12749687 true RECURRENT-GB: Repeat ExCision Upon Recurrence: REthinking Neurosurgical Treatment of GlioBlastoma RECURRENT-GB Primary Objective: In participants with a recurrent GB, does repeat tumour resection surgery improve quality of life and survival when added to second-line medical therapy? Background and study aims Glioblastoma (GB) is the most common type of brain cancer in adults, with around 3,200 new cases in the UK each year. Without treatment, average survival is less than 6 months. With surgery to remove as much cancer as possible, followed by radiotherapy and chemotherapy (temozolomide), survival can extend to 14-16 months. Despite this, the tumour inevitably grows back and is called a ‘recurrent GB’. It is unclear what the most appropriate treatment for recurrent GB is. As a result, there is a wide variation in practice across the UK in whether or not patients are offered repeat surgery or whether to use only non-surgical treatments (chemotherapy and/or radiotherapy). This study will determine if repeat surgery when a GB grows back, before further chemotherapy or radiotherapy, improves quality of life and survival. It was co-designed with UK-wide patient and relative advisory groups from the BrainsTrust charity, Brain Tumour Charity Research Involvement Network (BTC-RIN), Thames Valley Patient & Public Involvement (PPI) group, and specialist nurses who care for patients with GB. Who can participate? Adults will be recruited from at least 20 UK NHS hospitals who are aged 18 years and above, have previously undergone surgery to remove a GB, are now diagnosed with a recurrent GB, and have not experienced recurrence or progression within 6 weeks of completing radiotherapy (6-week or short course), with or without concomitant chemotherapy. What does the study involve? As part of routine NHS care, patients with recurrent GB will be discussed in a ‘multi-disciplinary team’ (MDT) meeting, where a group of medical specialists will discuss treatment options. If the MDT considers both repeat surgery and second-line chemotherapy reasonable, the patient will be invited to participate in this trial. If they agree to take part, they will be assigned at random to one of two groups: Group 1: Offered repeat surgery followed by further chemotherapy and/or radiotherapy Group 2: Offered further chemotherapy and/or radiotherapy without repeat surgery Participants will be followed up weekly with three questions rating their general health and quality of life, plus additional questionnaires on various aspects of their health and quality of life every 6 weeks. Depending on participant preference, responses will be collected electronically via a smartphone app (RADAR-base) or via links to an online form sent by email/text, or via a telephone interview. If participants choose to complete questionnaires using the RADAR-based app, they will also be invited to provide optional short speech samples, which may offer insights into aspects of well-being. The study also requires participants to nominate a ‘proxy’, ideally who will be their primary carer*/support through their treatment (family member/friend), to complete similar questionnaires about the participant’s quality of life, as they may not always feel well enough to respond and at three timepoints, their own quality of life. Nominated proxies will be provided with a Proxy Information Sheet and invited to give their consent to complete questionnaires on behalf of the participant. The follow-up period of the trial is up to 12 months post-randomisation. Due to the natural history of recurrent glioblastoma, some participants may pass away prior to this time point. In addition to the health and quality of life questionnaires described above, participants will be invited to take part in an optional component of the trial, which aims to measure their physical activity levels using a smartwatch. Participants who wish to participate in this part of the trial will be provided with a complimentary smartwatch and asked to wear it for a minimum of 7 days every six weeks, to coincide with when they fill out their 6-weekly questionnaires. Physical activity data (e.g. activity levels, sleep patterns and, where supported by the device, time spent at home) will be collected remotely by researchers. No additional blood tests or hospital visits are required from participants. The trial will also look at the costs involved in treatment of recurrent glioblastoma to determine which treatment combination offers the best value for money to the NHS. What are the possible benefits and risks of participating? Benefits and risks not provided at time of registration Where is the study run from? John Radcliffe Hospital, Headington, UK. When is the study starting and how long is it expected to run for? April 2026 to June 2030. Who is funding the study? 1. National Institute for Health and Care Research, UK. 2. BrainStorm Charity (Smartwatches for Substudy), UK. Who is the main contact? Recurrent GB team, recurrentgb@nds.ox.ac.uk Deterioration-free survival (DFS): Time from randomisation to either a ≥10-point deterioration from baseline in Global Health Status (GHS) without subsequent recovery, or death Q29 & Q30 of EORTC QLQ-C30 questionnaire and mortality data from hospital records/NHS Spine baseline, then weekly up to 12 months Overall survival (OS): Time from randomisation to death, up to 12 months hospital records/NHS Spine one time point for data collection at the end of the study Progression-free survival (PFS): Time to radiological tumour progression or death (MRI/MDT), up to 12 months hospital records/NHS Spine one time point for data collection at the end of the study Health-related quality of life (HRQoL) the EORTC QLQ-C30 and QLQ-BN20 baseline and 6-weekly Physical/social functioning, motor and communication deficits domains of QLQ-C30/BN20 baseline and 6-weekly Performance status and Activities of Daily Living (ADLs) WHO ECOG + QLQ-C30 items baseline and 6-weekly Seizure frequency and neurocognitive/physical symptoms QLQ-C30/BN20 baseline and 6-weekly Surgical complications: Incidence/type within 31 days post-op (intervention arm) hospital records/NHS Spine one time point Completion of adjuvant therapy: Proportion starting/completing therapy, up to 12 months hospital records/NHS Spine one time point Extent of resection: Residual tumour volume on MRI within 72 hours post-op (intervention arm) hospital records/NHS Spine one time point Health economics QALYs via EQ-5D-5L, resource use from hospital records baseline and 3-monthly; incremental cost per QALY modelled over lifetime Carer QoL EQ-5D-5L (proxy) baseline and 6-monthly Ethics approval required Wales REC 7

Health and Care Research Wales Castlebridge 4 15-19 Cowbridge Road East

Cardiff United Kingdom CF11 9AB 26/WA/0086 10.1186/ISRCTN12749687 358925 CPMS: 62049 358925 62049 Interventional Randomized controlled trial Open (masking not used) Active Parallel Treatment Not applicable 2030-06-30T00:00:00.000Z United Kingdom England Scotland Wales Barts Health NHS Trust

The Royal London Hospital 80 Newark Street

London England E1 2ES R1H@2.16.840.1.113883.2.1.3.2.4.18.48 Belfast Health and Social Care Trust

Trust Headquarters A Floor - Belfast City Hospital Lisburn Road

Belfast England BT9 7AB A3X4A@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Birmingham NHS Foundation Trust

Queen Elizabeth Hospital Mindelsohn Way Edgbaston

Birmingham England B15 2GW RRK@2.16.840.1.113883.2.1.3.2.4.18.48 North Bristol NHS Trust

Southmead Hospital Southmead Road Westbury-on-trym

Bristol England BS10 5NB RVJ@2.16.840.1.113883.2.1.3.2.4.18.48 Cambridge University Hospitals NHS Foundation Trust

Cambridge Biomedical Campus Hills Road

Cambridge England CB2 0QQ RGT@2.16.840.1.113883.2.1.3.2.4.18.48 Cardiff & Vale University Lhb

Woodland House Maes-y-coed Road

Cardiff Wales CF14 4HH 7A4@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Coventry and Warwickshire NHS Trust

Walsgrave General Hospital Clifford Bridge Road

Coventry England CV2 2DX RKB@2.16.840.1.113883.2.1.3.2.4.18.48 NHS Lothian

Waverley Gate 2-4 Waterloo Place

Edinburgh Scotland EH1 3EG SS999@2.16.840.1.113883.2.1.3.8.2.16.1 Hull University Teaching Hospitals NHS Trust

Hull Royal Infirmary Anlaby Road

Hull England HU3 2JZ RWA@2.16.840.1.113883.2.1.3.2.4.18.48 Imperial College Healthcare NHS Trust

The Bays St Marys Hospital South Wharf Road

London England W2 1BL RYJ@2.16.840.1.113883.2.1.3.2.4.18.48 King's College Hospital NHS Foundation Trust

Denmark Hill

London England SE5 9RS RJZ@2.16.840.1.113883.2.1.3.2.4.18.48 Leeds Teaching Hospitals NHS Trust

St. James's University Hospital Beckett Street

Leeds England LS9 7TF RR8@2.16.840.1.113883.2.1.3.2.4.18.48 The Walton Centre NHS Foundation Trust

Lower Lane Fazakerley

Liverpool England L9 7LJ RET20@2.16.840.1.113883.2.1.3.2.4.18.48 Northern Care Alliance NHS Foundation Trust

Salford Royal Stott Lane

Salford England M6 8HD RM3@2.16.840.1.113883.2.1.3.2.4.18.48 South Tees Hospitals NHS Foundation Trust

James Cook University Hospital Marton Road

Middlesbrough England TS4 3BW RTR@2.16.840.1.113883.2.1.3.2.4.18.48 Nottingham University Hospitals NHS Trust - Queen's Medical Centre Campus

Nottingham University Hospital Derby Road

Nottingham England NG7 2UH RX1RA@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Plymouth NHS Trust

Derriford Hospital Derriford Road Derriford

Plymouth England PL6 8DH RK9@2.16.840.1.113883.2.1.3.2.4.18.48 Lancashire Teaching Hospitals NHS Foundation Trust

Royal Preston Hospital Sharoe Green Lane Fulwood

Preston England PR2 9HT RXN@2.16.840.1.113883.2.1.3.2.4.18.48 Barking, Havering and Redbridge University Hospitals NHS Trust

Queens Hospital Rom Valley Way

Romford England RM7 0AG RF4@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospital Southampton NHS Foundation Trust

Southampton General Hospital Tremona Road

Southampton England SO16 6YD RHM@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals of North Midlands NHS Trust

Newcastle Road

Stoke-on-trent England ST4 6QG RJE@2.16.840.1.113883.2.1.3.2.4.18.48 University College London Hospitals NHS Foundation Trust

250 Euston Road

London England NW1 2PG RRV00@2.16.840.1.113883.2.1.3.2.4.18.48 Oxford University Hospitals

John Radcliffe Hospital Headley Way Headington

Oxford England OX3 9DU RGT2V@2.16.840.1.113883.2.1.3.2.4.18.48 false 1. Aged 18 years or above 2. First recurrence/progression of IDH wild-type GB following previous maximal safe resection (attempted gross total resection of contrast-enhancing tumour) as confirmed by local Neuro-oncology Multidisciplinary Team (MDT) 3. WHO Performance Status 0-2 4. Neuro-oncology MDT feels that the patient should be offered the trial and confirms that repeat maximal safe resection (>90%) is feasible and a reasonable treatment option 5. Able to give informed consent 6. Able to provide a proxy who is willing to complete the trial questionnaires Mixed 18 Years 120 Years All 150 0 1. Recurrence/progression of GB within 6 weeks of completion of radiotherapy (6 weeks or short course), with or without concomitant chemotherapy (See note* below) 2. Multifocal recurrence/progression of GB 3. Contraindication to MRI 4. Glioblastoma located in the brainstem, basal ganglia or the thalamus *In the UK, standard treatment for operable glioblastoma consists of surgery followed by radiotherapy (with or without concomitant chemotherapy), then a short treatment break before starting adjuvant chemotherapy. The exclusion criterion refers to recurrence or progression occurring within 6 weeks of completing radiotherapy. Patients are therefore only eligible for RECURRENT GB once they have completed radiotherapy and reached the point at which adjuvant chemotherapy would normally begin, or are further along in their treatment pathway. 2026-07-20T00:00:00.000Z 2029-06-30T00:00:00.000Z Repeat surgery for patients with recurrent glioblastoma Cancer This is a two-arm, pragmatic randomised controlled trial in adults with recurrent glioblastoma (GB). Participants will be followed for a maximum of 12 months from randomisation. Intervention arm: Repeat maximal safe resection followed by second-line medical therapy Participants randomised to the intervention arm will undergo repeat surgical resection of recurrent GB in the hospital. The aim of surgery is maximal safe resection and it is expected that the operating surgeon will use pre-operative MRI with diffusion tensor imaging (DTI) tractography for neuronavigation, as well as 5-aminolevulinic acid (5-ALA) intra-operative fluorescence. The operating surgeon may additionally use other adjuncts at their discretion to maximise safe resection, including intra-operative neuromonitoring, awake craniotomy with neuropsychological assessment, intra-operative ultrasound, or intra-operative MRI. Post-operative care will follow routine NHS practice, including a brain MRI with gadolinium contrast within 48–72 hours to assess the extent of resection. Following recovery from surgery, participants will receive all appropriate second-line medical therapies as determined by their multidisciplinary team (MDT), in accordance with national guidance and local NHS policy. There are no protocol-imposed restrictions on systemic therapy. Comparator arm: Standard of care (SOC) alone Participants randomised to the control arm will receive second-line treatment as recommended by their neuro-oncology MDT and in line with national guidance and local NHS practice. As there is no single standard treatment for recurrent GB, management may include chemotherapy, radiotherapy, re-irradiation, and repeat surgery if clinically indicated. No trial-mandated surgical intervention is delivered in this arm. All other aspects of clinical care will be as per routine NHS practice. Follow-up and assessments All participants will receive standard NHS follow-up. Participants will be asked to complete patient-reported outcome questionnaires during follow-up, which may be completed remotely via an online link (sent via email or SMS), via a trial-specific app, or by phone with the research team. Participants will be followed for up to 12 months from randomisation. Randomisation Participants will be randomised in a 1:1 ratio to either repeat maximal safe resection followed by second-line medical therapy or second-line medical therapy alone. Randomisation will take place after confirmation of eligibility, informed consent, and completion of baseline assessments. Allocation will be performed by authorised site research staff using a secure, web-based REDCap system hosted by the Oxford Clinical Trials Research Unit (OCTRU). Minimisation with a random component will be used to ensure balance across treatment arms. A small number of initial participants will be allocated using simple randomisation to seed the minimisation algorithm. Minimisation factors are: Baseline QLQ-C30 Global Health Status score (<10 vs ≥10), Age (<70 vs ≥70 years), Tumour location (eloquent vs non-eloquent), Timing of recurrence (before vs after 6th cycle of adjuvant temozolomide), Previous radiotherapy (≤3-week vs standard 6-week course), MGMT methylation status (unknown grouped with unmethylated), Recruiting centre. Procedure/Surgery Not expected to be made available 3a152e01-2064-48f4-a0c6-d95cb2295059 0de69869-d82d-4601-9d1e-24304012d60d 95c12306-378a-42ed-9e26-385ec627041b 73b6f8ec-cb9d-4483-9adc-b6794cde0888 b2b294a5-f6d4-4295-80a9-fb9c435471e5 No Puneet Plaha Principal investigator Scientific

