Condition category
Cancer
Date applied
07/10/2019
Date assigned
10/12/2019
Last edited
10/12/2019
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Primary liver cancer, predominantly hepatocellular carcinoma (HCC), is the second commonest cause of cancer death in the world. Deaths continue to rise, as most HCCs present at advanced stages when surgical cure is not possible and the only available medical treatment extends life by just a few weeks. There is therefore an urgent need to develop new treatments for HCC. There is excitement around a new class of immune system-based therapies that work by stimulating aspects of the immune system surrounding the tumour to promote anti-cancer immune responses. Preliminary clinical studies with one type of immune therapy suggest that 15- 20% of HCC patients benefit by gaining months or even years of life. CRUK has funded the creation of HUNTER: the Hepatocellular Carcinoma Expediter Network, to support an in-depth study of the immune components of the tissue microenvironment in which HCC develops, so that novel immune approaches for HCC can be developed. The HUNTER team has the combined expertise to recruit the patients, collect their tissues and data, study the immune cells around the cancers and how they talk to each other, while identifying the blood-based biomarkers that reflect what is happening in the tumour – to find out which new treatment to use for individual patients and how to monitor them. The team will also use the same tissues to create models that enable the development and testing of new biomarker-guided treatment approaches. The goal is to study the cancers and their immune surroundings in order to:
1. Identify biomarkers that predict patient survival and outcome with current therapies
2. Develop novel immune-based treatment approaches, possibly in combination with current therapies
3. Identify biomarkers to guide immune-based treatments or combination treatments
4. Develop models to test immune-based therapies or combinations

Who can participate?
Patients aged over 18 with primary liver cancer, secondary liver cancer or chronic liver disease, attending the Newcastle upon Tyne NHS Foundation Trust, or one of the collaborating centres, for consideration of liver-related treatment

What does the study involve?
The study involves participants giving consent for some extra blood (about two to three tablespoons) to be taken at the same time as routine blood samples which are taken during outpatient clinic visits as well as before and after investigations or treatments on the liver, surgical or oncology wards. Participants could also be asked for extra samples (at the same time as routine samples) at follow up appointments. In addition, leftover tissue may be collected from the liver after a liver biopsy or a liver operation (this would not involve any extra procedure). After the study is finished the researchers would like to keep the samples for use in future studies.

What are the possible benefits and risks of participating?
There will be no direct clinical benefit to participants. However, the outcome of the research could influence the care of other patients in the future. Participating in the study is expected to have no implications for participants or their treatment. All data will be stored securely. The researchers do not anticipate any disadvantages of taking part.

Where is the study run from?
1. Newcastle Upon Tyne Hospitals NHS Foundation Trust
2. University Hospitals Birmingham NHS Foundation Trust
3. Cambridge University Hospitals NHS Foundation Trust
4. Royal Free London NHS Foundation Trust
5. University Hospital Southampton NHS Foundation Trust
6. King's College Hospital NHS Foundation Trust
7. Imperial College Healthcare NHS Trust
8. Royal Liverpool And Broadgreen University Hospitals NHS Trust
9. The Christie NHS Foundation Trust
10. Oxford University Hospitals NHS Foundation Trust
11. NHS Lothian
12. NHS Greater Glasgow and Clyde
13. Leeds Teaching Hospitals NHS Trust

When is the study starting and how long is it expected to run for?
December 2018 to November 2023

Who is funding the study?
Cancer Research UK

Who is the main contact?
Sarah Greenhalgh
Sarah.greenhalgh@ncl.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Mrs Sarah Greenhalgh

ORCID ID

Contact details

Faculty of Medical Sciences Project Management Team
Medical School
Framlington Place
Newcastle upon Tyne
NE2 4HH
United Kingdom

Type

Scientific

Additional contact

Prof Helen Reeves

ORCID ID

Contact details

Northern Institute for Cancer Research
Paul O'Gorman Building
Medical School
Framlington Place
Newcastle upon Tyne
NE2 4HH
United Kingdom
+44 (0)191 208 4423
helen.reeves@ncl.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

CPMS: 42961

Study information

Scientific title

HUNTER: Hepatocellular Carcinoma Expediter Network - created to define the hepatocellular carcinoma immune environment, the key mechanisms and biomarkers, and to develop the pre-clinical models needed, to deliver immunotherapy to patients with liver cancer

