Study of SIR-Spheres Plus Sorafenib as 1st Line Treatment for Non-resectable Primary Hepatocellular Carcinoma (HCC)

Inclusion Criteria:

• Unresectable HCC with or without systemic metastases.

• Willing, able and mentally competent to provide written informed consent prior to anytesting under this study protocol, including screening tests and evaluations that arenot considered to be part of the subject's routine care.

• Aged 18 years or older of either gender and any race, religion or socioeconomic group.

• Unequivocal diagnosis of primary HCC (as defined above)

• HCC that is not amenable to surgical resection or immediate liver transplantation, orthat is not optimally treatable with local ablative techniques such as radio-frequencyablation, consistent with the practice of the clinical trial centre.

• Measurable disease, defined as at least one lesion that can be accurately measured inat least one dimension (longest diameter to be recorded) as ≥10 mm with spiral CTscan.

• ECOG performance status 0 - 1.

• Adequate haematological, renal and hepatic function as follows:

• Leukocytes ≥ 2,500/μL

• Absolute Neutrophil Count ≥ 1,500/μL

• Platelets ≥ 50,000/μL

• Haemoglobin > 9.5 g/dL

• Total bilirubin ≤ 2.0 mg/dL (SIR-Spheres should not be administered as a whole livertreatment if the total bilirubin is > 2X the institutional upper limit of normal).

• INR ≤ 2.0

• ALP ≤ 5 x institutional upper limit of normal

• AST / ALT ≤ 5 x institutional upper limit of normal

• Albumin ≥ 2.5 g/dL

• Creatinine ≤ 2.0 mg/dL

• The blood results must be less than 29 days old at the time of confirming patienteligibility to receive protocol treatment.

• Life expectancy of at least 3 months without any active treatment. This is defined asa patient who has OKUDA I or II inoperable HCC.

• Suitable for protocol treatment as determined by clinical assessment undertaken by theInvestigator.

• Female patients must be either postmenopausal or, if premenopausal, must have anegative pregnancy test and agree to use two forms of contraception if sexually activeduring their study participation.

• Male patients must be surgically sterile, or if sexually active and having apre-menopausal female partner then must be using an acceptable form of contraception.

• Hepatic arterial anatomy suitable for implantation of SIR-Spheres, as assessed byhepatic angiogram.

• Lung shunt fraction less than or equal to 20% as assessed by a Tc-99m macroaggregatedalbumin liver to lung breakthrough scan.

Exclusion Criteria:

• Had previous external beam radiation therapy to the liver.

• Any ascites or other clinical signs of liver failure, on physical examination.

• Abnormal synthetic and excretory liver function tests (LFTs) as determined by serumalbumin (must be < 2.5 g/dL) and total bilirubin (must be > 2.0 mg/dL), respectively.

• Tumours amenable to surgical resection for cure at presentation.

• Greater than 20% lung shunting of the hepatic artery blood flow determined by Tc-99MAA scan.

• Pre-assessment angiogram and Tc-99 MAA scan that demonstrates significant anduncorrectable activity in the stomach, pancreas or bowel.

• Been treated with Capecitabine within the previous 8 weeks, or who will be treatedwith Capecitabine within 8 weeks of treatment with SIR-Spheres, due to the possiblerisk of potentiating or causing liver dysfunction.

• Complete main portal vein thrombosis.

• Subjects who have had hepatic artery directed therapy.

• Subjects who have had prior chemotherapy or other medical agents used to treathepatocellular carcinoma.

• Prior external hepatic radiation therapy for HCC, or any other concomitant therapy forHCC or any investigational agent planned while on this protocol.

• Subjects with inferior vena cava (IVC) tumour thrombus or invasion

• Currently receiving any other investigational agents for the treatment of theircancer.

• Any other concurrent malignancy, except for adequately treated basal cell or squamouscell skin cancer, in situ cervical cancer, or other cancer for which the patient hasbeen disease-free for at least five years.

• Presence of clinical signs of CNS metastases due to their poor prognosis and becauseprogressive neurologic dysfunction would confound the evaluation of neurologic andother adverse events.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection (except viral hepatitis), symptomatic congestive heart failure, unstableangina pectoris, cardiac arrhythmia, or psychiatric illness/social situations thatwould limit compliance with study requirements.

• Any of the following contraindications to angiography and selective visceralcatheterization:

• Bleeding diathesis, not correctable by the standard forms of therapy.

• Severe peripheral vascular disease that would preclude arterial catheterization.

• Portal hypertension with hepatofugal flow as documented on baseline spiral CTscan.

• History of allergic reactions attributed to compounds of similar chemical or biologiccomposition to SIR-Spheres.

• Inability or unwillingness to understand or sign a written informed consent document (non English-speaking patients may use an interpreter).

• Female subjects who are pregnant or currently breastfeeding.

• For female subjects, unless postmenopausal or surgically sterile, unwillingness topractice effective contraception, as defined by the Investigator, during the study.The rhythm method is not to be used as the sole method of contraception.

• For male subjects, unwillingness to practice effective contraception (as defined bythe Investigator) while taking part in this study, because the effect of theSIR-Spheres treatment on sperm or upon the development of an unborn child are unknown.

• Current enrolment in any other investigational drug or device study.