Efficacy Evaluation of TheraSphere in Patients With Inoperable Liver Cancer

Study Overview
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Brief Summary
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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.

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

Conditions
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Unresectable Hepatocellular Carcinoma

Intervention / Treatment
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* Device: TheraSphere


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control group<br>Standard-of-care sorafenib, with no added therapy | |
| Experimental: Treatment group<br>Standard-of-care sorafenib plus TheraSphere | Device: TheraSphere<br>* Yttrium 90 microspheres<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) Results Are Based on the Modified Intent-to-treat (mITT) | Time from randomization until date of death due to any cause as reported by study site. | From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months | 
| Overall Survival (OS) Per Protocol (PP) Population | Per Protocol = subset of the mITT population excluding patients with major protocol deviations which may affect the efficacy evaluation. | From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) From Time of Randomization Based on Investigator, According RECIST Criteria. | Time to progression (TTP) will be calculated as the interval between the randomization date and the date of first disease progression, including the appearance of new lesion(s) (per RECIST 1.1) and death for any cause or of last contact for patients alive. | From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months | 
| Time to Untreatable Progression (TTUP) From the Time of Randomization Based One or More of the Following: Investigator Assessment According to RECIST Criteria | Time to progression (TTP) will be calculated as the interval between the randomization date and the date of first disease progression, including the appearance of new lesion(s) and death for any cause or of last contact for patients alive. | From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months | 
| Tumor Response | Objective Response Rate by investigator determination per RECIST 1.1 | From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months |