18F-FSPG PET in Imaging Patients With Liver Cancer Before Undergoing Surgery or Transplant

Study Overview
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Brief Summary
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This clinical trial studies fluorine F 18 L-glutamate derivative BAY94-9392 (18F-FSPG) positron emission tomography (PET) in imaging patients with liver cancer before undergoing surgery or transplant. Diagnostic procedures, such as 18F-FSPG PET, may help find and diagnose liver cancer and find out how far the disease has spread.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the relationship between 18F-FSPG PET/computed tomography (CT), pathology, and cancer metabolism in patients with suspected hepatocellular carcinoma (HCC) scheduled for liver resection surgery and orthotopic liver transplant (OLT). II. To compare 18F-FSPG PET/CT with standard-of-care (SOC) diagnostic MRI imaging in patients with suspected HCC scheduled for liver resection surgery or OLT. III. To compare the uptake of 18F-FSPG PET/CT with 11C-acetate PET/CT AND 18F-FDG PET/CT in suspected HCC and background liver in patients scheduled for liver resection surgery or OLT. IV. To evaluate uptake of 18F-FSPG PET/CT in benign liver lesions compared to background. V. To evaluate uptake of 18F-FSPG PET/CT in malignant non-HCC liver tumors. OUTLINE: Patients undergo 18F-FSPG PET and either carbon-11 (11C)-acetate PET or 18F-FDG PET scans within 4 weeks of surgery or OLT.

Official Title
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PET Imaging of Hepatocellular Carcinoma With 18F-FSPG

Conditions
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Adult Hepatocellular Carcinoma, Resectable Hepatocellular Carcinoma, Cholangiocarcinoma, Benign Liver Tumor, Metastases to Liver

Intervention / Treatment
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* Biological: Fluorine F 18 L-glutamate Derivative 18F-FSPG
* Biological: Carbon C 11 Acetate
* Procedure: Positron Emission Tomography
* Other: Laboratory Biomarker Analysis
* Biological: Fluorine F 18 2-deoxy-2-(18F)fluoro-D-glucose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of HCC with one or more of the following: Liver mass with non-rim arterial phase hyperenhancement (APHE) and one of the following: 10-19 mm with >= 2 additional major features according to LI-RADS criteria (washout, enhancing capsule, and/or threshold growth), 10-19 mm with washout and visibility at antecedent ultrasound (US) but with no capsule or threshold growth, 10-19 mm with >= 50% size increase in <= 6 months but with no washout or capsule or >= 20 mm with >= 1 additional major feature according to LI-RADS criteria (washout, enhancing capsule, or threshold growth). Suggestive imaging findings plus AFP > 200 mg/dL; or Tumor confirmed by arteriography. or Diagnosis of a benign liver tumor with the following characteristics: Liver mass (>= 1 cm) that has suggestive imaging findings of a benign liver mass (adenoma, hemangioma, focal nodular hyperplasia). Prior SOC MRI of the benign liver lesion within 4 weeks of enrollment or Diagnosis of a malignant non-HCC liver tumor with one or more of the following characteristics: Liver mass (>= 1 cm) that is biopsy proven metastatic disease (metastatic colorectal cancer, metastatic pancreatic cancer). Liver mass (>= 1 cm) that is a non-HCC primary malignancy (cholangiocarcinoma). Prior SOC MRI of the malignant non-HCC liver tumor within 4 weeks of enrollment and 3. Each patient must have completed conventional imaging and staging and MRI before initiation of the investigational PET studies. and 4. Patients with HCC or cholangiocarcinoma must be a candidate for liver resection or orthotopic liver transplant (OLT) Exclusion Criteria: Patients under the age of 18 will be excluded from this study. Patients who have HCC or cholangiocarcinoma but are not candidates for liver resection surgery or OLT Patients with a known prior malignancy who have received systemic chemotherapy within five years. Basal cell carcinoma of the skin, carcinoma in situ of the cervix, prior HCC, and patients with liver mass(es) proven to be metastatic disease are not excluded. Pregnant and breastfeeding patients. Patients with poorly controlled diabetes mellitus (fasting blood glucose level > 200 mg/dL). Patients with a known Infiltrative variant of HCC.

