatocellular carcinoma despite TACE; prior TACE or drug‐eluting beads is allowed but must be > 28 days from study entry. Serious toxicity following prior TACE (or drug‐eluting beads); prior TACE or drug‐eluting beads must be > 28 days from study entry. Other medical comorbidities making TACE (or drug‐eluting beads) unsafe or risky, or both (e.g. combination of relative contraindications including age > 80 years, tumour > 10 cm, > 50% replacement of the liver by hepatocellular carcinoma, extensive multinodular bilobar hepatocellular carcinoma, biliary drainage). People treated with prior surgery are eligible for this study if they otherwise meet eligibility criteria. Person must be able to provide study‐specific informed consent prior to study entry. Exclusion criteria: Prior invasive malignancy (except non‐melanomatous skin cancer) 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. Note that prior chemotherapy for hepatocellular carcinoma or a different cancer is permitted. 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 comorbidity, defined as follows. Unstable angina or congestive heart failure, or both requiring hospitalisation within the 6 months prior to registration. Transmural myocardial infarction within the 6 months prior to study entry. Unstable ventricular arrhythmia within the 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 60 days prior to study entry. Bleeding due to any cause requiring transfusion within 60 days prior to study entry. 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. Any 1 hepatocellular carcinoma > 15 cm. Total maximal sum of hepatocellular carcinomas or a single conglomerate hepatocellular carcinoma > 20 cm. More than 5 discrete intrahepatic parenchymal foci of hepatocellular carcinoma. Direct tumour extension into the stomach, duodenum, small bowel, or large bowel. Measureable common or main branch biliary duct involvement with hepatocellular carcinoma. Extrahepatic metastases or malignant nodes (that enhance with typical features of hepatocellular carcinoma) > 3.0 cm, in sum of maximal diameters (e.g. presence of one 3.4‐centimetre metastatic lymph node or two 2‐centimetre 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. Use of regular phenytoin, carbamazepine, Hypericum perforatum (also known as St. John's wort), or rifampin. Use of combination antiretroviral therapy for HIV, as these agents may modulate cytochrome P450 isozymes. Prior liver transplant.