John Radcliffe Hospital, Headington

Oxford United Kingdom OX3 9DU +441865 234838 Puneet.Plaha@ouh.nhs.uk Public Melody Chin Public

Surgical Intervention Trials Unit (SITU) University of Oxford Botnar Research Centre Nuffield Orthopaedic Centre Old Road Headington

Oxford United Kingdom OX3 7LD +447917101649 recurrentgb@nds.ox.ac.uk Public University of Oxford https://ror.org/052gg0110 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 BrainStorm Charity 46174869 true Multi-centre investigation of cardiac diffusion tensor imaging (DTI) in healthy volunteers by SCMR Cardiac Diffusion Special Interest Group NETwork SIGNET There exists a wide range of reported diffusion tensor imaging (DTI) metrics in the literature, including reports that are potentially artifactual, which have been previously highlighted. This will be influenced by the subject cohort, e.g. health vs disease. Other potential sources of variation include differences in sites/operators/scanners, acquisition and post-processing methods. This variation needs to be better understood to support clinical validation of the technique. Early work has evaluated reproducibility in a ten-site study in isotropic phantoms and in a two-site study in healthy volunteers. In this study, we propose a broad multi-centre collaborative effort to evaluate inter-site variation due to differences in (i) site/operator/scanner, (ii) acquisition and (iii) post-processing methods. The results will guide the interpretation of the cardiac diffusion MRI literature, and help to refine strategies for standardisation and harmonisation of protocols. We propose in the first instance to study healthy volunteers to establish a baseline of variation due to technical (non-pathology related) factors. Background and study aims Cardiac diffusion tensor imaging (cDTI) is an emerging magnetic resonance imaging (MRI) based technique for examining the microstructure of the heart. The cardiac function and microstructure are highly interconnected. The adult heart comprises more than a billion heart muscle cells that are intricately connected and that contract in a highly coordinated manner to support the beating of the heart. Changes to the heart microstructure are an important feature in conditions such as heart attack or myocardial infarction (MI) and hypertrophic cardiomyopathy (HCM), where the heart muscle wall thickens. For example, an increase in collagen and scar following changes in microstructure following MI, and cell disarray in HCM, which can be assessed with cDTI. The microscopic displacement of water molecules due to diffusion is heavily influenced by the presence of cells and by the properties of these cells such as size, shape, orientation, integrity and so forth. Thus, by encoding the water diffusion information in the MRI image, one can evaluate the cardiac microstructure. In cDTI, several diffusion directions are encoded and then diffusion tensors (a mathematical model that can be pictured in 3D as an American football in shape) are fitted. From the diffusion tensor, several quantitative values can be derived such as the mean diffusivity (MD) that describes the average apparent diffusion, the fractional anisotropy (FA) that describes how pointed the tensor is, and the helix angle (HA) and sheetlet angle (E2A) that reflect the orientations of the heart muscle cells and their arrangement in sheetlets. The links between the diffusion tensor and cardiac microstructure have been verified in numerous preclinical ex vivo and in vivo studies. Early clinical studies have reported diffusion parameters in the pathologic heart. In particular, higher myocardial MD and lower FA have been reported in pathologies such as MI, HCM and aortic stenosis (AS). Similarly, differences in HA and E2A angles have been reported in conditions such as MI, HCM, AS and dilated cardiomyopathy (DCM). This is thought to be related to the underlying changes in the cardiac microstructure. The field of cardiac diffusion MRI remains technologically challenging due to a number of factors such as motion from the heart beating and breathing, distorted images and long scan times. Nonetheless, the field has been rapidly expanding over the past years, with publications in cDTI more than doubling over the decade up to 2020, and whole-heart cDTI within clinically feasible scan times looks increasingly likely to be achievable within the foreseeable future. The study aims to: 1. Evaluate variation in cDTI data due to differences in (i) site/operator/scanner, (ii) subject, (iii) acquisition and (iv) post-processing methods. 2. Identify the greatest sources of variation and inform strategies for optimisation, standardisation and harmonisation of cDTI. 3. Inform power calculations and data interpretation in future larger studies, in particular, where different sites/methods are used. Who can participate? Healthy volunteers aged 18 to 65 years old with a body mass index (BMI) of 18.5 to 29.9 kg/m2. For the travelling volunteer study: Ability to travel independently between sites and to have all scans done within 2 months from first scan; possession of valid documentation (e.g. passport and visa) to travel between sites with validity extending to at least 8 months following first MRI scan, and with a passport no older than 10 years at the time of the last scan. What does the study involve? Non-travelling healthy volunteers will be identified, approached and recruited by non-travelling volunteer sites in accordance with site-specific ethics for sites outside the UK. Non-travelling volunteers will only be consented under the respective site-specific ethics. These are non-NHS sites and non-HRA-relevant. Travelling volunteers will be recruited and consented by the study team at Royal Brompton Hospital to travel to multiple sites for a single MRI scan at each site. Potential volunteers who express interest in participating will be sent the participant information sheet (PIS) and research volunteer checklist. Before consent/scan, volunteers who wish to participate in the study will be asked to complete and return the research volunteer checklist for the study team to assess eligibility. Participants who meet eligibility requirements and are interested in participation will be invited to provide written consent. Consent will also be sought for the sharing and storing of personal information for study oversight, scan scheduling, safety monitoring, booking travel and reimbursement. Volunteers will be invited to undergo a single MRI examination at each site. Before each scan, the participant’s height and weight will be measured. A site-specific MRI screening questionnaire shall be completed to help ensure safety in the MRI scanner. The MRI scan will typically last between 60 to 90 minutes. Surface electrodes (stickers) will be placed on the chest to monitor heart beat during the scan. What are the possible benefits and risks of participating? This study is done solely for research purposes and participants will not benefit from taking part. Their participation may, however, benefit future care. The scans will be for research purposes only and cannot be used for clinical diagnosis. MRI is safe and no ionising radiation (energy that can potentially cause damage to cells) is used for this scan. There are no known risks from the technique. Some people may experience claustrophobia (fear of confined spaces). The MRI staff will do all that they can to make participants feel comfortable during the scan. Participants may withdraw from the study at any time. For travelling volunteers, there is a small risk associated with travel. Participants are asked to highlight any concerns they may have about such travel. Travel and accommodation will be arranged through reputable vendors, and participants will be kept updated on any travel advisories at the time. Where is the study run from? This is an international multi-centre initiative, initiated by the Society of Cardiovascular Magnetic Resonance Cardiac Diffusion Special Interest Group. The Project Management Committee responsible for taking decisions on the study has members based in Switzerland, the UK and the USA. When is the study starting and how long is it expected to run for? September 2026 to August 2029 Who is funding the study? Investigator initiated and funded Who is the main contact? Dr Irvin Teh, i.teh@leeds.ac.uk Cardiac DTI data including mean diffusivity, fractional anisotropy, helix angle and E2 angle. For non-travelling volunteers, these will be acquired at baseline. For travelling volunteers, these will be acquired at all travelling volunteer sites within 2 months of baseline. Signal-to-noise ratio and potential non-compliance of scans with the protocol collected during each scan Ethics approval required University of Leeds School of Medicine Research Ethics Committee (SoMREC)

Worsley Building, University of Leeds

Leeds United Kingdom LS2 9JT MREC 23-027 10.1186/ISRCTN46174869 343837 343837 Multi-centre prospective observational study Observational Cross sectional study Diagnostic 2029-08-31T00:00:00.000Z United Kingdom England Wales Belgium Denmark France Japan Poland Switzerland United States of America Barts Health NHS Trust

The Royal London Hospital 80 Newark Street

London England E1 2ES R1H@2.16.840.1.113883.2.1.3.2.4.18.48 Cardiff University Brain Research Imaging Centre

-

Cardiff Wales CF24 4HQ Royal Brompton Hospital

Sydney Street

London England SW3 6NP RJ182@2.16.840.1.113883.2.1.3.2.4.18.48 University College London

Gower Street

London England WC1E 6BT 10007784@2.16.840.1.113883.2.1.3.8.2.9.1 University of Leeds

Woodhouse Lane

Leeds England LS2 9JT 10007795@2.16.840.1.113883.2.1.3.8.2.9.1 University of Oxford

University Offices

Oxford England OX1 2JD 10007774@2.16.840.1.113883.2.1.3.8.2.9.1 Aarhus University Hospital

Aarhus Denmark 8200 Beth Israel Deaconess Medical Center

Boston United States of America MA 02215 Boston Children's Hospital

Boston United States of America MA 02115 Brussels University Hospital

Brussels Belgium 1090 Jette Cleveland Clinic

Cleveland United States of America OH 44195 Copenhagen University

Copenhagen Denmark 1172 København CREATIS-Lyon

Lyon France 69100 Villeurbanne Emory University

Atlanta United States of America GA 30322 ETH Zurich

Zurich Switzerland 8092 Zürich Geneva University Hospital

Geneva Switzerland 1205 Genève Hokkaido University Hospital

Hokkaido Japan 060-8648 Live Healthy Imaging

Houston United States of America TX 77401 Medical University of Gdansk

Gdansk Poland 80-210 Massachusetts General Hospital

Boston United States of America MA 02114 National Heart, Lung, and Blood Institute - Medstar Washington Hospital

Bethesda United States of America MD 20892 Poznan University of Medical Sciences

Poznan Poland 61-701 Rigshospitalet

Copenhagen Denmark 2100 København Stanford University

Stanford United States of America CA 94305 Texas A&M University

Houston United States of America TX 77840 University of Bordeaux

Bordeaux France 33076 Imelda Hospital

Bonheiden Belgium 2820 Bonheiden Healthy volunteer 1. Healthy volunteer 2. Male or female; sites shall aim to recruit equal numbers, i.e. male (n = 6) / female (n = 6) 3. Age 18 to 65 years old 4. Body mass index (BMI) 18.5 to 29.9 kg/m2 5. For travelling volunteer study: Ability to travel independently between sites, and to have all scans done within 2 months from first scan; possession of valid documentation (e.g. passport and visa) to travel between sites with validity extending to at least 8 months following first MRI scan, and with passport no older than 10 years at time of last scan. Mixed 18 Years 65 Years All 252 0 1. Safety or clinical concerns precluding participation 2. Any history of health conditions that may affect the heart (e.g. hypertension, diabetes, arrhythmias, angina, myocardial, valve and vessel disease) 3. Pregnancy or breastfeeding, including suspected pregnancy 4. Claustrophobia that limits/prevents participants from remaining in the MRI scanner 5. Inability to lie flat on the scanner table 6. Physical frailty 7. Contraindications to MRI (some pacemakers, intraorbital debris, intraauricular implants, intracranial clips, etc) 8. Those who could be considered to have a particularly dependent relationship with an investigator, e.g. members of staff or students 9. Involvement with the research apart from volunteering 10. Any relevant health conditions precluding safe travel between sites within 2 2-month time frame (For travelling volunteer study) 2026-09-17T00:00:00.000Z 2027-06-30T00:00:00.000Z Evaluation of cardiac microstructure with cardiac DTI Circulatory System Single MRI scan for non-travelling volunteers Single MRI scan for travelling volunteers at each site, over multiple sites Non-travelling healthy volunteers will be identified, approached and recruited by non-travelling volunteer sites in accordance with site-specific ethics for sites outside the UK. Non-travelling volunteers will only be consented under the respective site-specific ethics. These are non-NHS sites and non-HRA-relevant. Travelling volunteers will be recruited and consented by the study team at Royal Brompton Hospital to travel to multiple sites for a single MRI scan at each site. Potential volunteers who express interest in participating will be sent the participant information sheet (PIS) and research volunteer checklist. Prior to consent/scan, volunteers who wish to participate in the study will be asked to complete and return the research volunteer checklist for the study team to assess eligibility. Participants who meet eligibility requirements and are interested in participation will be invited to provide written consent. Consent will also be sought for the sharing and storing of personal information for study oversight, scan scheduling, safety monitoring, booking travel and reimbursement. Volunteers will be invited to undergo a single MRI examination at each site. Prior to each scan, participants’ height and weight will be measured. A site-specific MRI screening questionnaire shall be completed to help ensure safety in the MRI scanner. The MRI scan will typically last between 60 to 90 minutes. Surface electrodes (stickers) will be placed on the chest to monitor heartbeat during the scan. Other The datasets generated during and/or analysed during the current study will be stored in a publicly available repository. Anonymised research data will be made available by UoL to the research community for the current study and future research as governed by the Collaboration Agreement. Access to publicly available data by third parties will be governed by an agreement with an End User / Data Sharing Agreement. Stored in publicly available repository 2025 Protocol article in https://doi.org/10.1016/j.jocmr.2025.101948 (added 02/12/2025) Protocol

