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Trial registered on ANZCTR


Registration number
ACTRN12623000762651
Ethics application status
Approved
Date submitted
22/03/2023
Date registered
12/07/2023
Date last updated
12/07/2023
Date data sharing statement initially provided
12/07/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
Evaluation of molecular biomarkers for hepatocellular carcinoma (HCC) therapy
Scientific title
Evaluation of molecular biomarkers for hepatocellular carcinoma (HCC) therapy to predict progression free survival after therapy
Secondary ID [1] 309276 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hepatocellular Carcinoma 329428 0
Liver Cancer 329429 0
Liver Cirrhosis 329430 0
Condition category
Condition code
Oral and Gastrointestinal 326376 326376 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Cancer 326528 326528 0 0
Liver

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This is a single centre, prospective, exploratory and observational study of adults (aged 18 and over) who are undergoing therapy for hepatocellular carcinoma (HCC).

Study question 1:
Following HCC therapy, how do biomarkers change over time? Can this help inform HCC prognosis and predict early recurrence?

Suitable patients will be identified during the HCC multi-disciplinary meeting and will be approached by an investigator via face to face, telehealth or telephone contact. This may be done during or outside of a scheduled HCC clinic.

Time points for blood tests include baseline (just prior to therapy), immediately after therapy then every 3 months, for up to 2 years. An additional time point for blood sample collection will be added at approximately week 4-6 for patients who receive routine follow imaging at the time and also for patients receiving systemic therapy.

Laboratory tests such as digital droplet PCR will be utilized to determine patient specific mutations. Novel biomarkers such as serum markers (Alfa-fetoprotein, Des-gamma-carboxy prothrombin), somatic mutations (TERT promoter), methylation markers may be tested.

Study question 2:
In the subset of patients with HCC referred for consideration of liver transplant assessment, how do their biomarkers change over time prior to transplantation?

We aim to describe biomarker kinetics in patients with HCC following referral for liver transplant assessment. These patients may be recruited regardless of previous therapy.

In this part of the study, we aim to collect blood samples every three months, prior to liver transplantation. This will be performed during their routine imaging as part of standard of care.

Following liver transplantation, these patients will cross over into study question 1.
Intervention code [1] 325711 0
Diagnosis / Prognosis
Comparator / control treatment
We plan to recruit controls for this study. Controls will include healthy patients, patients with liver cirrhosis and patients with sepsis. As this is an exploratory study to perform an early evaluation of novel biomarkers to inform the design of larger studies.

As a pragmatic approach, we aim to recruit 40 controls, with aetiologies of liver disease in cirrhotic controls representative of the study population. This number has been selected to ensure sufficient numbers to draw conclusions for this study. Blood samples will be collected at a single time point, and patients’ past medical and medication history will be recorded.
Control group
Active

Outcomes
Primary outcome [1] 334230 0
The ability of a novel biomarker panel to predict progression-free survival following HCC therapy.

Clinical outcomes will be assessed from review of patient medical records, using statistical analysis including survival (cox proportional hazards) and area under the receiver-operating-characteristic curve analysis.

The novel biomarker panel may include serum markers (alfa-fetoprotein, Des-gamma-carboxy prothrombin), somatic mutations (TERT promoter mutations), methylation markers.
Timepoint [1] 334230 0
Study question 1 - Up to 2 years post HCC therapy

Time points for blood sampling are every 3 months up to 2 years. An additional time point for blood sample collection will be added at approximately week 4-6 for patients who receive routine follow up imaging at the time and also for patients receiving systemic therapy. This will continue until progression of HCC or up to 2 years post HCC therapy. At each time point the novel biomarker panel will be tested as well as assessment of pre-specified primary and secondary outcome measures.

Study question 2 - Up to 2 years post liver transplantation

Patients who are anticipated to require liver transplantation will have blood sampling every 3 months up until liver transplantation. Following this, patients will have bloods sampled every 3-6 months until recurrence of HCC or up to 2 years post HCC therapy. At each time point the novel biomarker panel will be tested as well as assessment of pre-specified primary and secondary outcome measures.
Secondary outcome [1] 419917 0
The ability of novel biomarkers to predict overall survival

Clinical outcomes will be assessed from review of patient medical records, using statistical analysis including survival (cox proportional hazards) and area under the receiver-operating-characteristic curve analysis.

