Clinical trial NCT03878550: Case-Control Study of the Glycotest™ HCC Panel Vs AFP for the Detection of Early-stage Hepatocellular Carcinoma
Official title: Case-Control Study of the Glycotest™ HCC Panel Vs AFP for the Detection of Early-stage Hepatocellular Carcinoma
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Carcinoma, Hepatocellular
Cirrhosis, Liver
Lead sponsor: Glycotest, Inc.
Sponsor class: INDUSTRY
First posted: 2019-03-18
Enrollment: 766
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population will comprise male and female adult patients with early-stage HCC against a background of cirrhosis (cases) as well as at-risk cirrhotic patients (controls). Enrollment of the aggregate of HCC cases with single lesions ≥ 3 cm and with multiple lesions will be capped at 50% of total cases. Enrollment of Chronic Hepatitis C cases and controls with sustained virologic response (SVR) to therapy will be matched. Cases and controls will be matched based on age, sex and etiology.

Brief summary: Clinical guidelines (AASLD) recommend the use of abdominal ultrasound (US) for surveillance testing for the early detection of Hepatocellular Carcinoma (HCC). The serum protein biomarker alpha-fetoprotein (AFP) is commonly used to augment US but its use alone is not recommended by clinical guidelines. Despite evidence that HCC surveillance improves early detection and reduces mortality from HCC, current HCC surveillance tests lack sensitivity, leaving a significant proportion of patients to present with late-stage disease. The Glycotest HCC Panel has shown better sensitivity than AFP, which is ineffective for the detection of early-stage HCC. This clinical study seeks to validate the Glycotest HCC Panel using a large multicenter cohort of cases and controls that includes patients diagnosed with early-stage HCC against a background of cirrhosis and cirrhotic patients without HCC (at risk) undergoing an established surveillance protocol.

Detailed description: Study Rationale:

This study is designed to compare the ability of the Glycotest HCC Panel with that of AFP to differentiate between patients with early-stage Hepatocellular Carcinoma (HCC) against a background of cirrhosis from cirrhotic patients without HCC (at risk).

Primary Objective:

The primary objective of this study is to determine whether the Glycotest HCC Panel outperforms AFP in terms of area under the receiver operating characteristic curve (AUROC) for the differentiation of patients with early-stage HCC from those without HCC in the at-risk population.

Secondary Objective:

The secondary objective of this study is to determine whether the Glycotest HCC Panel outperforms AFP in terms of clinical sensitivity (as estimated using the 90% specificity estimate as the decision threshold) for the detection of patients with early-stage HCC.

Study Design:

This is a phase 2, multicenter, laboratory-blinded, case-control study of the Glycotest HCC Panel vs AFP for the discrimination of patients with early-stage HCC from those at risk. Case and control samples will be obtained from multiple institutions using prospective collection. The study will consist of a screening/baseline visit for all patients; controls initially assessed by abdominal US will also undergo a 6-month follow-up visit to confirm absence of HCC at enrollment. Assays will be performed by Glycotest with analysts blinded to clinical data.

Population:

The study population will comprise male and female adult patients with early-stage HCC against a background of cirrhosis (cases) as well as at-risk cirrhotic patients (controls). Enrollment of the aggregate of HCC cases with single lesions ≥ 3 cm and with multiple lesions will be capped at 50% of total cases. Enrollment of Chronic Hepatitis C cases and controls with sustained virologic response (SVR) to therapy will be matched. Cases and controls will be matched based on age, sex and etiology.

Number of Subjects:

Maximum of 388 cases and 378 controls;

* 150 cases and 140 controls (training set)
* Maximum of 238 cases and 238 controls (validation set)

Study Duration:

30 months ( approximately 24 months accrual + 6 month follow up)

Study Phases Patients potentially eligible for the study population will undergo informed consent prior to screening/baseline visits.

Screening Once consented, a subject's demographics, medical record, laboratory data, and imaging will be reviewed. Patients are considered eligible for enrollment once they meet all study enrollment criteria.

Enrollment Screening data will be re-reviewed if necessary and recorded. Serum from blood samples (5 mL) will be obtained for measurement of Glycotest HCC Panel score (which includes AFP).

