Efficacy Evaluation of TheraSphere in Patients With Inoperable Liver Cancer

A Phase III Clinical Trial of Intra-arterial TheraSphere® in the Treatment of Patients With Unresectable Hepatocellular Carcinoma (HCC)

The safety and effectiveness of TheraSphere will be evaluated in patients with unresectable hepatocellular carcinoma in whom treatment with standard-of-care sorafenib is planned. All patients receive the standard-of-care sorafenib with or without the addition of TheraSphere.

Inclusion Criteria:

• Signed informed consent prior to any study-related evaluation
• Male or female patients over 18 years of age
• Unresectable HCC confirmed by histology or by non-invasive AASLD criteria
• Measurable disease defined as at least one uni-dimensional measurable lesion by CT or MRI according to RECIST 1.1
• Child Pugh score ≤ 7 points
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤ 1
• Life expectancy of 12 weeks or more
• Eligible to receive standard-of-care sorafenib
• Platelet count of > 50 x 10⁹/L or > 50% prothrombin activity
• Hemoglobin ≥ 8.5 g/dL
• Bilirubin ≤ 2.5 mg/dL
• Alanine transaminase (ALT) and Aspartate Aminotransferase (AST)< 5 X upper limit of normal
• Amylase or lipase ≤ 2X upper limit of normal
• Serum creatinine ≤ 1.5 X upper limit of normal
• International normalized ratio (INR) < 2.0

Exclusion Criteria:

• Main portal vein thrombosis
• Eligible for curative treatment (ablation or transplantation)
• History of previous or concurrent cancer other than HCC unless treated curatively 5 or more years prior to entry
• Confirmed presence of extra-hepatic disease except lung nodules and mesenteric or portal lymph nodes ≤ 2.0 cm each
• Risk of hepatic or renal failure
• Tumor replacement ≥ 70% of total liver volume based on visual estimation by investigator OR tumor replacement ≥ 50% of total liver volume in the presence of albumin <3 mg/dL
• History of severe allergy or intolerance to contrast agents, narcotics sedatives or atropine that cannot be managed medically
• Contraindications to angiography and selective visceral catheterization.
• History of organ allograft
• Known contraindications to sorafenib including allergic reaction, pill-swallowing difficulty, evidence of severe or systemic diseases, uncontrolled severe hypertension or history of cardiac arrhythmias, congestive heart failure . New York Heart Association class 2, myocardial infarct within 6 months, prolonged QT/QTc >450ms, evidence of torsades de pointe, or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial, significant GI bleed within 30 days, metastatic brain disease, renal failure requiring dialysis
• Taking any of the following: Rifampicin, St. John's Wort, phenytoin, carbamazepine, phenobarbital, dexamethasone
• Taking any other systemic anticancer agent (docetaxel, doxorubicin, irinotecan)
• Taking any substrate agents for Cytochrome P450 (CYP) 2B6 (bupropion, cyclophosphamide, efavirenz, ifosfamide, methadone, paclitaxel, amodiaquine, repaglinide)
• Taking any UDP-glucuronosyltransferase (UGT) 1A1 and UGT 1A9 substrates (e.g. irinotecan)
• Taking P-Gp substrates (e.g. Digoxin)
• Prior liver resection must have taken ≥2 months prior to randomization
• Treatment with other locoregional therapies (other than study treatment) has not been planned for the duration of the clinical study period
• Prior external beam radiation treatment to the chest, liver or abdomen
• Prior yttrium-90 microsphere treatment to the liver
• Prior treatment with transarterial chemoembolization (TACE) or bland embolization must have occurred >2 months prior to randomization and must have been applied to a treatment field and/or lobe not targeted for treatment under this protocol. For patients with tumor progression in the treatment field and /or lobe previously treated with TACE, vessels feeding the tumor(s) must be assessed for adequate blood flow using angiography (cone beam computerized tomography (CBCT) strongly recommended), and TACE or bland embolization must have been applied >6 months prior to randomization.
• Anti-cancer therapy or any treatment with an investigational agent within 30 days prior to randomization
• Adverse effects due to prior therapy unresolved at randomization
• Prior systemic treatment for the treatment of HCC, including sorafenib given for more than 4 weeks during the 2 previous months prior to randomization, no prior sorafenib related toxicity
• Evidence of pulmonary insufficiency or inadequately treated moderate grade or severe/very severe grade chronic obstructive pulmonary disease
• Intervention for, or compromise of, the Ampulla of Vater
• Clinically evident ascites (trace ascites on imaging is acceptable)
• Pregnancy or breast feeding
• Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization
• Disease or condition that would preclude safe use of TheraSphere, including concurrent dialysis treatment, or unresolved serious infections. Patients infected with HIV can be considered, however, they must be well managed and well controlled with undetectable viral load
• Participation in concurrent clinical trials evaluating treatment intervention(s)