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Diagnosis of cirrhosis and no HCC confirmed by medical imaging including MRI or CT performed within 6 months of study enrollment. If lesions are present, a Liver Imaging Reporting and Data System (LI-RADS) score of LR-1 or LR-2.

Diagnosis of HCC confirmed by medical imaging (MRI or CT performed within 6 months of study enrollment with LI-RADS score of LR-5) and/or biopsy with histopathology.

Theo DeVos

Nick Potter

This is a multi-center study to prospectively gather clinically-characterized plasma samples to determine the diagnostic performance characteristics (sensitivity and specificity) of the HCCBloodTest among patients with cirrhosis with and without HCC

Patients with clinically-diagnosed cirrhosis without HCC (Group 1) and patients with early-stage HCC (Group 2) will be invited to participate in this study consisting of one visit for all subjects. At Visit 1, Day 0, after subjects have provided informed consent and HIPAA consent, demographics (age, gender, ethnicity), etiology of liver disease and medical history as well as a list of current medications will be obtained; inclusion and exclusion criteria will be reviewed; and subjects will be registered into the study and will undergo a venipuncture to obtain four (4) lavender top K2 ethylenediaminetetraacetic acid (EDTA) 10 millilitre (mL) tubes of blood.

The HCCBloodTest will be performed on the blood samples collected from study subjects by the Sponsor at its laboratory in Berlin, Germany, to determine the performance characteristics of the HCCBloodTest in the study population.

The HCCBloodTest is an in-vitro polymerase chain reaction (PCR) assay for the qualitative detection of Septin 9 gene methylation (SEPT9) in DNA isolated from 3.5 mL of patient plasma. The SEPT9 gene is a key regulator of cell division and tumor suppressor and the hypermethylation of the assessed marker site is associated with liver carcinogenesis.

Results from the HCCBloodTest will be not be provided to the investigators or study subjects and, therefore, will be not be used in clinical decision-making or impact clinical care of the study participants in any manner.

De-identified, clinically characterized plasma specimens for a bio-repository will be retained for up to twenty (20) years for future HCC-related test development.

HCCBloodTest for Detection of Hepatocellular Carcinoma (HCC)

HCCBloodTest for Detection of Hepatocellular Carcinoma (HCC): Marker Performance Validation and Technical Development Study

The HCCBloodTest is an in-vitro PCR based assay for the qualitative detection of the methylation status of a SEPT9 gene promoter DNA sequence. Plasma will be prepared from blood samples collected from study subjects and will be tested by the Sponsor with HCCBloodTest at its laboratory in Berlin, Germany. Positivity based on PCR results will be reported for study subjects. Test performance characteristics including sensitivity and specificity will be reported for the study population.

Innovis LLC

Epigenomics, Inc

Neoplasm Metastasis

Atrophy

Neoplastic Processes

Micronutrients

Pharmaceutical Solutions

Iron

Ferrosoferric Oxide

Parenteral Nutrition Solutions

This study is a single arm prospective study that will enroll 25 patients with primary and metastatic liver tumors and hepatic cirrhosis eligible for liver SBRT who will be receiving treatment at a single center - Allegheny General Hospital.

This is a prospective observation study of 1.5T MR-Linac-SPION imaging with Ferumoxytol for radiotherapy planning in patients with pre-existing liver condition in order to increase safety of liver SBRT with assessment of tumor and hepatic parenchyma response.

Ferumoxytol injection

Alexander Kirichenko, MD, PhD

There is a high prevalence of hepatic cirrhosis in patients with hepatocellular carcinomas (HCC), or chemotherapy-induced hepatic atrophy or hepatosteatosis in patients with liver metastases associated with high risk of radiation-induced liver disease (RILD) after stereotactic body radiotherapy (SBRT). MRI-SPION radiotherapy planning will facilitate detection and maximize avoidance of residual functionally active hepatic parenchyma from over-the-threshold irradiation thus increasing safety of liver SBRT in patients with pre-existing liver conditions. The investigators have previously demonstrated that liver SBRT with SPECT/CT functional treatment planning utilizing 99mTc sulfur colloid in transplant eligible patients associated with minimal hepatotoxicity and without hastening of advanced hepatic cirrhosis progression while patients await liver transplant. Switching from nuclear medicine to an MR-Linac-SPION based quantitative treatment-planning platform will substantially improve diagnostic accuracy in defining safe volumes of residual functional hepatic parenchyma for liver SBRT planning on MR-Linac.

Setting/Participants:

The study will be performed at a single center - Allegheny General Hospital (AGH) in a setting of referral-based outpatients within the Allegheny Health (AHN) network.

25 patients with primary and metastatic liver tumors and hepatic cirrhosis eligible for liver SBRT will be enrolled in this study.