Acronym

HUNTER

Study hypothesis

Primary liver cancer, predominantly hepatocellular carcinoma (HCC), is the second commonest cause of cancer death in the world. Deaths continue to rise, as most HCCs present at advanced stages when surgical cure is not possible and the only available medical treatment extends life by just a few weeks. There is therefore an urgent need to develop new treatments for HCC. There is excitement around a new class of immune system-based therapies that work by stimulating aspects of the immune system surrounding the tumour to promote anti-cancer immune responses. Preliminary clinical studies with one type of immune therapy suggest that 15- 20% of HCC patients benefit by gaining months or even years of life. CRUK has funded the creation of HUNTER: the Hepatocellular Carcinoma Expediter Network, to support an in-depth study of the immune components of the tissue microenvironment in which HCC develops, so that novel immune approaches for HCC can be developed. The HUNTER team has the combined expertise to recruit the patients, collect their tissues and data, study the immune cells around the cancers and how they talk to each other, while identifying the blood-based biomarkers that reflect what is happening in the tumour – so that we will know which new treatment to use for individual patients and how to monitor them. The team will also use the same tissues to create models that enable the development and testing of new biomarker-guided treatment approaches.

The goal is to study the cancers and their immune surroundings, so that we can:
1. Identify biomarkers that predict patient survival and outcome with current therapies
2. Develop novel immune-based treatment approaches, possibly in combination with current therapies
3. Identify biomarkers to guide immune-based treatments or combination treatments
4. Develop models to test immune-based therapies or combinations

Ethics approval

Approved 13/09/2019, North East - Newcastle & North Tyneside 2 Research Ethics Committee (NHS BT Blood Donor Centre, Holland Drive, Newcastle upon Tyne, Tyne and Wear, NE2 4NQ; Tel: +44 (0)207 1048091; Email: nrescommittee.northeast-newcastleandnorthtyneside2@nhs.net), ref: 19/NE/0251

Study design

Observational; Design type: Cohort study

Primary study design

Observational

Secondary study design

Cohort study

Trial setting

Hospitals

Trial type

Diagnostic

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Liver cancer

Intervention

The study aims are to understand the immune changes that occur in patients with liver disease that promote the development of liver cancer. With this information, the researchers aim to identify novel strategies that are urgently needed to treat patients with Liver cancer. Alongside this, they need to identify the biomarkers that will help us choose the best treatment, or combination of treatments. To explore how interventions or treatments manipulating the immune system will work, the researchers need to develop modelling systems that recreate the diseased environment and immune system and cancer, in which to test them.

To deliver this, the researchers need patients (with cancer and without) and their tissues, teams of people who can recruit patients and collect tissues and data, expert scientists and immunologists who know how to interrogate the cancers and the immune cells, translational scientists who can develop the models, and people who can analyse the data and translate it back to patient care. The researchers also need to communicate well, sharing and integrating all the data from the patients and their tissues effectively. To support this key project, CRUK have funded the creation of the HUNTER network.

Hypothesis: Defining the HCC immune environment will accelerate the delivery of effective immunotherapies for our patients.