Migrated from study website field

e76d1eb1-9231-4350-9993-e9462f6cd04b c4ffa628-22d9-4691-b310-17503d85cb27 ffe974b1-e720-486f-8a2c-0f8667a8cfe1 15ebfb77-4ca0-413c-afd4-894d24258789 Yes Irvin Teh https://orcid.org/0000-0002-6705-3129 Scientific Principal investigator

University of Leeds

Leeds United Kingdom LS2 9JT +44 (0)1133438306 i.teh@leeds.ac.uk Public Kathryn Richards Public

University of Leeds

Leeds United Kingdom LS2 9JT +44 (0)1133928250 k.h.richards@leeds.ac.uk Public University of Leeds University/education https://ror.org/024mrxd33 Non-commercial Investigator initiated and funded 12925425 true Under stress: Why women of black African-Caribbean heritage are at elevated risk of stroke Primary hypothesis 1: There will be a difference in the increase in large and small vessel pulsatility during mental stress in normotensive Black African-Caribbean women versus normotensive White European women. Primary hypothesis 2: There will be a difference in the increase in large and small vessel pulsatility during mental stress in hypertensive Black African-Caribbean women versus hypertensive White European women Background and study aims Black African and Caribbean women are three times more likely to experience stroke and are more likely to have a stroke at a young age. What causes this is unknown, but stress appears to play an important role. High levels of daily stress may increase the risk of stroke in Black African Caribbean women. This is because Black women often have bigger spikes in blood pressure during stress. These large and frequent blood pressure spikes may cause damage to the brain over time. Therefore, we want to understand how the brain responds to these spikes in blood pressure and explore whether the blood vessels in the brain are less able to protect against these blood pressure spikes in Black African Caribbean women. Who can participate? Women of Black African and Black Caribbean heritage and women of White European heritage, between 18 and 75 years old. What does the study involve? Taking part involves two visits: one visit to the Clinical Research Facility in Bristol, which will take about 3 hours and one visit to the Cardiff University Brain Imaging Research Centre in Cardiff, which will take around 2 hours. Visit 1: Screening tests to ensure eligibility. Completion of questionnaires assessing social determinants of health and health behaviours including physical activity levels, diet, sleep quality, experience of discrimination, and stress levels. Non-invasive assessment of blood pressure and leg blood flow responses to a math task. Venous blood sample to determine stress hormone levels at rest and during a math task. Visit 2: Non-invasive assessment of large artery stiffness. Participants will then undergo a brain MRI. Scans will be taken at rest, during a mental math task and during occlusion of the forearm with a blood pressure cuff pumped to a high pressure (i.e., metaboreflex test). What are the possible benefits and risks of participating? This study is testing the impact of stress on blood pressure and brain function. Taking part will help us understand why high levels of stress increase the risk of stroke in Black women. This can also help identify preventative treatments. You will get a full blood pressure screen, which may be of some benefit to you from a health check-up perspective. You will also get information on your cholesterol levels and diabetes risk This study involves minimal risks Venous blood sample and cannulation: mild discomfort during venepuncture/cannulation and mild swelling or bruising at the site. Monitoring heart rate, blood pressure and breathing: mild discomfort from the inflation of the blood pressure cuff around the finger. Mental math test: the task may cause some stress, however, this will stop when the task stops. Metaboreflex test: mild arm discomfort with the blood pressure cuff being inflated to stop blood from leaving your arm. Brain MRI: MRI is a safe, non-invasive and painless procedure. However, some people find being inside the scanner claustrophobic. Some people may experience discomfort from lying down in the scanner for 1 hour. Where is the study run from? University of Bristol (UK) When is the study starting and how long is it expected to run for? April 2024 to January 2028 Who is funding the study? British Heart Foundation (UK) Who is the main contact? Dr Lydia Simpson, Lydia.simpson@bristol.ac.uk Cerebral pulsatility index measured from MRI at rest and during Paced Auditory Serial Addition Task (PASAT) 1. White matter hyperintensities measured using MRI at rest 2. Blood-brain barrier integrity measured using MRI at rest 3. Grey matter perfusion measured using MRI at rest 4. Cardiovascular hemodynamics measured continuously during a 10-minute resting period and during the PASAT: 4.1. Heart rate measured continuously via ECG 4.2. Beat-to-beat blood pressure measured via finger photoplethysmography 4.3. Continuous femoral blood flow measured via Doppler ultrasound 5. Stress hormones (cortisol and catecholamines) during mental stress measured from venous blood samples taken at rest and during the PASAT 6. Systemic arterial stiffness measured using carotid-femoral pulse wave velocity at rest 7. Cerebral arterial stiffness measured from MRI at rest Ethics approval required North East - Newcastle & North Tyneside 2 Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 24/NE/0209 10.1186/ISRCTN12925425 347113 CPMS: 64223, Sponsor Ref: 2024 - 4520 347113 64223 Sponsor Ref: 2024 - 4520 Observational cross-sectional study Observational Cross sectional study Other 2028-01-01T00:00:00.000Z United Kingdom England Wales NIHR Bristol Clinical Research Facility

60 St Michael's Hill

Bristol United Kingdom BS2 8DX CRF34@2.16.840.1.113883.2.1.3.8.1.2 Cardiff University Brain Imaging Centre

Maindy Road

Cardiff United Kingdom CF24 4HQ Healthy volunteer Patient All participants: 1. Female 2. 18-75 years of age 3. Non-obese (BMI <35 kg/m2) Normotensive participants: 1. Office BP < 140/90 mmHg and daytime ambulatory BP <135/85 mmHg 2. No medications except oral contraceptives Hypertensive participants: 1. Office BP > 140/90 mmHg and daytime ambulatory BP > 135/85 mmHg or diagnosis of hypertension 2. No medications except treatment for hypertension and/or oral contraceptives Adult 18 Years 75 Years Female 64 All participants: 1. Body mass index ≥35 kg/m2 2. Major illness e.g. cancer, inflammatory disease (including vasculitis) or receiving palliative care 3. Medical history of respiratory, cardiovascular (excluding hypertension), cerebrovascular, metabolic, renal or endocrine disorders (i.e. severe cardiac electrical conduction abnormalities, chronic heart failure, Chronic Obstructive Pulmonary disease, diabetes, polycystic ovary syndrome) 4. Inherited disorders e.g., sickle cell anaemia 5. Pregnancy/breastfeeding women 6. Taking nitrate, steroid, anti-coagulant or immunosuppressant medication or medication as part of a clinical trial 7. Diagnosed cardiovascular (including arrhythmia), respiratory (including asthma), renal or ophthalmic disease 8. Congenital or acquired neurological conditions (including dementia), language disorders, repeated or chronic pain conditions (excluding menstrual pain and minor sporadic headaches) 9. Diabetes or HbA1c >6.5% 10. Symptoms of febrile illness within two weeks of participation 11. Excessive alcohol consumption (exceeding 28 units/week) or intravenous drug use 12. Needle phobia 13. History of panic attacks 14. Inability to understand instructions given in English 15. Current smoker 16. Pacemaker, implantable cardiac defibrillator, cerebral metallic clips or other implanted metallic devices/structures 17. Unable to tolerate scanner or history of claustrophobia 18. Learning disability or significant hearing and/or visual impairment, which may affect participants ability to communicate from within the MRI scanner 19. Inability to understand English Normotensive: 1. Women with a history of hypertension, including hypertension in pregnancy Hypertensive participants: 2. Secondary causes of hypertension 2025-02-18T00:00:00.000Z 2027-10-01T00:00:00.000Z Hypertension Circulatory System This study will be a cross-sectional study of four groups: normotensive Black African and Black Caribbean women, normotensive White European women, hypertensive Black African and Black Caribbean women and hypertensive White European women. Two study visits: Visit 1: Consent and screening visit and determination of hemodynamic and sympathetic responses to mental stress. Visit 1 will be undertaken at the NIHR Clinical Research Facility, Bristol. First, consent will be obtained, and participants' eligibility will be determined. Following screening, several questionnaires will be completed to assess social determinants of health and health behaviours. Venous blood samples will be taken at rest to measure catecholamines and cortisol. BP, heart rate, respiratory activity and vascular ultrasound will be measured at rest and during a mental arithmetic task, used to induce mental stress. A second blood sample will be taken during the mental arithmetic task to determine changes in catecholamines and cortisol, from rest. Study visit 2: MRI visit and determination of cerebrovascular responses to mental stress. Visit 2 will be undertaken at Cardiff University Brain Research Imaging Centre (CUBRIC). Participants will be familiarised using a mock MRI scanner. Resting pulse wave velocity will be assessed. BP, peripheral oxygen saturation, respiratory activity, and end-tidal partial pressure of CO2 and O2 will be measured, and MRI imaging will be completed at rest and during 1) mental arithmetic task and 2) during metaboreflex testing. Other The datasets generated and/or analysed during the current study will be available upon request from Dr Lydia Simpson (Lydia.simpson@bristol.ac.uk) Available on request bcb1d7fe-5be0-4292-93af-3e67bd08d1d8 d041b078-9a2a-4344-a8b6-dd91c4e97648 ce82fe3b-8c6c-4174-92ee-2e83132aff8a Yes Lydia Simpson Public Scientific Principal investigator

Biomedical Sciences Building University of Bristol

Bristol United Kingdom BS81TD +44 (0)7795123830 Lydia.simpson@bristol.ac.uk Public British Heart Foundation Charity https://ror.org/02wdwnk04 Non-commercial British Heart Foundation http://dx.doi.org/10.13039/501100000274 11023869 true The effects of Piano Instruction for Adult Novices as Online Cognitive intervention (PIANO-Cog) on executive function, fluid intelligence and white and grey matter microstructure compared to passive control in healthy older adults PIANO-Cog Our primary hypotheses are: 1. PIANO-Cog will be a feasible online cognitive training intervention for healthy non-musicians over the age of 50 years old. 2. A future fully-powered RCT into the effects of 8-weeks of home-based PIANO-Cog training compared to no-training control will be feasible. Our secondary hypotheses are that, in healthy non-musicians (>50 years), 8 weeks of piano training will: 1. Lead to improvements in processing speed, response inhibition and attention switching as measured by digit-symbol substitution test, a Stroop test, Go/No-go test and verbal fluency category switching tasks 2. Lead to grey and white matter microstructural changes in auditory, motor and somatosensory networks measured using DTI and metrics from the biophysical models, NODDI and SANDI. Specifically, we expect to see an increase in soma density and soma size metrics from SANDI model and increased orientation dispersion and intracellular density metrics from the NODDI model following piano training compared to the control group. 3. Underlying microstructural changes will be associated with changes in processing speed (digit-symbol task) and EF (N-back, Stroop and Go/No-go tasks). Background and study aims As we age, our cognitive abilities can decline. Research suggests that activities combining sensory and motor skills, like musical training, might help improve cognitive functions in older adults. This study aims to test a self-guided piano training program called PIANO-Cog, which participants can do at home. The goal is to see if this program is acceptable to participants and if a larger study would be feasible. Who can participate? Cognitively healthy volunteers over the age of 50, with little-to-no musical training, can take part in this study. What does the study involve? Participants will undergo 2 hours of cognitive testing and a 30-minute MRI scan before and after an 8-week intervention period. They will be randomly assigned to either the piano training group or a control group. The piano group will receive a 30-minute training video each week and are asked to practice for 30 minutes, 5 days a week. The control group will continue their usual activities and avoid any musical or cognitive training during the study. What are the possible benefits and risks of participating? Participants may not directly benefit from the study. Those in the piano training group will receive a keyboard for 8 weeks, but it must be returned after the study. Control group participants will get the piano training videos after the study ends. There are small risks associated with MRI scanning, such as discomfort in confined spaces and the need to remain still. Cognitive testing can be tiring, but breaks will be provided as needed. Where is the study run from? Cardiff University Brain Research Imaging Centre (CUBRIC), Maindy Road, Cardiff (UK) When is the study starting and how long is it expected to run for? March 2023 to July 2025 Who is funding the study? School of Psychology, Cardiff University (UK) Who is the main contact? Fionnuala Rogers (RogersF2@cardiff.ac.uk) 1. Recruitment rate = 100 x (number of participants who provided consent / number of participants eligible) % 2. Retention rate = 100 x (number of participants who complete follow-up testing / number of participants who provided consent) 3. Adherence rate (frequency) = 100 x (number of days’ practice logged / 40 days) % 4. Adherence rate (duration) = 100 x (number of minutes practice logged / (40 days x 30 minutes average session duration = 1,200 minutes) % 5. Acceptability of the intervention is assessed using an evaluation survey consisting of 27 x 6-point Likert scale items on how participants perceived the quality, difficulty level and content of the training. Four qualitative questions are also included to ask participants for their individual feedback. 1. Processing speed measured as the number of correct responses within 90 seconds on the symbol-digit test from the WAIS-III. 2. Inhibitory control for motor responses measured as the rate of correct responses and latencies on the Go/No-go test. 3. Inhibitory control for distractor information measured as the number of correct responses and latencies on a computerised Stroop task for congruent versus incongruent trials. 4. Working memory capacity measured as the number of correct responses on the digit span task (forward and backward conditions) from the WAIS-III. 5. Updating of working memory measured as the error rates on the N-back. 6. Visual attention and attention-switching measured by completion times on the Trail-Making Task Parts A and B respectively. 7. Verbal fluency measured by the number of correct responses provided on the letter, category and category-switching subtests of the D-KEFS verbal fluency test. 8. Verbal memory measured as the total number of words recalled on the California Verbal Learning Test - II. 9. Musical abilities measured as score from the micro-PROMS which assess a participant's ability to detect changes in samples of music. 10. Piano performance measured as the number of correct notes and timing accuracy measured whilst playing 5-finger scales using a MIDI-keyboard and Reaper, compared with a reference. 11. Changes in grey matter microstructure assessed by the soma size and soma density metrics from the Soma And Neurite Density Imaging (SANDI) model which will be applied to multi-shell high angular resolution diffusion imaging data (msHARDI) collected using ultra-high gradients of the Siemens Connectom. 12. Changes in white matter microstructure assessed using the Neurite Orientation Dispersion and Density Imaging (NODDI) model which provides the isotropic signal fraction (ISOSF) as an estimate of free water, intracellular signal fraction as an estimate of axon density, and the orientation dispersion index (ODI) as an estimate of axon orientation and dispersion. Ethics approval required School of Psychology Research Ethics Committee, Cardiff University

