Clinical trial NCT06084234: National Liver Cancer Screening Trial
Official title: National Liver Cancer Screening Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Carcinoma, Hepatocellular
Liver Cancer
Liver Cirrhosis
Hepatitis B
Keywords: Hepatocellular carcinoma surveillance
GALAD
Alpha Fetoprotein
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: University of Pennsylvania
name: University of Michigan
name: Dana-Farber Cancer Institute
name: Baylor College of Medicine
name: Fred Hutchinson Cancer Center
First posted: 2023-10-16
Enrollment: 5500
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a randomized open-label study comparing US ± AFP vs. GALAD-based surveillance every 6 (± 3-month window) months starting at randomization.
Primary purpose: SCREENING

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

Patient must meet all of the following inclusion criteria:

1. Adult patients ages 18-85 with cirrhosis from any etiology or with chronic hepatitis B with a PAGE-B score greater than 9 within 12 months of enrollment
2. Patient is eligible for HCC surveillance according to treating physician or by the site investigator
3. Able to provide informed consent
4. Life expectancy \>6 months (after consent) as determined by the treating provider or site investigator

Exclusion Criteria:

Patient will be excluded for any of the following exclusion criteria:

1. Child Pugh C cirrhosis
2. History or clinical symptoms of hepatocellular carcinoma or cholangiocarcinoma
3. History of solid nodule on baseline ultrasound (i.e., lesion 1cm or greater) within 9 months prior to consent without subsequent diagnostic CT/MRI demonstrating benign nature)
4. AFP \>20 ng/mL within 6 months prior to consent, in the absence of a contrast-enhanced CT or MRI within 6 months of AFP (before or after) level demonstrating lack of suspicious liver lesions
5. Newly diagnosed LR-3 greater than or equal to 1 cm within 6 months prior to consent
6. History of LR-4, LR-5, or LR-M on multi-phase CT or contrast-enhanced MRI within 6 months prior to consent
7. Presence of another active cancer besides non-melanomatous skin cancer or indolent cancer under active surveillance (e.g., prostate cancer or renal cell carcinoma) within the 2 years prior to consent
8. Patient's provider is planning to use MRI- or CT- based surveillance moving forward
9. History of a transjugular intrahepatic portosystemic shunt (TIPS)
10. History of Fontan associated liver disease or cardiac cirrhosis
11. History of solid organ transplantation
12. Actively listed for liver transplantation
13. Diagnosis of alcohol-associated hepatitis within 3 months prior to consent
14. Documented current or continued signs and symptoms of acute Wilson disease (acute liver failure, acute neurological deficits, hemolysis)
15. In patients with primary sclerosing cholangitis (PSC): Current active cholangitis within 90 days prior to consent
16. Known or documented habitual non-adherence to previous research studies or medical procedures or unwillingness to adhere to protocol (e.g., unwilling to obtain consent or samples)
17. In patients living with HIV: CD4+ T cell count less than 100 cells/mm3 within 60 days prior to consent
18. Known pregnancy at consent
19. Active warfarin use

Primary outcomes:
measure: Proportion of HCC detected at late stage
timeFrame: 5.5 years
Secondary outcomes:
measure: HCC Screening utilization
timeFrame: 5.5 years
measure: Proportion of HCC detected at a late-stage (defined based on BCLC stage)
timeFrame: 5.5 years
measure: Incidence of late-stage HCC
timeFrame: 8 years
measure: Proportion of HCC cases that receive Curative therapy
timeFrame: 5.5 years
measure: Number of participants who encountered screening related physical harm
timeFrame: 5.5 years
measure: Number of participants who encountered screening related financial harm
timeFrame: 5.5 years
measure: Number of participants who encountered screening related Psychological harm
timeFrame: 5.5 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Redwood City
country: United States
facility: Stanford University
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Manhasset
country: United States
facility: The Feinstein Institutes, Northwell Health, Inc.
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center and Parkland Hospital
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: UT Southwestern Medical Center
name: Amit Singal, MD, MS
role: PRINCIPAL_INVESTIGATOR
References: