Condition category
Cancer
Date applied
25/11/2019
Date assigned
03/03/2020
Last edited
03/03/2020
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Following curative chemo-radiation (CRT), about 20-30% of patients with locally advanced human papillomavirus related (positive) oropharyngeal cancer (HPV+OPC) undergo unnecessary neck dissection or biopsies based on positive or equivocal post-CRT 18F-FDG PET-CT (PET-CT). As the positive predictive value of such PET scans is sub-optimal, a more reliable marker of 'true' residual disease is required as a means of guiding management decisions. The newly developed ultra-sensitive and specific assay 'HPV-detect' can non-invasively measure the post-CRT plasma HPV DNA levels, and can be used to guide management decisions potentially avoiding unnecessary surgical procedures. The aim of this study is to find out whether HPV DNA measured using HPV-detect is a predictor of the absence of residual disease following primary RT/CRT for HPV+ positive oropharyngeal cancer.

Who can participate?
Patients aged 18 or over with squamous cell carcinoma of the oropharynx undergoing curative RT/CRT

What does the study involve?
This is a sample and data collection/analysis study only. Diagnostic tumour biopsy blocks are required for all patients. Blood samples will be collected from consenting HPV+ patients at baseline, weekly during CRT, weekly for 4 weeks after treatment, at 6 weeks, 3, 6, 9 and 12 months after CRT. HPV negative patients will donate samples at baseline, at 6 weeks, and at 3, 6, 9 and 12 months only. In HPV+ patients an additional tissue sample will also be collected after any surgical procedures and/or biopsies and additional blood samples will also be obtained before and after any surgical procedure or biopsy.

What are the possible benefits and risks of participating?
There is no direct benefit for individual patients participating in this study. It is hoped that the information gained from this study will help to improve the treatment options and/or quality of life for patients with HPV-positive locally advanced head and neck cancer in the future. Patients will be asked to donate blood samples during the study, which may be associated with some degree of discomfort, risk of bleeding or infection. However, it is anticipated that the risks associated with these procedures will be minimal. Blood samples collected up to the 3-month timepoint will be taken at the same time as routine blood samples. Blood sampling at the routine follow up appointment after 3 months may be in addition to standard practice at some centres. Tissue blocks will be requested from tissue taken routinely at diagnosis and after any surgery or biopsies performed post (chemo)radiotherapy.

Where is the study run from?
Cancer Trials and Statistics Unit, Institute of Cancer Research (UK)

When is the study starting and how long is it expected to run for?
May 2019 to July 2023

Who is funding the study?
Medical Research Council (UK)

Who is the main contact?
Dr Marie Emson
inovate-icrctsu@icr.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Dr Marie Emson

ORCID ID

Contact details

Clinical Trial and Statistics Unit
The Institute of Cancer Research Clinical Trials and Statistics Unit
15 Cotswold Road
Sutton
SM2 5NG
United Kingdom
+44 (0)208 722 4056
inovate-icrctsu@icr.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

CPMS 42229

Study information

Scientific title

Investigation of novel plasma Human Papilloma Virus DNA assay for treatment response estimation in head and neck cancer

Acronym

INOVATE

Study hypothesis

Approximately 2000 patients are diagnosed annually in the UK with oropharyngeal (throat) cancer caused by human papillomavirus (HPV) infection. The standard treatment is chemotherapy and radiotherapy followed by surgical removal of any cancer left behind. The surgery is undertaken based on results of a scan (18F-FDG PET-CT). However, approximately 20-30% of patients will receive unnecessary surgical intervention, as residual cancer is not confirmed on pathological examination post-surgery. Following surgery approximately 25% of patients will have immediate complications and all will suffer significant permanent side effects (pain, shoulder dysfunction, altered quality of life). Therefore a more reliable marker of true residual disease is required as a means of guiding management decisions.
As HPV positive(+) oropharyngeal cancers release HPV-DNA into the blood stream its presence can serve as a detection marker of residual cancer after treatment. HPV-detect, an assay developed and tested in a single-centre, prospective pilot study at the Royal Marsden Hospital/Institute of Cancer Research, is a way to measure HPV-DNA levels using a blood test. Further validation of HPV-detect is now required in a prospective multi-centre study. The study is needed to establish its usefulness in patient care and evaluate its potential to predict the absence of residual disease and avoid unnecessary surgery. INOVATE is a multicentre study which aims to collect biological samples from 143 HPV+ and 48 HPV negative patients with oropharyngeal cancer. Patients will be asked to donate archival diagnostic tumour tissue samples and blood samples taken at specified time points up to 1 year following treatment. HPV-DNA levels will be measured using HPV-detect and the results correlated with the 18F-FDG PET-CT results at 12 weeks. In addition, barriers to adoption of the test and how to address these will be studied. A health economic analysis will study the cost benefits of implementing the test in the UK.

Ethics approval

Approved 30/10/2019, London - Bloomsbury Research Ethics Committee (HRA RES Centre Manchester, Barlow House 3rd Floor, 4 Minshull Street, Manchester, M1 3DZ, UK; Tel: +44 (0)207 104 8127; Email: nrescommittee.london-bloomsbury@nhs.net)ref: 19/LO/1558

Study design

Non-randomized observational cross-sectional

Primary study design

Observational

Secondary study design

Cross sectional 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

Head and neck cancer

Intervention

INOVATE is a multicentre prospective biological sample collection and analysis study which aims to validate circulating Human Papilloma Virus (HPV) DNA as a marker of residual disease in patients with HPV+ oropharyngeal cancer. The study will be open to newly diagnosed patients with HPV+ and HPV- tumours (negative controls) who are due to receive radical radiotherapy alone or chemotherapy and radiotherapy (RT/CRT). The study will comprise the collection and analysis of tissue and blood samples. For tissue samples, the researchers will request and use the archival formalin-fixed paraffin-embedded blocks from biopsies obtained for the diagnosis of cancer or at surgery. Therefore, no additional biopsies will be required. Venous blood samples will be collected before treatment and at regular intervals during and following completion of treatment.
Patient suitability for the study will initially be assessed at the multidisciplinary team’s (MDT) assessment meeting. Any patient who expresses an interest and is technically suitable for the study will be informed about the INOVATE study.
Following the discussion patients will be given the patient information sheet. It is proposed that as this is not a treatment study any patient who requests to consent to the study on the same day will be allowed to do so. Patients who wish to consider their participation in the study will be invited to return to the hospital at least 24 hours later to confirm participation and to sign the consent form.

SCREENING ASSESSMENTS
There are no additional screening assessments specific to the INOVATE study. It is anticipated that patients will be screened prior to standard treatment with RT/CRT as per local practice.
Consenting patients will be registered into the study after diagnosis, routine screening and confirmation of HPV status. All patients will be required to donate a blood sample at baseline ie after registration but before any standard treatment commences.
HPV negative patients will be requested to donate further blood samples at 6 weeks post-RT/CRT and at 3, 6, 9 and 12 months after treatment.
HPV positive patients will be requested to donate blood samples weekly during RT/CRT and weekly for 4 weeks thereafter, at 6 weeks, 3, 6, 9 and 12 months post-CRT. If the patient's RT treatment is extended into week 7 an additional blood sample will be taken to ensure that a sample is collected at the end of treatment. Additional tissue and blood samples will also be requested for HPV+ patients before and after any surgical procedures or biopsies performed post-RT/CCRT. Tissue collected at this time is part of the centres’ routine practice and the study will request access to these tissue blocks.
Blood samples collected up to the 3-month timepoint will be taken at the same time as routine blood samples. Blood sample donation at the routine follow up appointment post-3 months may be in addition to standard practice at some centres. Centres are advised to inform patients that some samples may be in addition to standard practice during the informed consent process and this is also detailed in the patient information sheet.

FOLLOW UP
There are no scheduled follow up visits for INOVATE. However, data will be collected from the patients' routine follow up visits following treatment according to local practice.

Approx 12 weeks after the completion of RT/CRT all patients will be routinely required to have an 18F-FDG-PET-CT scan to assess response to treatment. All centres who have expressed an interest in taking part in INOVATE have confirmed that this scan is used routinely at 12 weeks at their centres. ICR-CTSU will collect data from 18F-FDG PET-CT scans performed as part of routine practice. Sites are requested to send a copy of the report for the 3 month 18F-FDG PET-CT scan to the ICR-CTSU office. This report should be redacted to protect the patient’s personal data.
ICR-CTSU may request redacted reports of other 18F-FDG PET-CT scans carried out during the lifetime of the study.
It is anticipated that patients with equivocal PET-CT and a lymph node greater than 1cm or a positive PET-CT will be routinely recommended to have a biopsy and/or neck dissection. The type of surgery will be at the discretion of the local MDT.
Clinical data will be collected by ICR-CTSU from routine follow up appointments until 12 months post-RT/CCRT but this will not require any additional visits or action from the participants in the study. Sites will be requested to report any confirmation of residual disease at 12 weeks or later confirmation of disease progression/recurrence to the ICR-CTSU Trials Office on eCRFs. If HPV+ patients are required to progress to surgery/biopsies sites are asked to notify ICR-CTSU in an expedited manner on the appropriate eCRF. This will enable ICR-CTSU to prompt sites about the additional tissue and blood sample collection for HPV+ patients who will be scheduled for surgery.

STAKEHOLDER ANALYSIS AND HEALTH ECONOMICS STUDY
The National Institute for Health Research London in vitro Diagnostics Cooperative (NIHR London IVD) at Imperial will undertake stakeholder analyses to understand risks, adoption barriers and assess the potential impact of HPV-detect in the NHS. This study will involve members of the research team at participating sites who may be selected to be interviewed on a one-to-one basis about current use of HPV-detect and to identify user needs, user experience, perceived trust and acceptance of the use of HPV-detect.
PLEASE NOTE: The details of the health economics study will be added to the protocol by amendment prior to initiation.

The patient information sheet (PIS) will inform the patient about the clinical data collection for the study. The PIS will also clearly state that patients, their research doctors and other members of the patient's clinical care team at the site will not be informed of their HPV-detect test result and that the result will not affect their future treatment.

Intervention type

Other

Phase

Drug names

Primary outcome measure

The specificity of HPV-detect (using plasma HPV DNA levels) in correctly identifying those with no residual disease, at 3 months following completion of primary RT/CRT; defined as the proportion of patients who are HPV-detect negative among those with no residual disease according to 18F-FDG PET at the same timepoint.

Secondary outcome measures

1. The sensitivity of HPV-detect (using plasma HPV DNA levels) in correctly identifying those with residual disease at 3 months following completion of primary RT/CRT; defined as the proportion of patients who are HPV-detect positive among those with residual disease according to 18F-FDG PET-CT at the same timepoint
2. The proportion of patients who have no residual disease on biopsy/neck dissection amongst those with residual disease according to 18F FDG PET-CT but HPV-detect negative at 3 months after primary RT/CRT
3. Repeated measures of plasma HPV DNA levels up to a period of 12 months post RT/CRT (timepoints defined in the Interventions field) will be associated with the clinical and radiological response
4. Sensitivity and specificity of HPV-detect in measuring plasma HPV DNA levels compared with HPV DNA levels from diagnostic tissue at baseline; defined as the proportions of true positives and the proportions of true negatives, respectively
5. The pattern of plasma HPV DNA responses to RT/CRT presented by calculating the percentage change in HPV DNA level at each assessment timepoints from baseline (timepoints defined in the Interventions field)

Overall trial start date

01/05/2019

Overall trial end date

31/07/2023

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Aged 18 years or above.
2. Newly diagnosed patients with T1-T2/N1-3 or T3-T4/ N0-3 squamous cell carcinoma of the oropharynx
3. Availability of tissue from one archival diagnostic tumour tissue block
4. Confirmed HPV status (p16InK4A IHC/ISH)
5. Patients must be candidates for and willing to undergo curative RT/CRT
6. Written informed consent

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 191; UK Sample Size: 191

Participant exclusion criteria

1. Previous or concurrent illness or situation, which in the investigator’s opinion would interfere with collection of the complete sample collection
2. Any invasive malignancy within previous 5 years (other than non melanomatous skin carcinoma or cervical carcinoma in situ
3. Clinical evidence of metastatic disease

Recruitment start date

10/01/2020

Recruitment end date

24/05/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

The Royal Marsden NHS Foundation Trust
Fulham Road
London
SW3 6JJ
United Kingdom

Trial participating centre

Royal United Hospitals Bath NHS Foundation Trust
Combe Park
Bath
BA1 3NG
United Kingdom

Trial participating centre

James Cook University Hospital
South Tees Hospitals NHS Foundation Trust Marton Road
Middlesbrough
TS4 3BW
United Kingdom

Trial participating centre

Northern General Hospital
Sheffield Teaching Hospitals NHS Foundation Trust Herries Road
Sheffield
S5 7AU
United Kingdom

Trial participating centre

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

Trial participating centre

Norfolk and Norwich University Hospitals NHS Foundation Trust
Colney Lane Colney
Norwich
NR4 7UY
United Kingdom

Trial participating centre

Gloucestershire Hospitals NHS Foundation Trust
Trust HQ Alexandra House
Cheltenham
GL53 7AN
United Kingdom

Trial participating centre

Walsgrave General Hospital
University Hospitals Coventry and Warwickshire NHS Trust Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom

Trial participating centre

Royal Devon & Exeter Hospital
Royal Devon And Exeter NHS Foundation Trust Barrack Road
Exeter
EX2 5DW
United Kingdom

Trial participating centre

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

Trial participating centre

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

Trial participating centre

Abertawe Bro Morgannwg University LHB
One Talbot Gateway Seaway Drive Seaway Parade Industrial Estate Baglan
Port Talbot
SA12 7BR
United Kingdom

Trial participating centre

University Hospital Aintree
Aintree University Hospital NHS Foundation Trust Fazakerley Hospital Lower Lane
Liverpool
L9 7AL
United Kingdom

Trial participating centre

Queens Medical Centre
Nottingham University Hospitals NHS Trust Trust Headquarters Derby Road
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

Colchester District General Hospital
East Suffolk And North Essex NHS Foundation Trust Turner Road
Colchester
CO4 5JL
United Kingdom

Trial participating centre

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

Trial participating centre

University Hospitals Bristol NHS Foundation Trust
Marlborough Street
Bristol
BS1 3NU
United Kingdom

Trial participating centre

Belfast City Hospital
Belfast Health & Social Care Trust Lisburn Road
Belfast
BT9 7AB
United Kingdom

Trial participating centre

Queen Alexandra Hospital
Portsmouth Hospitals NHS Trust Southwick Hill Road
Portsmouth
PO6 3LY
United Kingdom

Sponsor information

Organisation

The Institute of Cancer Research, London

Sponsor details

c/o Barbara Pittam
15 Cotswold Road
Sutton
SM2 5NG
United Kingdom
+44 (0)208 7225 3604
barbara.pittam@icr.ac.uk

Sponsor type

Research organisation

Website

http://www.icic.es/en

Funders

Funder type

Research council

Funder name

Medical Research Council; Grant Codes: MR/R015589/1

Alternative name(s)

MRC

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

1. Protocol available on request from inovate-icrctsu@icr.ac.uk
2. Peer-reviewed scientific journals
3. Internal report
4. Conference presentation
5. Publication on website
6. Results will be presented to the joint Independent Data Monitoring and Steering Committee (IDMSC). Progress
reports but not results will be submitted to the NCRI Head and Neck Studies Group. It is intended that the results will be published in a high impact journal

IPD sharing statement
The datasets generated during and/or analysed during the current study are/will be available upon request from inovate-icrctsu@icr.ac.uk.

Intention to publish date

31/07/2024

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

25/11/2019: Trial's existence confirmed by the NIHR.