70 Park Place

Cardiff United Kingdom CF10 3AT EC.23.05.16.6801GRA 10.1186/ISRCTN11023869 Two-arm single-blinded randomized controlled trial (pilot feasibility study) Interventional Randomised controlled trial Prevention Quality of life 2025-07-30T00:00:00.000Z United Kingdom Wales CUBRIC

Maindy Road

Cardiff Wales CF24 4HQ Healthy volunteer 1. >50 years old 2. Fluent English speakers 3. Have normal/corrected-to-normal vision and hearing 4. Have less than 4 years of formal musical or dance training 5. Are not involved in any musical activities 6. Have no neurological or psychiatric history that could affect learning (e.g., dementia, stroke or traumatic brain injury, depression requiring hospitalisation) 7. No self-reported difficulty with hand movement 8. No self-reported learning disabilities Mixed 50 Years 99 Years All 50 0 1. Impaired hearing or vision 2. Neurological diagnosis 3. Current involvement in other cognitive training or musical activities (e.g., choir singing, dance or exercise to music classes) 4. More than 4 years of formal music or dance lessons 5. Currently taking psycho-reactive medications which affect memory performance 6. Participants with MRI contra-indications (e.g., pacemakers, stents, cochlear implants, or other metal in the body such as metallic plates, screws or clips) will not be scanned, but will still be eligible for training and cognitive and motor testing 2024-08-15T00:00:00.000Z 2025-06-01T00:00:00.000Z Age-related cognitive decline and neurodegeneration. Mental and Behavioural Disorders Cognitively healthy non-musicians over 50 years will be recruited and screened for cognitive impairment and < 4 years music experience. They will be assigned to either self-guided piano training or a passive control for 8 weeks. Piano training consists of video-guided tutorials which can be carried out in participant's homes. Cognitive assessments and diffusion MRI will take place before and after the intervention period. The groups will be stratified by sex and by two age categories: 50-65 years and >65 years. Pseudo-random numbers will be used to generate randomised group allocation per stratum using R version 4.41, and implemented by the lead researcher. Neither participants nor the researcher conducting baseline testing will be informed of group allocation until after baseline testing is completed, as the algorithm determining group allocation will take place only at the end of testing. Behavioural The datasets generated during and/or analysed during the current study will be stored in a publicly available repository. Cognitive and MRI data will be made openly available on OSF. Stored in publicly available repository 2025 Protocol article in https://pubmed.ncbi.nlm.nih.gov/41402938/ (added 17/12/2025) Protocol

d7fd40f8-d488-4f8a-b227-6b7f788f8593 133c1761-b04e-45b4-b196-77e40088b78b 89aac1da-7f5c-43a3-bb69-a61101f00459 Yes Participant information sheet 46395 PIS Piano MRI Study v3 14.06.24.pdf a048a395-338f-41a0-bc11-04c3f3916ab3 true application/pdf 1512874 00c2411713294de3331f7e242ec509ed Fionnuala Rogers https://orcid.org/0000-0002-1001-7653 Public Scientific Principal investigator

CUBRIC

Cardiff United Kingdom CF24 4HQ +44 (0)29 2087 0365 RogersF2@cardiff.ac.uk Public Cardiff University University/education https://ror.org/03kk7td41 Non-commercial School of Psychology, Cardiff University http://dx.doi.org/10.13039/501100008533 17123858 true PRINCE: Prospective, randomised, multicentre trial of first line systemic treatment and radiotherapy in stage IV non-small cell lung cancer PRINCE (TOURIST Platform) The PRINCE trial will test the hypothesis that early high-dose palliative thoracic radiotherapy is clinically effective in health utility for patients with stage IV non-small cell lung cancer. Background and study aims Radiotherapy of the chest area is widely used in the treatment of lung cancer. Its use in stage IV non-small cell lung cancer (NSCLC) has evolved across the world based on local experience, as doctors attempt to ease symptoms, maintain/improve quality of life, and prolong survival while minimising side effects. The way radiotherapy is being used is based on older evidence, and there is a need for new research to figure out the best timing and dosing of radiotherapy when used alongside current systemic treatments. The aims of this study are: 1. To work out the effect of early high-dose radiotherapy on the chest area on symptoms, disease progression, length, and quality of life 2. To assess the side effects of early high-dose radiotherapy on the chest area 3. To work out the cost-effectiveness of this type of radiotherapy 4. To identify potential barriers, evaluate and explain the treatment and outcomes and highlight issues from a patient, carer, and health care professional’s point of view. Who can participate? Patients aged 16 years and older with stage IV NSCLC who are fit for chemotherapy and/or immunotherapy and high-dose radiotherapy to the chest area, without symptoms requiring immediate radiotherapy. What does the study involve? Following consent, patients will undergo screening tests to ensure they are eligible. Once screened eligible, patients are randomly allocated to one of the two treatment groups. The two treatment groups are: Control group: chemotherapy and/or immunotherapy Radiotherapy group: chemotherapy and/or immunotherapy AND radiotherapy that will start within 12 weeks of randomisation and between cycle 1 and 4 of the chemotherapy and/or immunotherapy A patient is just as likely to receive either of the treatment groups. If allocated to the radiotherapy group, patients will have a radiotherapy planning session with a CT scan. Patients will attend usual clinic visits, at weeks 4, 6, 8, 10, 12, and 14, months 4, 6, 9, 12, 15, 18, and 21 for study assessments. The study assessments will vary depending on the visit but can include weight, asking about how the patient has been feeling and any health issues, asking about any changes to medication and level of self-care/daily activity/physical ability, and completing questionnaires. At months 4, 6, 9, 12, 15 and 21 a CT chest/abdomen/pelvis scan will be done. For the visits, if a patient is unable to attend the clinic, a member of the research team will contact them by telephone for assessments that can be done over the telephone. What are the possible benefits and risks of participating? There may or may not be a direct medical benefit from taking part in the trial. This trial will help to further our knowledge of how to treat stage IV NSCLC and this may benefit others with the same condition in the future. There may be some unpleasant side effects. There could be risks to your child if you become pregnant, or are breastfeeding. As part of the trial, there is a brain CT scan during the screening process. There are also CT chest/abdomen/pelvis scans throughout the trial totalling up to about seven scans, throughout the screening, treatment, and follow-up phases. The number of scans in the trial is similar to standard of care. CT scans and radiotherapy use ionising radiation that may cause cancer many years or decades after exposure. The chance of cancer being caused by ionising radiation associated with imaging or radiotherapy is very small in these patients. Where is the study run from? The Christie NHS Foundation Trust (UK) When is the study starting and how long is it expected to run for? July 2024 to December 2029 Who is funding the study? NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC) (UK) Who is the main contact? tourist-prince@soton.ac.uk https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-when-to-give-radiotherapy-for-advanced-lung-cancer-prince Health utility measured using EORTC QLU-C10D Area Under the Curve (AUC; using trapezoidal rule) to derive a health utility score per year. Questionnaires completed: Screening/Baseline, week 4, week 6, week 8, week 12, week 14, month 4, month 6, month 9, month 12, month 15, month 18, month 21. 1. Overall survival (OS), defined as time from randomisation to death from any cause. Censored at the last follow-up if event-free 2. Progression-free survival (PFS), defined as time from randomisation to disease progression (RECIST v1.1) or death from any cause. Censored at last follow-up if event-free 3. Quality of life using EORTC QLQ-C30 and EQ-5D-5L. Questionnaires completed: Screening/Baseline, month 4, month 6, month 9, month 12, month 15, month 21 4. Lung cancer symptoms using EORTC QLQ-LC13. Questionnaire completed: Screening/Baseline, month 4, month 6, month 9, month 12, month 15, month 21 5. Acute and late toxicity as assessed using NCI CTCAE v5.0. From informed consent to end of study Old ethics approval format Approved 07/05/2024; South Central - Oxford C Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)207 1048144, oxfordc.rec@hra.nhs.uk), ref: 24/SC/0133 10.1186/ISRCTN17123858 334993 CPMS: 61676, NIHR: 133518 334993 61676 133518 Randomized parallel-group controlled trial Interventional Randomised controlled trial Treatment 2029-12-31T00:00:00.000Z United Kingdom England Northern Ireland Scotland Wales Ireland Weston Park Hospital

Witham Road

Sheffield England S10 2SJ Addenbrookes Hospital

Hills Road

Cambridge England CB2 0QQ Kings Mill Hospital

Mansfield Road

Sutton-in-Ashfield England NG17 4JL Nottingham City Hospital

Hucknall Road

Nottingham England NG5 1PB The Christie Hospital

550 Wilmslow Road Withington

Manchester England M20 4BX Leighton Hospital

Leighton

Crewe England CW1 4QJ RM344@2.16.840.1.113883.2.1.3.2.4.18.48 Queen's Hospital

Barking, Havering and Redbridge University Hospitals NHS Trust, Rom Valley Way

Romford, Essex England RM7 0AG Royal Devon and Exeter Hospital

Barrack Road

Exeter England EX2 5DW Clatterbridge Cancer Centre

The Clatterbridge Cancer Centre NHS Foundation Trust 65 Pembroke Place

Liverpool England L7 8YA Colchester Hospital

Turner Road

Colchester England CO4 5JL Royal Surrey County Hospital

Egerton Road

Guildford England GU2 7XX RTJ05@2.16.840.1.113883.2.1.3.2.4.18.48 University College London Hospital

250 Euston Road

London England NW1 2PG Guy's and St Thomas' Hospital

Guy's and St Thomas' NHS Foundation Trust Westminster Bridge Road

London England SE1 7EH Southampton General Hospital

Tremona Road

Southampton England SO16 6YD Bristol Haematology and Oncology Centre

Horfield Road

Bristol England BS2 8ED Churchill Hospital

Old Road Headington

Oxford England OX3 7LE Royal United Hospital

Combe Park

Bath England BA1 3NG RVNG4@2.16.840.1.113883.2.1.3.2.4.18.48 Ipswich Hospital

Heath Road

Ipswich England IP4 5PD NEC14@2.16.840.1.113883.2.1.3.2.4.18.48 Queen Elizabeth Hospital Kings Lynn

Gayton Road Queen Elizabeth Hospital Site

King's Lynn England PE30 4ET M5Z2Q@2.16.840.1.113883.2.1.3.2.4.18.48 Mount Vernon Cancer Centre

Rickmansworth Road

Northwood England HA6 2RN RWH04@2.16.840.1.113883.2.1.3.2.4.18.48 Queen Alexandra Hospital

Southwick Hill Road Cosham

Portsmouth England PO6 3LY RHU03@2.16.840.1.113883.2.1.3.2.4.18.48 Musgrove Park Hospital

Musgrove Park

Taunton England TA1 5DA RH5A8@2.16.840.1.113883.2.1.3.2.4.18.48 Torbay Hospital

Newton Road

Torquay England TQ2 7AA RWV55@2.16.840.1.113883.2.1.3.2.4.18.48 Velindre Cancer Centre

Velindre Road

Cardiff Wales CF14 2TL RQFH5@2.16.840.1.113883.2.1.3.2.4.18.48 Altnagelvin Area Hospital

Glenshane Road

Londonderry Northern Ireland BT47 6SB ZT00501@2.16.840.1.113883.2.1.3.10.2 Belfast Health and Social Care Trust

Trust Headquarters A Floor - Belfast City Hospital Lisburn Road

Belfast England BT9 7AB A3X4A@2.16.840.1.113883.2.1.3.2.4.18.48 Beatson West of Scotland Cancer Centre

1053 Great Western Road

Glasgow Scotland G12 0YN G517H@2.16.840.1.113883.2.1.3.8.2.16.2 New Victoria Hospital

55 Grange Road

Glasgow Scotland G42 9LF G306H@2.16.840.1.113883.2.1.3.8.2.16.2 St Luke’s Radiation Oncology Network

St Luke’s Hospital Highfield Road, Rathgar

Dublin Ireland 6 Patient 1. >=16 years of age 2. Stage IV non-small cell lung cancer (NSCLC) (radiological diagnosis confirmed at multidisciplinary team [MDT] as a minimum) (additionally see #6 trial-specific requirement below) 3. Thoracic disease amenable to radiotherapy 4. Provision of written informed consent 5. For women of childbearing potential: a negative urine or serum pregnancy test within 7 days of trial entry into the main trial 6. Histologically or cytologically confirmed NSCLC 7. At least T2 and/or N1 disease 8. ECOG Performance Status (0-2) 9. The patient is deemed fit to receive a minimum of four cycles of systemic anti-cancer treatment according to local guidelines and assessment 10. Fit to receive high-dose palliative radiotherapy with acceptable pulmonary function according to local guidelines and assessment Mixed 16 Years 100 Years All 472 0 Current key exclusion criteria as of 28/04/2026: 1. The need for palliative radiotherapy to the thorax prior to randomisation 2. Co-morbidities which are considered a contraindication to radiotherapy by the treating clinical team, including interstitial lung disease and active connective tissue disorders 3. History of prior malignant tumours likely to interfere with the protocol treatment or comparisons 4. Leptomeningeal disease 5. Women who are pregnant or breastfeeding 6. Women of child-bearing potential who are not able or unwilling to use a highly effective method of contraception 7. Patients who, in the judgment of the investigator, will be unlikely or unable to comply with the requirements of the protocol 8. Primary targeted systemic therapy for NSCLC with a driver mutation (EGFR, ALK, ROS-1, BRAF) 9. Prior treatments for this NSCLC* 10. Patients participating in a clinical trial of an investigational medicinal product *Some treatments, delivered in the weeks prior to randomisation are acceptable (examples include: cycles 1 & 2 of standard of care systemic therapy, symptom directed (non-thoracic) palliative radiotherapy e.g. Stereotactic Radio-Surgery). Previous key exclusion criteria: 1. The need for palliative radiotherapy to the thorax prior to randomisation 2. Co-morbidities which are considered a contraindication to radiotherapy by the treating clinical team, including interstitial lung disease and active connective tissue disorders 3. History of prior malignant tumours likely to interfere with the protocol treatment or comparisons 4. Leptomeningeal disease 5. Women who are pregnant or breastfeeding 6. Women of child-bearing potential who are not able or unwilling to use a highly effective method of contraception 7. Patients who, in the judgment of the investigator, will be unlikely or unable to comply with the requirements of the protocol 8. Primary targeted systemic therapy for NSCLC with a driver mutation (EGFR, ALK, ROS-1, BRAF) 9. Prior treatments for this NSCLC* 10. Patients participating in a clinical trial of an investigational medicinal product *Cycle 1 of standard-of-care systemic therapy for this NSCLC may be delivered prior to randomisation 2024-07-30T00:00:00.000Z 2028-01-31T00:00:00.000Z Stage IV non-small cell lung cancer Cancer PRINCE is a randomised control trial in the TOURIST Platform. Patients may be identified at any point after the diagnosis of stage IV NSCLC by their usual care team. To permit timely randomisation and minimise treatment delays potentially eligible patients should be identified at the thoracic multidisciplinary team meeting prior to their first oncology appointment. PRINCE includes the addition of early high-dose palliative thoracic radiotherapy in patients receiving standard of care (SoC) first-line systemic treatment (chemotherapy, immunotherapy, or a combination of both) to assess if improvement in local disease control results in improved quality of life (QoL)/survival for patients. Once written informed consent has been gained, all screening and baseline procedures have been completed and the patient is confirmed eligible, they will be randomised (1:1) at the start of their systemic treatment to one of two study arms: Control Arm - SoC systemic therapy, Radiotherapy Arm - SoC systemic therapy and radiotherapy. Patients will have equal chances of receiving one of the two arms. There will be either 12 or 13 visits for radiotherapy, depending on clinician decision. Radiotherapy will begin anytime within 84 days after randomisation and between cycles 1 and 4 of systemic therapy. Patients will be followed up to Month 21, follow-up assessments include: 1. Adverse event, toxicity and medication assessment 2. Quality of life questionnaires 3. Smoking habit questions 4. Weight 5. CT with contrast chest/abdo/pelvis 6. Eastern Cooperative Oncology Group (ECOG) performance status When all patients have completed all of their study visits, survival and disease progression data will be collected directly from the hospital sites. An economic evaluation to measure the quality-adjusted life years at 21 months will be performed. A process evaluation using interviews (over the phone or using an online meeting system e.g. Zoom), diaries and a PPI questionnaire to identify issues for implementation from patients, patient carers and Health Care Professionals. 15 patients - individual interview and a diary to complete All patients - PPI QoL questionnaire completion 15 patient-carers - individual interview 10 health care professionals (across two trials in the TOURIST Platform) – individual interview Procedure/Surgery Data sharing statement to be made available at a later date

Study website Migrated from study website field

c773a0ab-a76c-479c-9ea5-f15985f2b468 74bcee34-2b84-48a3-8aaa-40974da0b308 444d16b6-59c5-46ca-b30b-7db8ffa2f9c0 No Izabela Eberhart Public Scientific

Southampton Clinical Trials Unit, MP131 Southampton General Hospital Tremona Road

Southampton United Kingdom SO16 6YD +44 (0)23 8120 5154 tourist-prince@soton.ac.uk Public The Christie NHS Foundation Trust Hospital/treatment centre https://ror.org/03v9efr22 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 15983654 true PROton beam Therapy versus Intensity-modulated radiotherapy for Sinonasal cancer PROTIS Treatment with proton beam therapy can improve disease-free survival rate compared with standard-of-care IMRT for non-metastatic sinonasal cancer Background and study aims Cancer of the sinuses (the air spaces in our nose and facial bones) is a rare disease, which is often found to be quite advanced by the time it is noticed. The treatment for sinus cancer usually involves surgery followed by radiotherapy, but radiotherapy may also be used without surgery. In some cases, chemotherapy may also be used to treat the cancer. Radiotherapy is an important part, either to treat the cancer itself (where surgery has not been done) or to treat the cancer cells that remain after surgery (without radiotherapy these cells would grow back). The current treatment is intensity-modulated radiotherapy (IMRT). Proton beam therapy (PBT) is a newer form of radiotherapy, which may be more effective at treating cancer or cancer cells to improve the chance of cure. It may also cause less damage to nearby normal structures, resulting in fewer side effects. However, this is unknown and it is also possible that some side effects may be increased by protons. PROTIS aims to compare PBT with IMRT, to see whether or not there is an improvement in cure rates and a difference in long-term side effects. Who can participate? Patients aged 25 years old and over diagnosed with sinus cancer, histologically confirmed by the hospital to be either sinonasal squamous cell carcinoma (SNSCC) or sinonasal adenocarcinoma (SNAC). What does the study involve? The study aims to recruit 276 patients, and each participant will be involved in the study for up to 5 years after treatment. When taking part in PROTIS, there is a 50:50 chance (which is decided randomly) that participants will be allocated to receive either IMRT (standard of care) or PBT. Regardless of which treatment participants receive, radiotherapy will be delivered daily (excluding weekends) for up to 7 weeks. If participants are receiving IMRT, it will be delivered at their local hospital as if they were not taking part in the trial. If they are to receive PBT, this will be delivered at one of the two NHS proton beam centres in the UK (The Christie, Manchester or University College London Hospital (UCLH), London). Usually, this will be the centre closest to the participants' home but other factors are considered for example capacity at the centres. This will mean travelling to the specialist unit and staying away from home during treatment (up to 7 weeks). Reasonable travel expenses are reimbursed, and the NHS provides apartment accommodation for the patient and one family member or carer. The doctor or nurse will provide further information about this. Before starting treatment, participants will need to attend a planning visit at the treating hospital. This may be at the proton beam centre if allocated to PBT in the trial. They will meet the members of the team and will attend some clinical appointments. During this time, they will have a mould/mask made which will be worn during all the radiotherapy treatments. These appointments are likely to occur across several days. There are several other treatments/assessments involved in the trial as well as the radiotherapy. Some of these are the same as standard of care but others are additional. To treat the cancer some participants will be offered surgery before radiotherapy; others may be offered chemotherapy. The decisions about what is required will be the same whether they are taking part in the trial or not. If they are having surgery, the team would like to take some biopsies, which can be used to answer some important research questions. To understand potential long-term side effects the clinical team will perform some tests/ assessments. The first set will be before starting radiotherapy, these are called baseline assessments. These tests include clinical assessment, blood tests, hearing tests, eye examinations, and tests to check the sense of smell and brain function including attention, memory, language, reaction time and perception, thinking and memory. Participants will also be asked to complete a few questionnaires about their quality of life. These same tests will then be repeated at different time points after their radiotherapy so that any changes can be tracked. What are the possible benefits and risks of participating? The results from this study will be used to help us improve treatments for patients with sinus cancer. It is known that most patients having radiotherapy will experience some side effects. Part of the PROTIS trial is to understand whether PBT can reduce the side effects of radiotherapy. At the moment we do not know if this is the case. Where is the study run from? The Christie NHS Foundation Trust are the sponsor and lead clinical site. The day-to-day running of the trial is via the Liverpool Clinical Trial Centre (LCTC) When is the study starting and how long is it expected to run for? October 2022 to September 2031 Who is funding the study? Cancer Research UK (Taylor Family Foundation) National Institute for Health and Care Research (NIHR) Who is the main contact? PROTIS@liverpool.ac.uk https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-proton-beam-radiotherapy-for-sinus-cancer-protis#undefined Disease-free survival (DFS) measured using a biopsy; a biopsy with pathological confirmation will define a DFS event. Where a biopsy is not possible, correlative imaging can be used as a surrogate to define a DFS event from randomisation to cancer recurrence, death from any cause, or 5-year follow-up. 1. Loco-regional tumour control measured using a clinical evaluation post-treatment. Additional non-trial visits will be carried out as per local policy and standard of care, from randomisation to tumour growth or 5 years follow-up. 2. Distant failure measured during follow-up via imaging if prompted by participants having symptoms of concern and as per standard of care from randomisation to distant failure or 5 years follow-up. 3. Overall survival measured using all deaths reported from randomisation to death or 5 years follow-up. 4. Acute severe (grade 3-5) toxicity events measured by physician recorded CTCAE v5.0 up to 12 weeks from completion of treatment. 5. Late severe (grade 3-5) toxicity events measured by physician recorded CTCAE v5.0 from 12 weeks to 5 years from completion of treatment. 6. Neuro-cognitive decline measured using EORTC core tests conducted and scored at sites and compiling the corresponding scoring manuals/algorithms at baseline, 12 weeks, 52 weeks, 2, 3, 4 and 5 years. 7. Visual function measured using visual acuity, visual fields, Lens exam, IOP, fundus exam, media clarity, levator function, pupil function, colour vision, ocular alignment/movement assessment, lid/lash/ocular surface exam and Optical Coherence Tomography (OCT) at baseline, 2 and 5 years. 8. Olfactory function measured using UPSIT at baseline and 2 years. 9. Pituitary function measured using blood tests collected as per standard of care Growth hormone (IGF-1), Adrenal (ACTH/cortisol (9am)), and Thyroid (TSH fT4 fT3), Gonadotrophins/ sex steroids (FSH/LH/SHBG testosterone or oestradiol, prolactin) at baseline, 52 weeks, 2 and 5 years. 10. Auditory function measured using pure tone audiometry +/- extended high frequencies at baseline and 2 years. 11. Trismus measured using maximum interincisal distance at baseline, 12, 52 weeks and 2 years. 12. Brain injury/necrosis measured using central review of MRI scans (collected as standard of care sinus/neck) at baseline, 52 weeks, 2, 3, 4 and 5 years. 13. Quality of Life measured using participant completed questionnaires; EORTC-QLQ-C30, EORTC-QLQ-BN20, EuroQoL EQ‐5D‐5L, ASBQ at baseline, end of treatment, 6, 12, 24, 52, 78 weeks, 2, 3, 4 and 5 years. Ethics approval required London-Surrey Research Ethics Committee

2 Redman Place Stratford

London United Kingdom E20 1JQ 23/LO/0933 10.1186/ISRCTN15983654 325882 CPMS: 56569 325882 56569 Open-label phase III multi-centre prospective randomized controlled trial Interventional Randomised controlled trial Treatment 2031-09-30T00:00:00.000Z United Kingdom England Wales The Christie NHS Foundation Trust

550 Wilmslow Road Withington

Manchester England M20 4BX RBV@2.16.840.1.113883.2.1.3.2.4.18.48 Cambridge University Hospitals NHS Foundation Trust

Cambridge Biomedical Campus Hills Road

Cambridge England CB2 0QQ RGT@2.16.840.1.113883.2.1.3.2.4.18.48 Nottingham University Hospitals NHS Trust - Queen's Medical Centre Campus

Nottingham University Hospital Derby Road

Nottingham England NG7 2UH RX1RA@2.16.840.1.113883.2.1.3.2.4.18.48 Manchester University NHS Foundation Trust

Cobbett House Oxford Road

Manchester England M13 9WL R0A@2.16.840.1.113883.2.1.3.2.4.18.48 Liverpool University Hospitals NHS Foundation Trust

Royal Liverpool University Hospital Prescot Street

Liverpool England L7 8XP REM@2.16.840.1.113883.2.1.3.2.4.18.48 Northern General Hospital

Northern General Hospital NHS Trust C Floor, Huntsmnan Building Herries Road

Sheffield England S5 7AU NTPP8@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Southampton NHS Trust

Southampton General Hospital Tremona Road

Southampton England SO16 6YD NV513@2.16.840.1.113883.2.1.3.2.4.18.48 University College London Hospitals NHS Foundation Trust

250 Euston Road

London England NW1 2PG RRV00@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Birmingham NHS Foundation Trust

Queen Elizabeth Hospital Mindelsohn Way Edgbaston

Birmingham England B15 2GW RRK@2.16.840.1.113883.2.1.3.2.4.18.48 Velindre NHS Trust