The novel biomarker panel may include serum markers (alfa-fetoprotein, Des-gamma-carboxy prothrombin), somatic mutations (TERT promoter mutations), methylation markers.
Timepoint [1] 419917 0
Study question 1 - Up to 2 years post HCC therapy

Time points for blood sampling are every 3 months up to 2 years. An additional time point for blood sample collection will be added at approximately week 4-6 for patients who receive routine follow up imaging at the time and also for patients receiving systemic therapy. This will continue until progression of HCC or up to 2 years post HCC therapy. At each time point the novel biomarker panel will be tested as well as assessment of pre-specified primary and secondary outcome measures.

Study question 2 - Up to 2 years post liver transplantation

Patients who are anticipated to require liver transplantation will have blood sampling every 3 months up until liver transplantation. Following this, patients will have bloods sampled every 3-6 months until recurrence of HCC or up to 2 years post HCC therapy. At each time point the novel biomarker panel will be tested as well as assessment of pre-specified primary and secondary outcome measures.
Secondary outcome [2] 419918 0
The ability of a novel biomarker panel to detect early disease recurrence

Clinical outcomes will be assessed from review of patient medical records, using statistical analysis including survival (cox proportional hazards) and area under the receiver-operating-characteristic curve analysis.

The novel biomarker panel may include serum markers (alfa-fetoprotein, Des-gamma-carboxy prothrombin), somatic mutations (TERT promoter mutations), methylation markers.
Timepoint [2] 419918 0
Study question 1 - Up to 2 years post HCC therapy

Time points for blood sampling are every 3 months up to 2 years. An additional time point for blood sample collection will be added at approximately week 4-6 for patients who receive routine follow up imaging at the time and also for patients receiving systemic therapy. This will continue until progression of HCC or up to 2 years post HCC therapy. At each time point the novel biomarker panel will be tested as well as assessment of pre-specified primary and secondary outcome measures.

Study question 2 - Up to 2 years post liver transplantation

Patients who are anticipated to require liver transplantation will have blood sampling every 3 months up until liver transplantation. Following this, patients will have bloods sampled every 3-6 months until recurrence of HCC or up to 2 years post HCC therapy. At each time point the novel biomarker panel will be tested as well as assessment of pre-specified primary and secondary outcome measures.
Secondary outcome [3] 419920 0
The ability of a novel biomarker panel to detect minimal residual disease

Clinical outcomes will be assessed from review of patient medical records, using statistical analysis including survival (cox proportional hazards) and area under the receiver-operating-characteristic curve analysis.

The novel biomarker panel may include serum markers (alfa-fetoprotein, Des-gamma-carboxy prothrombin), somatic mutations (TERT promoter mutations), methylation markers.
Timepoint [3] 419920 0
Study question 1 - Up to 2 years post HCC therapy

Time points for blood sampling are every 3 months up to 2 years. An additional time point for blood sample collection will be added at approximately week 4-6 for patients who receive routine follow up imaging at the time and also for patients receiving systemic therapy. This will continue until progression of HCC or up to 2 years post HCC therapy. At each time point the novel biomarker panel will be tested as well as assessment of pre-specified primary and secondary outcome measures.

Study question 2 - Up to 2 years post liver transplantation

Patients who are anticipated to require liver transplantation will have blood sampling every 3 months up until liver transplantation. Following this, patients will have bloods sampled every 3-6 months until recurrence of HCC or up to 2 years post HCC therapy. At each time point the novel biomarker panel will be tested as well as assessment of pre-specified primary and secondary outcome measures.

Eligibility
Key inclusion criteria
Study question 1:
1. Age 18 or greater
2. Adult patients undergoing therapy for Hepatocellular Carcinoma (HCC)
a. Therapy may include 3 broad categories
i. Interventional radiology
1. Transarterial Chemo-embolisaion (TACE)
2. Microwave ablation (MWA)
3. Radiofrequency ablation (RFA)
4. Selective Internal Radiation-Therapy (SIRT)
5. Percutaneous Ethanol Injection (PEI)
ii. Surgery
1. Liver resection
2. Liver transplantation
iii. Radiation oncology
1. Stereotactic Body Radiation Therapy (SBRT)
iv. Medical oncology
1. Systemic therapy
v. Other
3. Informed consent

Study Question 2:
1. Age 18 or greater
2. Adult patients diagnosed with HCC
a. Referred to the HCC Multi-disciplinary meeting for consideration of liver transplant assessment or
b. Referred to the pre-liver transplant clinic for consideration of liver transplant assessment
3. Patients must have been informed by a clinician from the Liver Transplant Unit that they are being considered for liver transplant assessment, with documentation in medical records
a. Patients may or may not yet have been formally assessed or wait listed for liver transplantation
4. Patients may or may not have undergone prior therapy for HCC
5. Informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Unable to consent
2. Withdrawal of consent

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
SAMPLE SIZE ESTIMATION & JUSTIFICATION
This is a pilot study to evaluate novel biomarker for treatment response in patients undergoing therapy for HCC.