KEY ASPECTS OF THE STUDY DESIGN & METHODOLOGY
1. STORED HISTORICAL SAMPLES. Shared tissues and data from patients who have previously consented to research studies. Within the HUNTER network of co-investigators, the researchers have a number of stored tissues resources available, which will be shared.
2. NATIONWIDE PATIENT RECRUITMENT. To study these inter-related aspects of the tumour immune response, the researchers need to recruit patients undergoing treatments as part of their usual care and collect their data, but also their tissues (liver and blood). Despite liver cancer being common, suitable patients undergoing treatments are not common, in part because so many patients are too unwell to be treated. The researchers need to study liver tissues, but surgery is offered to few, either because their cancer is too advanced to cure by surgery, or their liver function is not good enough for an operation. We do get biopsy tissues to confirm the diagnosis in some patients, but this is also relatively rare as in most patients, you can make the diagnosis on a scan, and biopsy is avoided because it is risky. So to recruit enough patients and their tissues, it is essential to work together to recruit patients and share their precious tissues for this comprehensive immune characterisation. Support from the Clinical Research Network (CRN) will enable us to recruit suitable patients from as many centres as possible.
3. SAMPLES SHARING. The centres using fresh tissues to isolate cells will do this immediately on site. Where possible, samples may be shared directly between units on the same day (e.g. London centres). Organoids (see RESEARCH DESIGN below) will be cultured where possible from all cases with tissue available – either on a site with the expertise (training is part of the award), or by funded technical staff in Newcastle – with samples shipped immediately in culture media to Newcastle. For the all the samples not used immediately in the recruiting centre, Newcastle will act as the storage and redistribution hub. In particular, this will be for the circulating biomarker identification, validation and quantification studies. Organoids made and stored in Newcastle will be distributed to the participating centres for modelling projects.
4. WHAT WILL HAPPEN TO THE PATIENTS - The project will start as soon as all regulatory approvals at the participating institutions are in place. The researchers will purposefully recruit patients with a range of stages of liver cancer, treated in different ways. The patients with cancers will be approached soon after their first presentation, at the specialist centre to which they are referred. The research study will be explained after their consultation, and the patient information and consent sheet given to them then – either by their doctor or one of the research nurses. Samples and data will be subsequently be collected from consenting patients. This would only be at planned visits – either to outpatients, day units or wards - for their planned treatment and follow up. There would be no additional visits. When patients attend follow up after their treatment, they may be asked to give more blood samples to look for changes in the candidate biomarkers in patients who do and don't respond. If patients receive treatment, they will be monitored with CT or MRI as per their local management guidelines. The details of which samples will be taken and when, is provided in the study protocol. While patients remain under follow-up, the researchers will continue to monitor their progress and record this. If patients become too unwell to attend, they will not be approached directly for research purposes. Their date of death would subsequently be recorded by their clinical care team.
5. THE NUMBERS OF PATIENTS - The researchers would like to recruit 1500 patients nationwide, including ~1000 with HCC and ~500 controls. They need tissues to study and the numbers of patients is partly based on practical issues, in terms of how many will likely be seen nationwide that are fit for treatment. Much of the tissues and living cells studies and models development will be performed on site at the centre recruiting the patient. Blood samples taken at the same time will be used to explore the changes in the blood that reflect changes in the tissues. Regardless of the centre, however, whether patients have resection or biopsy liver tissues available or not - the researchers want their blood for research. They need the blood to identify and validate prognostic blood test based biomarkers that will help predict prognosis, as well as potentially responses to treatments. They have planned to try to recruit roughly equal numbers at each stage (between 300 and 400) and Professor James Wason (Statistician) has advised on the numbers within each stage that would be needed to report a range of hazards ratios with 90% power.
The control patients will include patients with liver disease but no cancer, who are attending our hospitals for management of their underlying liver disease. These patients at risk of developing liver cancer and the research is therefore relevant to them personally. They will have samples collected after consent, in a similar fashion to patients with cancer. The nature of their liver disease and their liver function will be recorded as data. When candidate biomarkers are identified, it is important to be sure that these are cancer-specific changes, rather than relating to other variables that patients with HCC may also have (eg. viral hepatitis B or C, alcohol excess, obesity, type 2 diabetes, medications, presence of cirrhosis, liver function tests). Controls will also include patients having a biopsy or a liver resection of a different kind of liver tumour (eg. benign, cholangiocarcinoma, or secondary liver cancer). It is important to compare candidate biomarkers to see if they are specific for HCC tumours.
6. DATA & REPORTING - All clinical datasets will be collected by clinical research staff using a case record form. Clinical staff will not be aware of the research data, avoiding any researcher bias in clinical datasets. The data will be entered – in a coded fashion without identifying personal information – into a centralised data registry managed by Newcastle University Learning Department. Correlations between clinical datasets and research findings will be analysed periodically, most often before annual investigator meetings and for the generation of interim reports for CRUK, as well as at the time of abstract submission to scientific meetings. Reports, outputs and strategic future strategic direction will be monitored by the HUNTER advisory board, made up of representatives from each coinvestigator centre, as well as representatives from CRUK.
7. PPI - Prior to submitting the HUNTER application, the researchers sought advice and input from the LiverNorth patient support group. The patient information and consent forms have been reviewed and modified by LiverNorth members. At least one LiverNorth representative will be a part of the HUNTER advisory board. Part of their contribution will be to advise and help to develop the patient public interaction aspects for HUNTER, with the funding provided by CRUK for that purpose, within the award.