Unit 2 Charnwood Court Heol Billingsley

Cardiff Wales CF15 7QZ RQF@2.16.840.1.113883.2.1.3.2.4.18.48 East and North Hertfordshire NHS Trust

Lister Hospital Coreys Mill Lane

Stevenage England SG1 4AB RWH@2.16.840.1.113883.2.1.3.2.4.18.48 Gloucestershire Hospitals NHS Foundation Trust

Cheltenham General Hospital Sandford Road

Cheltenham England GL53 7AN RTE@2.16.840.1.113883.2.1.3.2.4.18.48 The Clatterbridge Cancer Centre NHS Foundation Trust

Clatterbridge Hospital Clatterbridge Road Bebington

Wirral England CH63 4JY REN@2.16.840.1.113883.2.1.3.2.4.18.48 Mount Vernon Cancer Centre

Rickmansworth Road

Northwood England HA6 2RN RWH04@2.16.840.1.113883.2.1.3.2.4.18.48 South Tees Hospitals NHS Foundation Trust

James Cook University Hospital Marton Road

Middlesbrough England TS4 3BW RTR@2.16.840.1.113883.2.1.3.2.4.18.48 Gloucestershire Hospitals NHS Foundation Trust

Cheltenham General Hospital Sandford Road

Cheltenham England GL53 7AN RTE@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Current inclusion criteria as of 31/10/2024: 1. Written and informed consent obtained from participants 2. Agreement of participant to comply with the requirements of the trial, including travel and residential stay at the proton centre if allocated to PBT 3. Histologically confirmed: 3.1. Sinonasal squamous cell carcinoma (SNSCC) or 3.2. Sinonasal adenocarcinoma (SNAC) 4. Primary tumour (T) staging (AJCC 8th edition): 4.1. T3-4 all subsites (maxillary, ethmoid, sphenoid or frontal sinuses, and/or nasal cavity) or 4.2. T2 nasal cavity involving ethmoid sinus 5. Age >=25 years old 6. WHO performance status 0-1 7. Multidisciplinary team (MDT) decision for curative intent treatment 7.1. with surgery or 7.2. without _____ Previous inclusion criteria: 1. Written and informed consent obtained from participants 2. Agreement of participant to comply with the requirements of the trial, including travel and residential stay at the proton centre if allocated to PBT 3. Histologically confirmed: 3.1. Sinonasal squamous cell carcinoma (SNSCC) or 3.2. Sinonasal adenocarcinoma (SNAC) 4. Primary tumour (T) staging (AJCC 8th edition): 4.1. T3-4 all subsites (maxillary, ethmoid, sphenoid or frontal sinuses, and/or nasal cavity) or 4.2. T2 nasal cavity involving ethmoid sinus 5. Age > = 16 years old 6. WHO performance status 0-1 7. Multidisciplinary team (MDT) decision for curative intent treatment 7.1. with surgery or 7.2. without Mixed 25 Years 110 Years All 276 0 1. Distant metastatic disease, as determined by routine pre-operative radiological staging investigations 2. Previous head and neck radiotherapy 3. Any invasive malignancy within the previous 2 years (other than non-melanomatous skin carcinoma or cervical carcinoma in situ) 4. Previous or concurrent illness that would interfere with completion of therapy, trial assessments or follow-up (in the opinion of PI) 5. Pregnant or breastfeeding women 6. Participants unwilling or unable to use adequate non-hormonal contraception 2024-09-16T00:00:00.000Z 2029-04-01T00:00:00.000Z Non-metastatic sinonasal cancer Cancer PROTIS is an open-label phase III multi-centre prospective randomised controlled trial. The overall aim is to assess whether proton beam therapy (PBT) compared with standard-of-care intensity-modulated radiotherapy (IMRT) improves cure rates for patients with sinonasal cancer. Secondary to this is to assess the long-term side effects and impact on quality of life. The trial aims to recruit 276 patients with non-metastatic sinonasal cancer from 20 UK sites. Patients have a 50:50 chance of being allocated to receive either standard of care IMRT or PBT. Treatment will be given over 6-7 weeks. Following treatment patients will enter a follow-up phase of up to 5 years (2 years minimum) where they will attend regular clinical visits. Participant identification Potential participants will be identified during multi-disciplinary team (MDT) meetings at their local hospital. During these meetings which include various clinical teams, diagnostic scans (MRI or CT-chest) and biopsies will be reviewed and decisions on patient treatment will be documented. Depending on the size and location of the tumour a patient may require surgery to try and remove the cancer or induction chemotherapy to reduce or shrink the cancer. These treatments will need to be delivered before beginning radiotherapy treatment (as standard of care). The decision for these treatments will be the same whether a patient is taking part in the trial. Depending on which treatment is recommended participants will enter the trial either via a surgical or oncology pathway. If a patient is identified as potentially eligible for the study, they will be approached by the clinical team (either surgical or oncology) and provided with information about the trial. Surgical It is expected that approximately 80% of patients will require surgery before radiotherapy. Informed consent will be taken and eligibility will be confirmed by appropriate members of the surgical team. The surgery itself is part of standard care for treating this disease and is not under investigation in this trial. Participants requiring surgery and attending either Liverpool or Manchester ONLY will also be asked to participate in a sub-study which will involve collecting tumour biopsies and additional blood collections (six in total). Oncology For participants who have not undergone surgery informed consent will be taken and eligibility will be confirmed by appropriate members of the oncology team. Participants will proceed straight to baseline tests. Participants who have undergone surgery will then attend oncology visits. The oncologist will reconfirm eligibility and the participant's consent. There is a small chance that following surgery this study is no longer suitable for the participant. If this is the case, the clinical team will discuss treatment options with the participants and withdraw them from the study. Otherwise, patients will continue to baseline tests. The oncology team may also advise that concurrent chemotherapy is needed at the same time as radiotherapy. Baseline tests These tests include clinical assessment, blood tests, hearing tests, eye examinations, tests to check sense of smell and paper-based brain function tests, as well as the completion of quality of life questionnaires. Tissue taken from cancer at diagnosis is requested to be sent to the labs. These assessments will require the participant to attend clinic and some, such as eye and hearing tests, are performed in different departments. These may need to be performed on different days depending on scheduling and potentially different locations depending on local hospital departmental set-up. Randomisation Participants are randomised on a 1:1 basis to receive either IMRT or PBT. Randomisation will be performed using minimisation to take account of the multiple stratification factors, including subsite (maxilla vs other), pathology (SNSCC vs high-grade SNAC vs low-grade SNAC), surgery (yes/no), use of chemotherapy (yes/no), stage (T2/3 vs T4a vs T4b) and recruiting centre. Once randomisation is confirmed the participant will be informed on the form of radiotherapy they will receive. Standard of care IMRT will be delivered at the local recruiting hospital. However, PBT can only be delivered at one of two NHS proton beam centres in the UK (The Christie, Manchester or UCLH, London). Upon randomisation, the clinical team will input data into the proton beam referral portal. Patients will be assigned to one of the centres based on factors including but not limited to availability and distance. During treatment, the team at the proton beam centre will assume all care responsibilities for the patient and will complete all on-treatment CRFs. Allocation to PBT will mean travelling to the specialist unit and staying away from home during treatment. Reasonable travel expenses would be reimbursed, and the NHS provides apartment accommodation for the patient and one family member or carer. Radiotherapy planning Visit Before starting radiotherapy treatment, participants will need to attend a planning visit at the treating hospital (proton beam centre if allocated PBT). During this visit, a special mould called a “mask” or “shell” will be made which will support the patient to be able to lie still and in the same position for each treatment. This is followed by diagnostic scans (performed while wearing the radiotherapy mask), which will be used to plan the radiotherapy treatment. Induction chemotherapy (if required) If the clinical team decides that chemotherapy is required to shrink the cancer before radiotherapy (induction) then this will be performed at the local recruiting hospital before starting radiotherapy. It is expected that 2 rounds of chemotherapy will be administered with the participant attending the radiotherapy planning session between rounds. Concurrent chemotherapy (if required) The clinical team may also decide that the participant requires chemotherapy delivered while receiving radiotherapy (concurrent chemotherapy). If this is to happen, chemotherapy will be provided at the hospital providing the radiotherapy. Radiotherapy Treatment Radiotherapy treatment will be delivered in 30-35 fractions. One fraction will be delivered once daily (excluding weekends) every week, for up to 7 weeks. During treatment, the clinical team will monitor symptoms and any side effects. At the immediate end of treatment, there will be a health status assessment and participants will be asked to complete some questionnaires. If attending a proton beam centre the participants will be discharged back to the care of the local recruiting hospital. After Treatment (follow-up) After treatment, participants will need to attend follow-up visits at the local recruiting hospital. Follow-up visits are timed to be aligned with routine care visits for MRI scans (3, 12, 24, 36, 48, 60m). Data from some of these scans will be sent to a radiologist to review for any signs of injury to the brain. The treating physician may request additional surveillance scans in line with local practice. As part of the trial follow-up, there will be some additional tests relating to long-term side effects and participants will be asked to complete quality-of-life questionnaires. The first visit is 6 weeks after finishing treatment. Then 3, 6, 12, 18 and 24 months after treatment, then once a year for the next 3 years. Procedure/Surgery Data sharing statement to be made available at a later date

d8634cf2-e7dc-4030-ba1c-f031af781a2b e2f59eba-5da9-4f81-b545-a37b58d363db 83d552ae-0a1e-4134-918e-a65968ff723d a73052e4-717e-4c90-aefe-37a122d6f47e 1307ce16-90a4-404f-8709-a2e6639af137 b6fd6666-e5b4-4250-b601-91e1e66da33d No Participant information sheet 44767_PIS_V2.0_11Dec2023.pdf 87f9648a-dbe3-4d8a-9489-3a0aa665e52b true application/pdf 331945 796b2929144058d19316a2563ec7ccd0 Participant information sheet ISRCTN15983654_PIS_V5.0_30Jan2025.pdf c7e48947-f610-4794-b868-da6059a5ca52 true application/pdf 686361 6063af458e390b00f741d69de03a6584 David Thomson, FRCR MD https://orcid.org/0000-0002-1146-608X Principal investigator

Department of Clinical Oncology, The Christie NHS Foundation Trust, Wilmslow Road

Manchester United Kingdom M20 4BX +44 (0)161 446 8457 David.thomson2@nhs.net Public Jason Fleming, FRCS PhD Scientific

Liverpool Head and Neck Centre, Aintree University Hospital, Lower Lane

Liverpool United Kingdom L9 7A +44 (0)151 529 5259 Jason.Fleming@liverpool.ac.uk Public PROTIS Study Team Public

