A TheraSphere® Advanced Dosimetry Retrospective Global Study in HCC

Study Overview
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Brief Summary
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This retrospective, multinational, single-arm study will be conducted in at least 8 sites. An interim analysis will be conducted with data from 100 patients with up to 10 well defined HCC tumor(s) and with at least one tumor ≥3 cm. Normal tissue absorbed dose using pre-procedural 99mTc MAA SPECT or SPECT/CT imaging will be measured to allow the mean absorbed normal tissue dose corresponding to a ≤15% probability of CTCAE grade 3 or higher hyperbilirubinemia (in the absence of disease progression) to be calculated. Total bilirubin will be recorded and graded according to CTCAE version 4.02. All dose-related SAEs at 3 months follow-up will be followed until resolution, death or lost-to-follow-up. AEs related to disease progression will not be considered related to TheraSphere.

Detailed Description
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Recently published evidence indicates a correlation between yttrium-90 dose delivered to the tumor and normal tissue with safety and efficacy outcomes but there are no validated methods to consistently measure dose delivered to the tumor and normal tissue. In contrast to the standard clinical approach based on average dose to one target volume, this trial, sponsored by Biocompatibles UK, will explore an alternative two-compartment TheraSphere dosimetry methodology to calculate absorbed dose to tumor and normal tissue

Official Title
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A TheraSphere® Advanced Dosimetry Retrospective Global Study Evaluation in Hepatocellular Carcinoma Treatment

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Device: TheraSphere


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Up to 10 well defined unilobar/bilobar HCC tumor(s) per lobe with at least one tumor ≥3 cm ± PVT Liver dominant disease (limited extra-hepatic metastases in the lung and/or lymph nodes are permitted (up to 5 lesions in the lung, with each individual lesion ≤2cm; any number of lymph node lesions with each individual lesion ≤2 cm). Child Pugh stage A or B7. BCLC A, B or C. Must be male or female, 18 years of age or older. Bilirubin ≤2 mg/dL. Tumor replacement <50% of total liver volume assessed by diagnostic imaging consisting of multi-phase contrast enhanced CT or contrast enhanced MRI. Diagnostic imaging consisting of multi-phase contrast enhanced CT or contrast enhanced MRI within 3 months prior to TheraSphere® administration. Infusion of 99mTc-MAA in a single arterial location sufficient to cover up to 10 well-defined tumors per lobe ≤ 6 weeks prior to TheraSphere® administration. Patients must have received TheraSphere® in a single treatment setting in one or more arterial locations sufficient to cover up to 10 well-defined tumors based on angiography. Subsequent TheraSphere® treatment to the second lobe may occur at least 4 weeks following the initial TheraSphere® treatment. For patients receiving a second TheraSphere® treatment bilirubin levels must have been recorded prior to the second treatment Patients must have had clinical evaluation (assessment of liver specific AEs) and laboratory evaluation (at least a serum bilirubin level) at baseline. Tumor(s), ≥3 cm, measurable by mRECIST and RECIST 1.1 at baseline Exclusion Criteria: Prior external beam radiation treatment to the liver. Prior loco-regional liver directed therapy (cTACE, DEB-TACE and SIR-Spheres). Prior liver transplantation. Whole liver TheraSphere® treatment following prior liver resection. TheraSphere administration to ≤2 segments (e.g., radiation segmentectomy). Additional active therapy (TACE and treatment with SIR-Spheres) between first TheraSphere treatment and 3 month (90 days) imaging. Hepatic vein invasion. Diagnosis of disease progression at peri-procedural imaging as compared to the baseline imaging (physician's discretion).

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Previous Therasphere treatment<br>Patients who had received TheraSphere yttrium-90 microspheres | Device: TheraSphere<br>* Patients who had received TheraSphere<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alternative two-compartment TheraSphere dosimetry methodology | Normal tissue absorbed dose using pre-procedural 99mTc MAA (Technetium-99m Macroaggregated albumin) SPECT (Single-photon emission computer tomography) or SPECT/CT (Single-photon emission computer tomography/Computer Tomography) imaging, to allow the mean absorbed normal tissue dose corresponding to a ≤15% probability of Common Toxicities Criteria for Adverse Events (CTCAE) grade 3 or higher hyperbilirubinemia (in the absence of disease progression) to be calculated. | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor dose | Tumor dose (to tumors ≥3 cm) using pre-procedural 99mTc MAA SPECT or SPECT/CT imaging. | Baseline | 
| Serious adverse events | All serious adverse events (SAEs) assessed as related or potentially related to TheraSphere | 3 months | 
| Specific non-serious adverse events (AEs) assessed as related or potentially related to the dose of TheraSphere | Specific non-serious adverse events (AEs) assessed as related or potentially related to the dose of TheraSphere, comprising of any of the following events: Hyperbilirubinemia Ascites Pain Fatigue Nausea | 3 months | 
| Clinical laboratory assessments | Clinical laboratory assessments | 6 weeks and 3 months | 
| Objective response (OR) of the target lesion and non-target sesions | Objective response (OR) of the target lesion (single largest lesion) and non-target lesion(s) at 3 months and 6 months (if available), and for all scans up to 400 days after TheraSphere administration by Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | 3 months and 6 months | 
| Volume changes | Volume changes (i.e., perfused liver volume and non-perfused liver volume) from baseline afterTheraSphere administration. | 3 and 6 months | 
| Overall Survival (OS) | Overall Survival (OS) | 6 months | 
| Target Alpha fetoprotein (AFP) response | Target Alpha fetoprotein (AFP) response (defined as a ≥50% decrease in AFP levels for patients with a baseline AFP level of ≥200 ng/mL). | 6 weeks and 3 months | 
| Albumin-bilirubin (ALBI) score | Albumin-bilirubin (ALBI) score, a measure of liver function for HCC patients after TheraSphere administration. | 6 weeks and 3 months | 
| Dose to Portal Vein Thrombosis (PVT) | Dose to Portal Vein Thrombosis (PVT) based upon pre- and postprocedure imaging (if PVT present). | baseline, 90 days, 180 days | 
| Dosimetric analysis time | Dosimetric analysis time (i.e., workflow). | baseline | 
| Dose accuracy | Dose accuracy based upon phantom imaging studies. | baseline | 
| Dose reproducibility | Measurement of inter-observer agreement based on a round robin review of the same 20 patients obtained from a minimum of 8 users (with each user at a different site) and an exploratory assessment of intra-observer agreement based on a review of 10 patients by a minimum of 8 users at least 2 weeks apart. The 10 patients for the intra-observer agreement will be a subset of the patients included in the assessment of inter-observer agreement. | baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TheraSphere, hepatocellular carcinoma, dosimetry