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Participants in this arm will undergo current standard of care surveillance procedures i.e. liver ultrasound with or without alpha fetoprotein (AFP) measurement.

For participants in this arm, study team will order GALAD measurement every 6 months +/- 3 months.

GALAD is a 3 biomarker panel incorporating AFP, AFP-L3% and DCP (all FDA approved), with patient age and sex.

GALAD

This intervention consists of current standard of care ultrasound based surveillance with or without alpha-fetoprotein measurement.

Liver Ultrasound with or without AFP

Amit Singal, MD, MS

Sneha Deodhar, MS

Kali Zhou, MD

Rae Davis

Neil Mehta, MD

Sherri Cummins

Naga Chalasani, MD

Irun Bhan, MD

Shay Robison

Neehar Parikh, MD, MS

Jessica Peruski

Reena Salgia, MD

Dibnain Nanda

Sanjaya Satapathy, MBBS, MS

Grace Kim

Jorge Marrero, MD,MS

Sara Fares

Fasiha Kanwal, MD, MSHS

The National Liver Cancer Screening Trial is an adaptive randomized phase IV Trial comparing ultrasound-based versus biomarker-based screening in 5500 patients with cirrhosis from any etiology or patients with chronic hepatitis B infection. Eligible patients will be randomized in a 1:1 fashion to Arm A using semi-annual ultrasound and AFP-based screening or Arm B using semi-annual screening using GALAD alone. Randomization will be stratified by sex, enrolling site, Child Pugh class (A vs. B), and HCC etiology (viral vs. non-viral). Patients will be recruited from 15 sites (mix of tertiary care and large community health systems) over a 3-year period, and the primary endpoint of the phase IV trial, reduction in late-stage HCC, will be assessed after 5.5 years.

The TRACER phase IV biomarker study is a randomized trial comparing ultrasound-based screening versus a biomarker-based strategy in patients with cirrhosis. In brief, 5500 patients with cirrhosis from any etiology would be randomized in a 1:1 fashion to Arm A offering semi-annual ultrasound +/- AFP-based screening or Arm B offering semi-annual biomarker-based screening. Randomization will be stratified by site, Child Pugh class (A vs. B), liver disease etiology (viral, non-viral, and non-cirrhotic HBV infection) and sex. Patients will be recruited from 15 sites (mix of tertiary care and large community health systems) over a 3-year period, and reduction in the proportion of late-stage HCC, will be assessed at the end of Year 5.5. If the results are promising, study team will continue extended follow-up and compare the incidence of late-stage HCC between the two arms at Year 8 and reduction in HCC mortality during long term follow up.

Study team will include adult patients, age ≥ 18 years, with Child Pugh class A or B cirrhosis of any etiology or non-cirrhotic chronic hepatitis B virus infection with PAGE-B score \>9. Study team will exclude patients post liver transplantation, patients with Child Pugh C cirrhosis, patients with significant comorbidity and limited life expectancy, and those with history of other malignancy, except non-melanoma skin cancer or indolent tumors, within 3 years prior to enrollment given lack of screening recommendations in those patient populations. Study team will also exclude patients with suspicious liver masses at baseline as well as those with a solid lesion ≥1 cm on ultrasound or AFP ≥20 ng/mL without diagnostic evaluation to exclude HCC. Study team will also exclude patients in whom the provider plans to follow the patient with CT or MRI-based surveillance. GALAD is not recommended in patients with pregnancy or active warfarin use given known impact on biomarker performance, so these patients will be excluded.

At enrollment, study team will record patient demographics and clinical characteristics using a combination of electronic medical records and patient questionnaires. Patients will then be offered semi-annual surveillance as defined by their study arm: ultrasound and AFP for patients in Arm A and the biomarker, GALAD, for patients in Arm B. Repeat surveillance tests will be offered every six months (per assigned arm) for patients with normal surveillance results. Diagnostic evaluation with multi-phasic CT or contrast-enhanced MRI will be recommended for any patients with abnormal screening results. Patients with normal diagnostic testing (i.e., false positive result) will be recommended to return to their assigned surveillance arm. Standardized criteria from the AASLD and LI-RADS will be used to define incident HCC. Study team will use a set of validated surveys (e.g., Psychological Consequences Questionnaire, Decision Regret scale, FACIT-COST) to measure secondary outcomes of interest including psychological and financial harms.