STATISTICAL METHODS TO BE UNDERTAKEN
Receiver-operating-characteristic analysis will be conducted to assess the discriminative performance of novel biomarkers in combination with serum biomarkers, against standard imaging techniques and standard of care serum alphafeto protein in evaluating treatment response.

POWER CALCULATION
As this is an exploratory study to perform an early evaluation of novel biomarkers to inform the design of larger studies. As a pragmatic approach to the above uncertainty, we aim to recruit 150 patients over 36 months.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
28/03/2022
Date of last participant enrolment
Anticipated
1/12/2023
Actual
Date of last data collection
Anticipated
31/12/2026
Actual
Sample size
Target
150
Accrual to date
123
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 24320 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 39879 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 313470 0
Charities/Societies/Foundations
Name [1] 313470 0
Austin Medical Research Foundation
Country [1] 313470 0
Australia
Funding source category [2] 313471 0
Hospital
Name [2] 313471 0
Austin Health Hepatocellular Carcinoma Multi-Disciplinary Team research fund
Country [2] 313471 0
Australia
Primary sponsor type
Individual
Name
A/Prof Adam Testro
Address
Victorian Liver Transplant Unit,
Level 8 Harold Stokes Building,
145 Studley Road,
Heidelberg, VIC 3084
Country
Australia
Secondary sponsor category [1] 315241 0
None
Name [1] 315241 0
Address [1] 315241 0
Country [1] 315241 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312666 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 312666 0
Level 8, Harold Stokes Building,
145 Studley Road,
Heidelberg,
VIC 3084
Ethics committee country [1] 312666 0
Australia
Date submitted for ethics approval [1] 312666 0
03/08/2021
Approval date [1] 312666 0
20/03/2022
Ethics approval number [1] 312666 0
HREC/78339/Austin-2021

Summary
Brief summary
This is an exploratory observational study of biomarkers in adults undergoing therapy for hepatocellular carcinoma (HCC).

Who is it for?
You may be eligible for this study if you are aged 18 and above, are undergoing therapy for HCC.

Study details
All participants in this study will have blood samples taken during their scheduled visits with their physician. Time points for blood tests include baseline (just prior to therapy), immediately after therapy then every 3 months, for up to 2 years. An additional time point for blood sample collection will be added at approximately week 4-6 for patients who receive routine follow imaging at the time and also for patients receiving systemic therapy.

In the subset of patients with HCC referred for consideration of liver transplant assessment, blood samples will be taken every three months, prior to liver transplantation. This will be performed during their routine imaging as part of standard of care. Following liver transplantation, these patients will be followed at the same timepoints as the main HCC group.

The following biomarkers will be evaluated: alfa-fetoprotein (AFP), Des-gamma-carboxy prothrombin (DCP), as well as exploratory somatic mutation and methylation markers.

It is hoped that this research will help identify circulating biomarkers that can predict outcome and response to therapy for HCC.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125486 0
A/Prof Adam Testro
Address 125486 0
Victoria Liver Transplant Unit
Level 8, Harold Stokes Building
Austin Health
145 Studley Road,
Heidelberg,
VIC 3084
Country 125486 0
Australia
Phone 125486 0
+61409978158
Fax 125486 0
Email 125486 0
adam.testro@austin.org.au
Contact person for public queries
Name 125487 0
Dr William Chung
Address 125487 0
Department of Gastroenterology,
Level 8, Harold Stokes Building,
Austin Health,
145 Studley Road,
Heidelberg,
VIC 3084
Country 125487 0
Australia
Phone 125487 0
+61419940776
Fax 125487 0
Email 125487 0
william.chung2@austin.org.au
Contact person for scientific queries
Name 125488 0
Dr William Chung
Address 125488 0
Department of Gastroenterology,
Level 8, Harold Stokes Building,
Austin Health,
145 Studley Road,
Heidelberg,
VIC 3084
Country 125488 0
Australia
Phone 125488 0
+61 394965000
Fax 125488 0
Email 125488 0
william.chung2@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data (IPD) will not be available as this has not been approved by the Austin Health ethics committee.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.