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- United Kingdom - - PROTIS@liverpool.ac.uk Public The Christie NHS Foundation Trust Hospital/treatment centre https://ror.org/03v9efr22 Non-commercial Cancer Research UK http://dx.doi.org/10.13039/501100000289 National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 16573769 true DOMENICA (GINECO-EN105b/ENGOT-en13 study): Randomized phase III trial in MMR deficient endometrial cancer patients comparing chemotherapy alone versus dostarlimab in first-line advanced/metastatic setting DOMENICA The DOMENICA study aims to evaluate the effectiveness of dostarlimab, as a new treatment for advanced/metastatic endometrial cancer by significantly reducing the chance of relapse. Background and study aims The DOMENICA study aims to evaluate the effectiveness of dostarlimab, as a new treatment for advanced/metastatic endometrial cancer by significantly reducing the chance of relapse. Dostarlimab is a type of immunotherapy (doesn’t target the tumour directly, but has an impact on the immune system to be able to attack and destroy the cancer cells). When the immune system detects a foreign body (virus, bacteria, etc), it produces antibodies which are proteins that combat infections. They can attach to other molecules or cells of your body, and work by helping your immune system to fight the cancer. The current standard treatment for this cancer is chemotherapy alone (paclitaxel and carboplatin). Despite chemotherapy, the cancer can progress in some patients. Who can participate? The study will be carried out among 142 patients with advanced or metastatic endometrial cancer, in more than 60 healthcare facilities in 7 countries (France, Belgium, Spain, Italy, Germany, Canada and United Kingdom) over an 8 year period. What does the study involve? In order to evaluate the efficacy of dostarlimab, it is necessary to compare this treatment to the standard treatment. In order to be able to make comparisons, it is necessary that the distribution between the 2 groups is randomly selected by a computer (this is called randomization). There will be the same number of patients in each treatment group therefore patients have 1 possibility out of 2 to receive dostarlimab. The duration of participation in this research study for each patient is around 5 years. Participation will be divided into 5 periods: • Collection of a tumour sample (standard of care, not an extra procedure), • Ensuring the criteria for inclusion is met, • Allocation of treatment, • Treatment period, • Follow up period. Participants will have the right to withdraw at any point and treatment will not be compromised. If successful this study could help patients get quicker access to the therapeutic innovation, especially immunotherapy. What are the possible benefits and risks of participating? Benefits: We hope that dostarlimab is more efficient than chemotherapy, and significantly reduces the rate of relapse of advanced or metastatic endometrial cancer. If successful this study could help patients get quicker access to the therapeutic innovation, especially immunotherapy. If you participate in this study, you will have access to immunotherapy much sooner than you otherwise would. However, you may not benefit from participating in this study. Your condition may remain the same, improve or worsen. Your participation will not limit the access to the standard treatments, in case of benefit or progression after the treatments dispensed in this study. By participating in this research, you will be helping scientists and clinicians better understand the disease and improve future treatment options. The information from this study will also hopefully help future endometrial cancer patients. Risks: Current information continues to support an acceptable benefit-risk profile for Dostarlimab when used with the precautions, dosing & safety monitoring outlined in the Protocol and routine pharmacovigilance practices. The study treatment may be responsible for side effects of which all of them may not have been identified even though the drugs proposed in this study have all been marketed in many countries worldwide for several years. Most of them are variable from one patient to another and can be mild, moderate or sometimes severe. Some may go away as soon as study treatment(s) is stopped. In some cases, they can be serious, long-lasting or may never resolve (irreversible). Where possible medicines will be prescribed to help attenuate side effects reported. In addition, by combining several drugs, side effects may be more frequent and/or more intense than when taking only one of these drugs. A list of ongoing medication, dietary supplement or phytotherapy will be captured prior to trial entry to ensure the risk of potential interactions is minimised. Safety of study treatments will be assessed at each visit by the study doctor. Additional treatments may be prescribed to control side effects. If they are significant, the doctor may change the treatment doses or stop study treatment(s)* for a given time or permanently. Side effects may occur based on the experience from other patients who have been treated with dostarlimab. They are listed in the Protocol and Patient Information Sheet according to their frequency regardless of their severity including very common (> 10 %), common (1-10 %), uncommon (0.1-1%) and rare but serious. If experienced patients will be prompted to contact there Doctor immediately. CT & MRI scans may involve venous perfusion of a contrast agent. As with any product, there is a risk of an allergic reaction to that product. Needle pricking during injection of the contrast agent, during treatment administration or blood sampling can cause pain, swelling, bruise, irritation or redness. During the electrocardiogram, may experience itching or bruising on the skin where the patches were placed. The effects of the study products on an unborn child or newborn are not known therefore participants are not allowed to participate in this research if pregnant or plan to be, this will be considered by the Principal Investigator at each site prior to consent of a potential participant. Prior to consent the Principal Investigator(s) at each site will ensure each patient is given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study, including any information on the mandatory and optional tumor biopsies. Participants will also be informed of there rights to discontinue from the study and/or study treatment at any time. Likewise participants may be discontinued from study treatment by the Principal Investigator at any time. Reasons for discontinuing study treatment prematurely include adverse events, clinical progression, PD according to RECIST v.1.1 (criteria per Investigator assessment), risk (as judged by the Investigator, Sponsor, or both), severe noncompliance with the protocol, pregnancy & lost to follow-up. The sponsor reserves the right to discontinue the study for medical reasons or any other reason at any time. Circumstances that may warrant termination or suspension include, but are not limited to: • Determination of unexpected, significant, or unacceptable risk to participants • Demonstration of efficacy that would warrant stopping • Insufficient compliance to protocol requirements • Data that are not sufficiently complete and/or evaluable Where is the study run from? ARCAGY-GINECO (France) When is the study starting and how long is it expected to run for? May 2023 to December 2029 Who is funding the study? ARCAGY-GINECO (France) Who is the main contact? DOMENICA@cardiff.ac.uk Progression-free survival (PFS), defined as the time from the date of randomization to the earliest date of assessment of PD or death by any cause in the absence of PD, whichever occurs first. Tumour response will be evaluated using RECIST v.1.1 based on Investigator assessment. The primary analysis population will be the intention-to-treat (ITT) population. 1. Quality of Life Questionnaires (QoL) will be assessed on EORTC QLQ-C30, EORTC QLQCIP20, EORTC QLQ-EN24 and EUROQOL EQ-5D completion. The targeted dimension will be the Global QoL/Health Status dimension of the QLQ-C30 at 18 weeks 2. Overall Response Rate (ORR) is defined as the proportion of patients with the best overall response (BOR) of CR or PR. Patients who have no postbaseline evaluable tumour assessments will be considered non-responders. Overall Response Rate (ORR) will be calculated based on ITT population, using Investigator’s tumor assessment. 3. Duration of Response (DOR) is defined as the time from first documentation of CR or PR until the time of first documentation of subsequent PD per RECIST v.1.1 based on Investigator assessment or death by any cause in the absence of PD per RECIST v.1.1, whichever occurs first. 4. Overall Survival (OS) is defined as the time from the date of inclusion until death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive. The analyses for Overall Survival will be based on ITT population, according to the treatment group subjects are randomized to at baseline. The distribution of OS will be compared between the two treatment groups. 5. Time to first and second Subsequent Treatment or death is defined as the time from the date of randomization to date of the first and second subsequent anticancer therapy or death. 6. Safety and tolerability will be assessed for all the patients in terms of : 6.1. AEs, deaths, laboratory data, vital signs and ECG. AE will be described according to MedDRA terms and graded according to CTCAE version 5.0 by investigators. 6.2. Self-report symptoms and adverse events by patients using PRO CTC-AE (Self-reported PRO) of cancer treatments Ethics approval required East Midlands - Nottingham 2 Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 23/EM/0142 10.1186/ISRCTN16573769 2021-002124-21 1006901 NCT05201547 CPMS: 60707, GINECO-EN105b/ENGOT-en13 NCT05201547 2021-002124-21 1006901 60707 GINECO-EN105b/ENGOT-en13 Phase III randomized open-label cross-over trial Interventional Randomised cross over trial Efficacy Safety 2029-12-31T00:00:00.000Z United Kingdom England Scotland Wales Belgium Canada France Germany Italy Spain Velindre Cancer Centre

Velindre Road

Cardiff Wales CF14 2TL RQFH5@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Cornwall Hospital (treliske)

Treliske

Truro England TR1 3LJ RJ845@2.16.840.1.113883.2.1.3.2.4.18.48 St James University Hospital

Beckett Street

Leeds England LS9 7TF Western General Hospital

Crewe Road South Edinburgh

Lothian Scotland EH4 2XU S116H@2.16.840.1.113883.2.1.3.8.2.16.2 Addenbrookes

Addenbrookes Hospital Hills Road

Cambridge England CB2 0QQ NV504@2.16.840.1.113883.2.1.3.2.4.18.48 Queen Elizabeth Hospital

Queen Elizabeth Medical Centre Edgbaston

Birmingham England B15 2TH RRK02@2.16.840.1.113883.2.1.3.2.4.18.48 Guys Hospital

Guys Hospital Great Maze Pond

London England SE1 9RT NV515@2.16.840.1.113883.2.1.3.2.4.18.48 University College Hospital Macmillan Cancer Centre

Huntley St

London England WC1E 6AG Northampton

Northampton General Hospital Cliftonville

Northampton England NN1 5BD NV157@2.16.840.1.113883.2.1.3.2.4.18.48 United Lincolnshire Hospitals NHS Trust

Lincoln County Hospital Greetwell Road

Lincoln England LN2 5QY RWD@2.16.840.1.113883.2.1.3.2.4.18.48 Patient 1. Female patient is at least 18 years of age 2. Patient has signed the Informed Consent (ICF) and is able to comply with protocol requirements 3. Patient with histologically proven endometrial adenocarcinoma with recurrent or advanced disease 4. Patient with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 5. Patient must have primary Stage IIIC2 or Stage IV disease or first recurrent endometrial cancer without curative treatment by radiation therapy or surgery alone or in combination, and meet at least one of the following situations: 5.1. Patient has primary Stage IIIC2 (with nodes involvement from the outset, not allowing a curative radiotherapy, or with remaining measurable lumbo-aortic nodes after lumbo-aortic dissection, which cannot be treated by curative radiotherapy) or Stage IV disease 5.2. Patient has first recurrent disease and is chemotherapy naïve for this 1st recurrence or metastatic setting 5.3. Patient may have received prior neo-adjuvant/adjuvant systemic chemotherapy or locoregional concomitant radio-chemotherapy for the primary cancer and had a recurrence ≥ 6 months after completing treatment (first recurrence only) 6. All histologic subtypes of endometrial adenocarcinoma could be included if MMRd/MSI-H 7. MMRd/MSI-H tumor (defined in routine local IHC), is mandatory for inclusion. In case of ambiguous result of IHC (lack of positive internal control, heterogeneous loss of MMR protein expression), the MMRd/MSI-H status will be assessed by PCR/NGS 8. Availability of 1 block for MMR/MSI status centralized confirmation for IHC or PCR/ NGS, and additional block(s) for Translational Research 9. Patient with measurable disease according RECIST 1.1 criteria 10. Patient could have been previously treated with hormone therapy, for the metastatic/advanced disease 11. Patient may have received pelvic and lombo-aortic external beam +/- vaginal brachytherapy 12. Patient has adequate organ function, defined as follows: 12.1. Absolute neutrophil count ≥ 1,500 cells/μL 12.2. Platelets ≥ 100,000 cells/μL 12.3. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L 12.4. Serum creatinine ≤ 1.5× upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 mL/min using the Cockcroft-Gault equation for patients with creatinine levels > 1.5× institutional ULN 12.5. Total bilirubin ≤ 1.5× ULN (≤ 2.0 x ULN in patients with known Gilbert’s syndrome) or direct bilirubin ≤ 1× ULN 12.6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5× ULN unless liver metastases are present, in which case they must be ≤ 5× ULN 12.7. International normalized ratio or prothrombin time (PT) ≤1.5× ULN and activated partial thromboplastin time ≤1.5× ULN.Patients receiving anticoagulant therapy must have a PT or partial thromboplastin within the therapeutic range of intended use of anticoagulants 13. Patient must have a negative serum pregnancy test within 72 hours of the first dose of study medication, unless they are of nonchildbearing potential. Nonchildbearing potential is defined as follows: 13.1. Patient is ≥ 45 years of age and has not had menses for > 1 year 13.2. A follicle-stimulating hormone value in the postmenopausal range upon screening evaluation if amenorrhoeic for < 2 years without a hysterectomy and oophorectomy 13.3. Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation: 13.3.1. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound, MRI, or CT scan 13.3.2. Tubal ligation must be confirmed with medical records of the actual procedure; otherwise, the patient must fulfil the criteria in Inclusion Criterion 14 13.3.3. Information must be captured appropriately within the site’s source documents 14. Patient of childbearing potential must agree to use a highly effective method of contraception (protocol section 18.9) with their partners starting from time of consent through 150 days after the last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient (Information must be captured appropriately within the site’s source documents) Mixed 18 Years 120 Years Female 260 264 1. Patient has received neoadjuvant/adjuvant systemic chemotherapy for primary Stage IIIc2 or IV disease and has had a recurrence or PD within 6 months of completing chemotherapy treatment prior to entering the study. Note: Low-dose cisplatin given as a radiation sensitizer or hormonal therapies do not exclude patients from study participation. 2. Patient has had >1 recurrence of endometrial cancer, treated with chemotherapy (surgery of the recurrence is allowed) 3. Patient previously treated with chemotherapy for non-curable advanced disease or metastatic disease 4. Patient has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent 5. Patient has received prior anticancer therapy (chemotherapy, targeted therapies, hormonal therapy, radiotherapy) within 21 days or <5 times the half-life of the most recent therapy prior to Study Day 1, whichever is shorter. Note: Palliative radiation therapy to a small field ≥1 week prior to Day 1 of study treatment may be allowed. 6. Patient with contraindication to chemotherapy or checkpoint inhibitor treatments 7. Patient has a concomitant malignancy, or has a prior non-endometrial invasive malignancy who has been disease-free for < 3 years or who received any active treatment in the last 3 years for that malignancy (Non-melanoma skin cancer is allowed) 8. Patient has known uncontrolled central nervous system metastases, carcinomatosis meningitis, or both Note: Patients with previously treated brain metastases may participate provided they are stable (without evidence of disease progression by imaging [using the identical imaging modality for each assessment, either MRI or CT scan] for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and have not been using steroids for at least 7 days prior to study treatment. Carcinomatous meningitis precludes a patient from study participation regardless of clinical stability. 9. Patient has a known history of human immunodeficiency virus (HIV; HIV1 or HIV2 antibodies) 10. Patient has known active hepatitis B (e.g., hepatitis B surface antigen reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative] is detected) 11. Patient has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic therapy (e.g., thyroid hormone or insulin) 12. Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of study treatment 13. Patient has not recovered (i.e., to Grade ≤ 1 or to baseline) from cytotoxic therapy-induced adverse events (AEs). Note: Patients with Grade ≤2 neuropathy, Grade ≤2 alopecia, or Grade ≤2 fatigue are an exception to this criterion and may qualify for the study. 14. Patient has not recovered adequately from AEs or complications from any major surgery prior to starting therapy 15. Patient has a known hypersensitivity to carboplatin, paclitaxel, or dostarlimab components or excipients 16. Patient is currently participating and receiving study treatment or has participated in a study of an investigational agent and received study treatment or used an investigational device within 4 weeks of the first dose of treatment 17. Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active infection requiring systemic therapy. Specific examples include, but are not limited to, active, non-infectious pneumonitis; uncontrolled ventricular arrhythmia; recent (within 90 days) myocardial infarction; uncontrolled major seizure disorder; unstable spinal cord compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study (including obtaining informed consent) 18. Use of any of the following immunomodulatory agents within 30 days prior to the first dose of study drug: 18.1. Systemic corticosteroids (at dose higher than 10 mg/day equivalent prednisone); if systemic corticoid use at higher dose, corticoid must be stopped at least 7 days before study treatment start 18.2. Interferons 18.3. Interleukins 18.4. Live vaccine Note: Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed as other killed vaccines, if done at least 2 weeks prior the first dose of study drug; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. 19. Patient is pregnant or breastfeeding or is expecting to conceive children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study treatment, or lactating woman 2024-03-01T00:00:00.000Z 2025-06-30T00:00:00.000Z Endometrial cancer Cancer Patients will be randomized 1:1 to receive either 4 cycles of dostarlimab every 3 weeks followed by dostarlimab every 6 weeks as maintenance up to 2 years* or 6 cycles of carboplatin-paclitaxel: • Arm A: Dostarlimab 500 mg, every 3 weeks, 4 cycles and then 1000 mg every 6 weeks until progression, unacceptable toxicity, patient/investigator decision to withdrawal or completion of 2 years of treatment • Arm B: Carboplatin AUC 5 or 6 plus Paclitaxel 175 mg/m2, every 3 weeks, 6 cycles. A cross over to dostarlimab is permitted at progression. *Treatment ends after 2 years, progression of disease, toxicity, withdrawal of consent, Investigator’s decision, or death, whichever occurs first. Continued treatment with dostarlimab beyond 2 years may be considered for patient in Complete Response and if the investigator considers that the patient may benefit from a longer duration of treatment, only after discussion with the sponsor and its agreement. Within 1 week, prior to C1D1, authorised UK investigators or a delegated member of the research team at the site, will register and randomise patients, who have given their informed consent, using the Interactive Voice/Web Response System (IVRS/IWRS). Randomization will be as a result of the local and centralised MMRd/MSI-H status; the block for central analysis will be sent the one of two French laboratories (Caen or Cochin) allocated via the IVRS/IWRS system. Sites will be provided with login details to the IVRS/IWRS system once authorised. A unique enrolment number will be assigned to potential patients once registered in the system. Courier labels for both laboratories (3x Caen, 3x Cochin) will be provided in the sample kits provided to sites. Drug Phase III Dostarlimab, carboplatin, paclitaxel The datasets generated and analysed during the trial are/will be available upon request directly from the sponsor ARCAGY-GINECO, domenica@arcagy.org Available on request