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: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Cohorts A and B are Parallel. Cohorts C and D are Single Group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Diagnostic (18F-FSPG PET)<br>Patients undergo an 18F-FSPG PET scan within 4 weeks of surgery or OLT. Patients may also receive a second 18F-FSPG PET scan following standard-of-care treatment. | Biological: Fluorine F 18 L-glutamate Derivative 18F-FSPG<br>* Undergo 18F-FSPG PET scan<br>* Other names: BAY94-9392;Procedure: Positron Emission Tomography<br>* Undergo 18F-FSPG, 11C-acetate, or 18F-FDG PET<br>* Other names: Positron Emission Tomography Scan;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Diagnostic (11C-Acetate PET or 18F-FDG PET)<br>Patients may undergo either carbon-11 (11C)-Acetate PET or 18F-FDG PET scans within 4 weeks of surgery or OLT. | Biological: Fluorine F 18 L-glutamate Derivative 18F-FSPG<br>* Undergo 18F-FSPG PET scan<br>* Other names: BAY94-9392;Biological: Carbon C 11 Acetate<br>* Undergo 11C-acetate PET scan<br>* Other names: 11C-acetate;Procedure: Positron Emission Tomography<br>* Undergo 18F-FSPG, 11C-acetate, or 18F-FDG PET<br>* Other names: Positron Emission Tomography Scan;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Fluorine F 18 2-deoxy-2-(18F)fluoro-D-glucose<br>* Undergo 18F-FDG PET scan<br>* Other names: 18F-FDG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 18F-FSPG PET standardized uptake value (SUV) | The Standardized Uptake Value (SUV) for 18F-FSPG PET images will be determined in the hepatocellular carcinoma (HCC) tumor lesions, non-HCC liver tumors (benign), and background liver (normal tissue). These metrics include SUVmax, SUVpeak, or SUVmean and are common PET imaging measures. | Within 4 weeks of standard-of-care imaging, within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy | 
| 11C-acetate standardized uptake value (SUV) | The Standardized Uptake Value (SUV) for 11C-acetate PET images will be determined in the tumor lesions and background liver (normal tissue). These metrics include SUVmax, SUVpeak, or SUVmean and are common PET imaging measures. | Within 4 weeks of standard-of-care imaging, within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy | 
| 18F-FDG standardized uptake value (SUV) | The Standardized Uptake Value (SUV) for 18F-FDG PET images will be determined in the hepatocellular carcinoma (HCC) tumor lesions and background liver (normal tissue). These metrics include SUVmax, SUVpeak, or SUVmean and are common PET imaging measures. | Within 4 weeks of standard-of-care imaging, within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy | 
| Pharmacokinetics of 18F-FSPG, 11C-acetate, and 18F-FDG | The pharmacokinetics of 18F-FSPG, 11C-acetate and 18F-FDG uptake will be determined using compartmental modeling of PET imaging data. Venous samples will be collected over the course of 18F-FSPG, 11C-acetate and 18F-FDG scans to confirm blood pool radioactivity, evaluate metabolism, and to calibrate image-derived input functions. We will also utilize blood samples collected prior to scanning to assay plasma levels of carbon-12 acetate and glucose in each patient to explore normalizing pharmacokinetic parameters across patients. | Within 4 weeks of standard-of-care imaging, within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy | 
| Number of lesions | The number of lesions detected by 18F-FSPG PET will be determined and compared to the number of lesions detected by standard-of-care MRI, 11C-acetate PET, or 18F-FDG PET on a per patient basis. | Within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy | 
| Sensitivity of 18F-FSPG PET imaging | Sensitivity is defined as the true positive rate. It is defined as true positive/(true positive + false negative). The determination of HCC status will be based on diagnostic pathology. | Within 4 weeks of standard-of-care imaging, within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy | 
| Specificity of 18F-FSPG PET imaging | Specificity is defined as the true negative rate. It is defined as true negative/(true negative + false positive). The determination of HCC status will be based on diagnostic pathology. | Within 4 weeks of standard-of-care imaging, within 4 weeks of liver resection surgery, within 12 months of orthotopic liver transplant and prior to therapy | 
| Diagnostic pathology | Tissue samples will be obtained for patients following either liver resection surgery or orthotopic liver transplant. Pathology will be performed on these tumor tissues as the gold-standard assessment to confirm the presence of HCC tumor. Histology will be correlated to PET imaging data. | After surgery; Through study completion, up to 4 years | 
| Tumor grade | Tissue samples will be obtained for patients following either liver resection surgery or orthotopic liver transplant. Tumor grade will be determined from pathology of tissue samples and correlated to PET imaging data for 18F-FSPG, 11C-acetate and 18F-FDG PET. The concordance of 18F-FSPG PET/CT and 11C-acetate PET/CT or 18F-FSPG PET/CT and 18F-FDG PET/CT will be evaluated. This will determine whether 18F-FSPG can be used singularly in place of combined use of 11C-acetate PET/CT (which typically detects low grade HCC) and 18F-FDG PET/CT (which typically detects high grade HCC). | After surgery; Through study completion, up to 4 years | 
| Immunohistochemistry | Tissue samples will be obtained for patients following liver resection surgery. The expression of immunohistochemical markers (ie. xC- and CD44) will be evaluated in these tumor tissues on an ordinal scale of 0, 1, 2 or 3 and correlated to 18F-FSPG PET imaging data. In addition, markers of inflammation and immune cell recruitment (ie. CD86, CD163, CD3), proliferation (Ki67), and apoptosis (Caspase 3) will also be evaluated and correlated to 18F-FSPG PET imaging data. | After surgery; Through study completion, up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic profile | HCC tumor and non-cancerous liver tissue samples will be obtained for patients following liver resection surgery. Overall, tumoral tissue, peritumoral tissue and grossly normal surrounding liver will be evaluated. Metabolic profiles will be analyzed by mass spectrometry. The unbiased metabolomic phenome will be determined and correlated to 18F-FSPG PET. | After surgery; Through study completion, up to 4 years | 
| Milan classification | Milan criteria will be applied to standard-of-care (SOC) MRI images. The number and size of lesions will be determined. A patient will be deemed to meet Milan criteria if they exhibit A) A single lesion 2 to 5 cm in diameter or B) Three or fewer tumors, each measuring 1 to 3 cm in diameter, and C) No evidence of extrahepatic involvement or microvascular invasion. The proportion of patients whose Milan classification by novel imaging classification changed following validation by histological confirmation will be determined. | Baseline prior to imaging and surgery |