Intervention type

Other

Phase

Drug names

Primary outcome measure

Patient survival measured in months after diagnosis of HCC

Secondary outcome measures

1. Radiological response to treatment measured using CT scans 1 month after treatment, and 3-monthly thereafter
2. Clinical response to treatment measured using clinical assessment and blood tests 1 month after treatment, and 3-monthly thereafter
3. Time to radiological progression measured using CT scans at 1-3 monthly intervals
4. Time to clinical progression measured using outpatient visits at 1-3 monthly intervals
5. Time to recurrence measured using CT scans at 1-3 monthly intervals

Overall trial start date

01/12/2018

Overall trial end date

30/11/2023

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Patients will be over 18 years of age
2. The recruited patients will have primary liver cancer, secondary liver cancer or chronic liver disease
3. Patients will be attending the Newcastle upon Tyne NHS Foundation Trust, or one of the collaborating centres, for consideration of liver related treatment
4. The patient will be willing and able to provide written informed consent to take part in the study

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 1500; UK Sample Size: 1500

Participant exclusion criteria

1. Patients who have received previous treatment for HCC, unless recruited just prior to starting 2nd line treatment
2. Patients deemed too distressed or unwell to approach about taking part in the research project
3. Patients who lack capacity to give informed consent
4. Patients who are not able to undertake study procedures

Recruitment start date

01/11/2019

Recruitment end date

01/11/2023

Locations

Countries of recruitment

United Kingdom

Trial participating centre

The Newcastle Upon Tyne Hospitals NHS Foundation Trust
Freeman Hospital Freeman Road High Heaton
Newcastle Upon Tyne
NE7 7DN
United Kingdom

Trial participating centre

University Hospitals Birmingham NHS Foundation Trust
Trust HQ, PO Box 9551 Queen Elizabeth Medical Centre Edgbaston
Birmingham
B15 2TH
United Kingdom

Trial participating centre

Cambridge University Hospitals NHS Foundation Trust
Addenbrookes Hospital Hills Road
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

Royal Free London NHS Foundation Trust
Royal Free Hospital Pond Street
London
NW3 2QG
United Kingdom

Trial participating centre

University Hospital Southampton NHS Foundation Trust
Mailpoint 18 Southampton General Hospital Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

King's College Hospital NHS Foundation Trust
Denmark Hill
London
SE5 9RS
United Kingdom

Trial participating centre

Imperial College Healthcare NHS Trust
St. Marys Hospital Praed Street
London
W2 1NY
United Kingdom

Trial participating centre

Royal Liverpool and Broadgreen University Hospitals NHS Trust
Royal Liverpool University Hospital Prescot Street
Liverpool
L7 8XP
United Kingdom

Trial participating centre

The Christie NHS Foundation Trust
550 Wilmslow Road Withington
Manchester
M20 4BX
United Kingdom

Trial participating centre

Oxford University Hospitals NHS Foundation Trust
John Radcliffe Hospital Headley Way Headington
Oxford
OX3 9DU
United Kingdom

Trial participating centre

NHS Lothian
Waverley Gate 2-4 Waterloo Place
Edinburgh
EH1 3EG
United Kingdom

Trial participating centre

NHS Greater Glasgow and Clyde
J B Russell House Gartnavel Royal Hospital 1055 Great Western Road
Glasgow
G12 0XH
United Kingdom

Trial participating centre

Leeds Teaching Hospitals NHS Trust
St. James's University Hospital Beckett Street
Leeds
LS9 7TF
United Kingdom

Sponsor information

Organisation

The Newcastle Upon Tyne Hospitals NHS Foundation Trust

Sponsor details

c/o Aaron Jackson
Newcastle Joint Research Office
Level 1
Regents Park
Newcastle upon Tyne
NE3 3HD
United Kingdom
+44 (0)1912825789
Aaron.jackson@nhs.net

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Charity

Funder name

Cancer Research UK; Grant Codes: C9380/A26813

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

1. The study protocol and other study information are not publically available at this point
2. Peer-reviewed scientific journals
3. Internal report
4. Conference presentation
5. Publication on website

IPD sharing statement
The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository. The HUNTER registry is an online resource, https://hunter-registry.ncl.ac.uk/. Access to the data will be available to those within the consortium. Requests from outside of the HUNTER consortium will be considered by the HUNTER Steering Group and may be subject to a charge.

Intention to publish date

30/11/2024

Participant level data

Stored in repository

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

21/10/2019: Trial's existence confirmed by the NIHR.