This prospective clinical trial will evaluate PET/CT and genomic liquid biopsy based biomarkers as predictors of clinical therapeutic response to immune-checkpoint inhibitor (ICI) therapy for patients with inoperable hepatocellular carcinoma (HCC). The primary objective of this diagnostic trial is to assess the accuracy of pre-treatment fluorine-18 (18F-) fluorocholine (FCH) PET/CT for predicting a lack of objective response (LOR) after 16 weeks of ICI therapy.

This is a prospective open-label single-arm diagnostic clinical trial evaluating fluorine-18 fluorocholine (FCH) PET/CT and cell-free DNA mutation profiling (also referred to as genomic liquid biopsy) as diagnostic tools for predicting therapeutic response in advanced HCC patients receiving immune-checkpoint inhibitor (ICI) therapy. All enrolled subjects will undergo diagnostic testing with FCH PET/CT and genomic liquid biopsy before ICI treatment. A fluorine-18 fluorodeoxyglucose (FDG) PET/CT may also be performed before treatment and after 8 weeks if the pre-treatment FCH PET/CT shows low or heterogeneous tumor uptake. The accuracy of tumor biomarkers based on PET/CT and liquid biopsy for predicting therapeutic outcome and disease progression will be determined using objective clinical endpoints based on the radiographic classification of treatment response by RECIST v1.1 applied to CT or MRI performed after 16 weeks of treatment.

Inclusion Criteria:

• Age 18 years or older (no upper limit of age)
• Hepatocellular carcinoma diagnosis made histologically or radiographically in accordance to National Comprehensive Cancer Network guidelines (3.2019 version or higher)
• Does not qualify for surgical resection or locoregional therapy alone or has disease that has progressed after surgical resection and/or locoregional therapy
• Has measurable disease defined as at least one tumor lesion that can be accurately measured according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 on CT/MRI completed within past 6 weeks of eligibility screening
• Under the care of a licensed medical oncologist
• Life expectancy > 6 months
• Deemed eligible for treatment with an immune checkpoint inhibitor agent based on the treating medical oncologist's assessment of previous treatment failure, clinical/performance/virology status, and liver/renal/hematologic function.
• Child-Pugh score of 9 or less
• Creatinine clearance ≥ 40 mL/min, measured or calculated using the Cockcroft-Gault formula
• ALT and AST ≤7x upper limit of normal
• Total bilirubin ≤4 mg/dL
• Albumin ≥2.8 g/dL

Exclusion Criteria:

• Weight > 500 lbs (PET/CT limit)
• Pregnant or lactating female (those of child-bearing potential must be re-screened within 7 days prior to PET/CT imaging)
• Serious underlying medical condition that would impair patient's ability to tolerate the imaging procedure
• Concurrent treatment with a non-targeted therapeutic agent. Concurrent enrollment in an ICI-treatment trial and combination ICI treatment are allowed.

Limited de-identified genomic and phenotypic individual participant data will be made available after the end of the trial via the NIH database of genotypes and phenotypes (dbGaP) in accordance with the NIH Genomic Data Sharing Policy. The individual level data made available by dbGaP is safeguarded by a process of controlled-access with data use limitations to be determined.

Starting 6 months after last publication at conclusion of the trial.

Controlled-Access. Contact NIH dbGaP for more information.