This is a randomized open-label study comparing US ± AFP vs. GALAD-based surveillance every 6 (± 3-month window) months starting at randomization.

National Liver Cancer Screening Trial

Proportion of HCC detected at a late stage, defined as HCC beyond Milan Criteria (one tumor less than or equal to 5 cm or 2-3 tumors each less than or equal to 3 cm, in the absence of vascular invasion or extra-hepatic metastases)

Defined as proportion time covered by screening; each completed screening test (US +/- AFP or GALAD) will provide up to six months of coverage (numerator) divided by the total follow-up for each patient.

Defined as HCC beyond BCLC stage A (single tumor of any size without vascular invasion or extrahepatic spread; or 2-3 tumors equal to or less than 3 cm each, without vascular invasion or extrahepatic spread)

Defined as incidence of HCC (extended follow-up) beyond Milan Criteria or BCLC stage A

Defined as count of participants in receipt of liver transplantation, surgical resection, local ablative therapy, or radiation segmentectomy

Physical harms will be defined as count of participants in receipt of diagnostic imaging for false positive or indeterminate results.

Financial harms will be defined by direct costs (charges for all screening and diagnostic testing and co-pays) and indirect costs (e.g., travel and lost wages)

Count of participants who encountered Psychological harms that includes cancer-specific worry and decisional regret.

National Cancer Institute (NCI)

University of Pennsylvania

University of Michigan

Dana-Farber Cancer Institute

Baylor College of Medicine

Fred Hutchinson Cancer Center

University of Texas Southwestern Medical Center

Professor

Approximately 1400 HCC surveillance subjects (controls) will be enrolled.

Approximately 700 subjects with untreated clinically diagnosed HCC will be enrolled.

HCC subjects will have one blood sample collected.

Blood Sample Collection

Surveillance subjects will have a blood sample collected and will be followed for up to 6 months. A second blood sample will be collected at the 6 month visit which will be scheduled no longer than 6 months from enrollment.

Laura Strong

The primary objective of this study is to obtain de-identified, clinically-characterized whole blood specimens for use in developing and evaluating the performance of new biomarker assays for detection of hepatocellular carcinoma (HCC).

Subjects with untreated Hepatocellular Carcinoma (HCC) and subjects undergoing HCC surveillance will be enrolled and have blood samples collected. Subjects undergoing HCC surveillance will be followed for up to 6 months. Another blood sample will be collected at the 6 month visit which will be scheduled no longer than 6 months from enrollment.

Blood samples will not be used other than to develop and evaluate the performance of blood-based biomarker assays to detect cancer. Samples may be stored for up to 10 years.

Blood Sample Collection to Evaluate Biomarkers for Hepatocellular Carcinoma

2017-01: Blood Sample Collection to Evaluate Biomarkers for Hepatocellular Carcinoma

Individual participant data that underlie the results reported in publications of the study will be shared after deidentification. This may include text, tables, figures, and appendices. The study protocol, statistical analysis plan, informed consent form, and clinical study report will also be shared.

Biomarkers under evaluation include differential methylation of nucleic acids and altered expression of proteins in blood from subjects with HCC compared to those without (but are at risk of developing the disease so are under surveillance)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
National Liver Cancer Screening Trial	NCT06084234	Carcinoma, Hepa... Liver Cancer Liver Cirrhosis Hepatitis B	GALAD Liver Ultrasoun...	18 Years - 85 Years	University of Texas Southwestern Medical Center
Blood Sample Collection to Evaluate Biomarkers for Hepatocellular Carcinoma	NCT03628651	Hepatocellular ... Hepatocellular ...	Blood Sample Co... Blood Sample Co...	18 Years -	Exact Sciences Corporation

Spots Global Cancer Trial Database for hepatocellular carcinoma surveillance