Follow up Medical record review/imaging at 6 months from enrollment for control patients originally assessed using abdominal US.

Eligibility criteria: Inclusion Criteria:

Cases

1. Males and females ages 18 years or older.
2. Treatment-naïve HCC as defined by LI-RADS (Liver Imaging Reporting and Data System) LR-5 or OPTN (Organ Procurement and Transplantation Network) 5 CT or MRI criteria (all lesions must exhibit arterial phase hyper-enhancement), or histologic evidence.
3. Early-stage HCC defined by single lesion ≤ 5 cm or ≤ 3 lesions ≤ 3 cm determined at enrollment or within 100 days prior without vascular invasion.
4. Cirrhosis based on serum biomarkers (FibroSure®/FibroTest \> 0.74, APRI (AST to Platelet Ratio Index) \> 2, or FIB-4 (Fibrosis-4) \> 3.25), histology, imaging, elastography, or clinical evidence of portal hypertension in the setting of known chronic liver disease.
5. Child-Pugh score A-B8.
6. Subject must be able to understand and provide informed consent.

Controls

1. Males and females ages 18 or older.
2. Cirrhosis based on serum biomarkers (FibroSure®/FibroTest \> 0.74, APRI \> 2, or FIB-4 \> 3.25), histology, imaging, elastography, or clinical evidence of portal hypertension in the setting of known chronic liver disease.
3. Evidence of the absence of a solid hepatic mass, suspicious for HCC, at enrollment or within 100 days prior based on one of the following:

   1. Negative multiphase CT scan or MRI with contrast at screening/baseline visit, OR
   2. Negative abdominal US at both screening/baseline visit AND 6-month follow-up visit, OR
   3. Negative abdominal US at screening/baseline visit AND negative multiphase CT scan or MRI with contrast at 6-month or earlier follow-up visit.
4. Child-Pugh score A-B8.
5. Subject must be able to understand and provide informed consent.

Exclusion Criteria:

Cases

1. Uncontrolled ascites.
2. Uncontrolled encephalopathy.
3. History of liver transplant.
4. Diagnosis of active malignancy or history of active malignancy within 5 years prior to enrollment, including mixed HCC-CCA (cholangiocarcinoma). If previously diagnosed with malignancy, subject must be in remission for at least 5 years prior to enrollment. Prior history of HCC, including resection of HCC at any time, is excluded.
5. Prior treatment of tumor.
6. Any significant non-liver-related medical condition in which expected survival is less than 1 year.

Controls

1. Imaging evidence of solid hepatic mass, suspicious for HCC, including lesions meeting LI-RADS LR-3 or LR-4, OPTN-3 or OPTN-4, or LI-RADS LR-M criteria.
2. Uncontrolled ascites.
3. History of liver transplantation.
4. Uncontrolled encephalopathy.
5. Diagnosis of active malignancy or history of active malignancy within 5 years prior to enrollment (if previously diagnosed with malignancy, subject must be in remission for at least 5 years prior to enrollment). History of HCC including resection of HCC at any time, is excluded.
6. Any significant non-liver-related medical condition in which expected survival is less than 1 year.

Primary outcomes:
measure: AUROC
timeFrame: At enrollment
Secondary outcomes:
measure: Sensitivity
timeFrame: At enrollment
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars- Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: San Francisco
country: United States
facility: Kaiser Permanente Northern California
state: California
city: San Francisco
country: United States
facility: University of California- San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: Miami VA Healthcare System
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland, Baltimore
state: Maryland
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: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania (HUP)
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor Scott & White Research Institute
state: Texas
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Jerusalem
country: Israel
facility: Hebrew University- Hadassah Medical Center
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Josep Llovet, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania Medical Center
name: Jorge Marrero, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UT Southwestern Medical Center
name: Amit Singal, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wang M, Sanda M, Comunale MA, Herrera H, Swindell C, Kono Y, Singal AG, Marrero J, Block T, Goldman R, Mehta A. Changes in the Glycosylation of Kininogen and the Development of a Kininogen-Based Algorithm for the Early Detection of HCC. Cancer Epidemiol Biomarkers Prev. 2017 May;26(5):795-803. doi: 10.1158/1055-9965.EPI-16-0974. Epub 2017 Feb 21.