Study Interventions and Measures:

MRI cellular imaging of hepatic parenchyma with SPION will be performed on a 1.5T MRI (Elekta MR-Linac) on the day of radiotherapy planning. Hepatic SPION accumulation will be quantified and delineated to designate volumes for conformal avoidance on the MR-Linac during liver SBRT. This quantitative assessment will be compared to the already established methodology using CT/SPECT images developed at AGH. Treatment outcomes and toxicity due to improved conformal avoidance of functional normal liver volumes will be assessed for these patients. Dose-response of tumor and hepatic parenchyma to SBRT will be examined using MR-Linac imaging, pathologic criteria and molecular profiling of explanted livers in a subset of patients who received liver SBRT as a bridge to transplant.

Main outcome of the study:

Development and evaluation of a novel MRI-Linac based functional treatment planning platform with DICOM-compatible applications for visualization and subsequent conformal avoidance of residual, functionally active hepatic parenchyma in patients undergoing liver SBRT to primary and metastatic malignancies with the assessment of tumor and hepatic parenchyma response using MR imaging correlated with both pathologic and genomic criteria in a subset of patients receiving SBRT as a bridge to liver transplant.

Radiotherapy With Iron Oxide Nanoparticles (SPION) on MR-Linac for Primary & Metastatic Hepatic Cancers

Adaptive Stereotactic Radiotherapy With Superparamagnetic Iron Oxide Nanoparticles (SPION) Cellular Magnetic Resonance Imaging on MR-Linac (MR-L-SPION) for Primary and Metastatic Hepatic Malignancies With Assessment of Treatment Response.

Only de-identified data will be shared with collaborators of the trial.

The primary goal of the study is to develop MRI-linac SPION based radiotherapy planning platform for detection and conformal avoidance of residual, functionally active hepatic parenchyma during liver SBRT for primary and metastatic hepatic malignancies in patients with hepatic cirrhosis. Treatment outcomes and toxicity due to improved conformal avoidance of functional normal liver volumes will be assessed for these patients.

Progression in Child-Pugh and MELD scores, disease free survival, and overall survival (with and without liver transplant) will be evaluated via Kaplan Meier analysis. Freedom from MELD score progression will be measured against residual volumes of functionally active hepatic parenchyma defined on MRI-linac SPION via Cox proportional hazard regression models. Statistical analysis will be conducted with MedCalc version 11.3.

MRI and planning CT images will be co-registered using deformable image registration, and volumes with SPIO accumulation will be delineated as avoidance structures by the physician and clinical physicist. DICOM-compatible applications will be developed for contouring and quantitative assessment of functionally active volumes of hepatic parenchyma obtained from MR-Linac-SPIO images with subsequent conformal avoidance in the beam placement process during 3-D Conformal radiotherapy planning.

A non-contrast enhanced liver MR images will be acquired per fraction with propagation of the previously identified avoidance volumes in the adapted plans.

Follow-up MR-imaging of the patients will be obtained to assess tumor and hepatic parenchyma response treatment.

The dose-response of tumor and hepatic parenchyma to SBRT will be examined using MR imaging (on MR-Linac), pathologic criteria and molecular profiling of explanted livers in a subset of patients who received liver SBRT as a bridge to transplant.

In patients undergoing liver transplant MRI data sets will be merged with 3D dosimetry data and evaluated by a clinical physicist. Radiographic liver responses will be compared with explant liver pathology. The pathologic and genomic analysis will document both tumor and hepatic parenchymal response to SBRT. The chronology of tumor and hepatic parenchymal response and regeneration to radiotherapy will be evaluated. Initial 3D dosimetry will be combined with the pathologic assessment to determine any dose threshold for healthy liver regeneration following SBRT with MR-Linac SPION functional imaging.

Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)

Associate Professor Temple University School of Medicine System Director Stereotactic Body Radiotherapy and GI Cancer Programs Division of Radiation Oncology Allegheny Health Network Cancer Institute

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
HCCBloodTest for Detection of Hepatocellular Carcinoma (HCC)	NCT03804593	Cirrhosis, Live... Hepatic Cirrhos... Hepatocellular ... Liver Cancer		18 Years -	Epigenomics, Inc
HCCBloodTest for Detection of Hepatocellular Carcinoma (HCC)	NCT03804593	Cirrhosis, Live... Hepatic Cirrhos... Hepatocellular ... Liver Cancer		18 Years -	Epigenomics, Inc
Radiotherapy With Iron Oxide Nanoparticles (SPION) on MR-Linac for Primary & Metastatic Hepatic Cancers	NCT04682847	Liver Neoplasms Hepatic Cirrhos... Hepatic Carcino... Liver Cancer Liver Metastase... Liver Carcinoma Hepatocellular ... Hepatocellular ... Hepatic Atrophy	Ferumoxytol inj...	18 Years - 89 Years	Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)

Spots Global Cancer Trial Database for hepatic cirrhosis