90d71728-7936-4844-b56a-7c1381c927db 7fea7abe-5c19-4580-a4ad-107c5c1d3409 1fd1136c-4950-4b85-8e78-0c1f71c52c03 5c58d518-3ff5-4b14-a634-3d5300fb899a 717452f5-7dea-4c4b-ab48-16de36a566fc Yes Participant information sheet ISRCTN16573769 DOMENICA_ICF_English_v3.3 12-09-24 Clean.pdf 59cb6124-3a3f-4588-bd82-b3d8e0f4fc22 true application/pdf 579004 04effbd948c51eafab65fdea3842f104 Participant information sheet ISRCTN16573769 DOMENICA_ICF_English_v4.0_06May2024.pdf c6503a86-4be7-4ff1-b20b-0868f56640f8 true application/pdf 1008633 48fb81ccf7b8e999878c458d9f9a38f1 Emma Hudson Principal investigator

Velindre Cancer Centre Velindre Road Whitchurch

Cardiff United Kingdom CF14 2TL - Emma.Hudson@wales.nhs.uk Public Florence Joly Principal investigator

Centre François Baclesse

Caen France 14000 - f.joly@baclesse.unicancer.fr Public Joanna Canham Public

Centre for Trials Research College of Biomedical & Life Sciences Cardiff University Neuadd Meirionnydd Heath Park

Cardiff United Kingdom CF14 4YS - DOMENICA@cardiff.ac.uk Public Arcagy Gineco Research organisation https://ror.org/03mzxvt76 Non-commercial ARCAGY GINECO 46454974 true A Phase IIa double-blind, randomized placebo-controlled trial of tocilizumab to investigate the effect on health-related quality of life in adults with Long COVID and persistent inflammation PHOSP-I Primary objective The primary objective is to compare the effect of 12 weeks of subcutaneous (s/c) tocilizumab versus 12 weeks of s/c placebo on health-related quality of life. Secondary objectives 1. To compare the effect of 12 weeks of s/c tocilizumab versus 12 weeks of s/c placebo on symptoms, mental health, physical performance, daily physical activity, cognitive impairment, multi-organ function and systemic inflammation. 2. To investigate the sustainability of any effect at 12 weeks after medication/placebo cessation on the primary and secondary outcome measures. Sub-study exploratory objectives: 1. To compare the effects of 12 weeks of tocilizumab versus 12 weeks of placebo on respiratory health using pulmonary function testing and computed tomography (CT) thoracic imaging. 2. To compare the effects of 12 weeks of tocilizumab versus 12 weeks of placebo on multi-organ health using magnetic resonance imaging. Background and study aims To date, over 1 million adults have been admitted into UK hospitals with COVID-19. Approximately only one in three people feel fully recovered 1 year after discharge. There are an estimated 2 million people living with Long Covid. Previous research has shown that proteins involved in inflammation are higher in adults who have the worst health outcomes. One of these proteins is called interleukin-6 (IL-6). Tocilizumab is a drug which lowers the levels of IL-6. The aim of this study is to test whether tocilizumab can help people with ‘inflammatory’ Long Covid feel better. Who can participate? People who do not feel fully recovered at least 3 months after COVID-19 and have ongoing whole-body inflammation measured by a commonly used blood marker What does the study involve? Participants will be put into two groups at random. One group will receive tocilizumab injections for 12 weeks and the other group will receive placebo injections (sterile solution without the drug). Injections will be weekly or fortnightly depending upon the participant’s weight. The main outcome is a questionnaire to assess how people feel related to their health. Other outcomes involve questionnaires to assess symptoms, physical and mental health, an assessment of brain fog, tests of physical performance and activity, and a breathing test. Blood and urine samples will be collected for detailed assessment. After consent and eligibility, there are three main research visits: at the start and end of the treatment period, and 12 weeks after the end of the treatment period. Any adverse events will be reported. Two optional sub-studies involve taking images/scans of the lungs and body organs, and more detailed breathing tests. What are the possible benefits and risks of participating? Tocilizumab is used across the world to treat other inflammatory conditions such as rheumatoid arthritis. It is given by an injection under the skin. Side effects from the medication include lowering the immune system and liver problems. Participants at high risk of these problems will be excluded. This trial is categorised as Type B = somewhat higher than the risk of standard medical care. The study is using tocilizumab out of current clinical indications and licensing. However, tocilizumab at the dose we are proposing is currently used safely in other long-term conditions where IL6 is raised and part of the underlying inflammatory pathway causing disease. Current standard practice for Long COVID involves no medication specifically for the Long COVID disease process and specifically no anti-interleukin (IL) 6 agents. Therefore, any side effects of the medication are above the risk of standard medical care for Long COVID. There is no indication that patients with Long COVID would have a higher risk of side effects than other patient populations. A comprehensive compilation of clinical and nonclinical data on tocilizumab is available in the Investigators Brochure. The main side effects are: Very common (>10%): upper respiratory tract infections, injection site reaction Common (10%-1%): cellulitis, oral herpes simplex, Herpes zoster, abdominal pain, mouth ulceration, gastritis, rash, pruritus, urticaria, headache, dizziness, increased hepatic transaminases, increased weight, hypertension, leucopenia, neutropenia, hypercholesterolemia, peripheral oedema, hypersensitivity reaction, cough, dyspnoea, conjunctivitis Uncommon (<1%): diverticulitis, stomatitis, gastric ulcer, increased total bilirubin, hypertriglyceridemia, nephrolithiasis, hypothyroidism The researchers will mitigate these as far as possible by excluding participants that would be high risk of side effects and by careful monitoring of potential side effects which can be measured through serial blood tests. The main side effects are neutropenia (a low type of white cell count), thrombocytopenia (low platelet count) and hepatitis (liver inflammation), therefore blood tests of neutrophils, platelets and liver function tests will be monitored every 4 weeks. Specific and clear dose adjustments are provided in the protocol based on the tocilizumab investigator brochure (IB). There is no data to support the safety of tocilizumab during pregnancy to date and therefore for this trial the assumption is Tocilizumab is not safe during pregnancy and therefore any participant or participant’s spouse who is either pregnant or planning a pregnancy in the same timeframe would be excluded. Pregnancy tests (urine) will be performed at each visit. A serum pregnancy test will be performed at screening. Where is the study run from? University of Leicester (UK) When is the study starting and how long is it expected to run for? March 2023 to December 2025 Who is funding the study? Genentech Roche (USA) Who is the main contact? 1. Mrs Victoria Harris, phosp-i@leicester.ac.uk 2. Prof Rachael Evans, phosp-i@leicester.ac.uk Health-related quality of life measured using Euroqol five-dimension five-level questionnaire – utility index assessed at baseline, after 12 weeks (+2 weeks) of IMP/Placebo and after a further 12 weeks (+2 weeks) after the end of the intervention period Current key secondary outcomes: Measured at baseline, after 12 weeks (+ 2 weeks) of IMP/Placebo and after a further 12 weeks (+2 weeks) after the end of the intervention period: 1. Symptoms measured using Symptom Questionnaires – fatigue and breathlessness (FACIT-Fatigue and Dyspnoea-12) 2. General and respiratory disease-specific health-related quality of health measured using EQ5D-5L Visual Analog Scale, St George’s Respiratory Questionnaire (SGRQ) and COVID-19 Yorkshire Rehabilitation Scale – modified version (C19YRSm) 3. Mental health measured using anxiety and depression questionnaires GAD-7 and PHQ-9 4. Physical performance measured using the Incremental Shuttle Walking Test, the Short Physical Performance Battery (SPPB) and hand grip strength 5. Daily physical activity measured using an accelerometer worn for 14 days 6. Cognitive impairment measured using Montreal Cognitive Assessment (MoCA) 7. Multi-organ function measured using blood biomarker levels (including full blood count, natriuretic peptides, kidney and liver function) and spirometry. 8. Systemic inflammation measured using a blood test for C-reactive protein 9. Frailty and activities of daily living measured using Fried’s frailty criteria and Nottingham Activities of Daily Living Scale, respectively Exploratory outcomes: Respiratory health substudy: Pulmonary pathophysiology assessed by CT thorax and full pulmonary function tests at baseline and after 12 weeks (+4 weeks) after IMP/Placebo: 1. Pulmonary pathology on CT thoracic imaging such as ground-glass opacities, interstitial abnormalities, established pulmonary fibrosis, or small airways disease suggestive of ongoing post-COVID pulmonary changes 2. Pulmonary function tests include spirometry, transfer factor, residual volume and total lung capacity Multi-organ health substudy: MRI markers of multi-organ inflammation evaluated by describing the presence or absence of multiorgan abnormality (defined as MRI abnormalities involving two or more organs including the lungs) at baseline and after 12 weeks (+4 weeks) after IMP/Placebo: 1. The composite score based on relative difference in myocardial extracellular volume, myocardial T1, liver cT1, renal T1, and lung parenchymal signal intensity heterogeneity index post-treatment will be used. Urine, Blood and Stool Bioresource. Exploratory objectives using the bioresource: 1. Inflammatory profile measured using blood (up to 100 ml) and urine (up to 100 ml) samples obtained at up to four time points: baseline, after 8 weeks (+/-2 weeks) of treatment/placebo, end of treatment/placebo at 12 weeks (+2 weeks) and 12 weeks (+2 weeks) after treatment/placebo 2. A subset of serum, plasma, whole blood, cells and urine samples will be subject to multi-omic assays to analyse the effect of treatment vs placebo on putative inflammatory biomarkers in the blood and urine, and their association with outcomes. This may include, but is not limited to, measurement of proteins, gene expression (mRNA), metabolites, cell populations and lipids related to the inflammatory response and other biological processes (for example, tissue damage and repair). 3. DNA will be analysed using either genome-wide microarray or next-generation sequencing (targeted, whole exome or whole genome) approaches to identify whether specific genetic variants, or combinations thereof, are associated with treatment response and outcomes 4. Stool samples will be collected for virus detection and other analyses at baseline, end of treatment/placebo at 12 weeks and 12 weeks after treatment/placebo. Previous key secondary outcomes: Measured at baseline, after 12 weeks (+ 2 weeks) of IMP/Placebo and after a further 12 weeks (+2 weeks) after the end of the intervention period: 1. Symptoms measured using Symptom Questionnaires – fatigue and breathlessness (FACIT-Fatigue and Dyspnoea-12) 2. General and respiratory disease-specific health-related quality of health measured using EQ5D-5L Visual Analog Scale and St George’s Respiratory Questionnaire 3. Mental health measured using anxiety and depression questionnaires GAD-7 and PHQ-9 4. Physical performance measured using the Incremental Shuttle Walking Test, the Short Physical Performance Battery (SPPB) and hand grip strength 5. Daily physical activity measured using an accelerometer worn for 14 days 6. Cognitive impairment measured using Montreal Cognitive Assessment (MoCA) 7. Multi-organ function measured using blood biomarker levels (including full blood count, natriuretic peptides, kidney and liver function) spirometry, and urine and stool samples. 8. Systemic inflammation measured using a blood test for C-reactive protein 9. Frailty and activities of daily living measured using Fried’s frailty criteria and Nottingham Activities of Daily Living Scale Exploratory outcomes: Respiratory health substudy: Pulmonary pathophysiology assessed by CT thorax and full pulmonary function tests at baseline and after 12 weeks (+4 weeks) after IMP/Placebo: 1. Pulmonary pathology on CT thoracic imaging such as ground-glass opacities, interstitial abnormalities, established pulmonary fibrosis, or small airways disease suggestive of ongoing post-COVID pulmonary changes 2. Pulmonary function tests include spirometry, transfer factor, residual volume and total lung capacity Multi-organ health substudy: MRI markers of multi-organ inflammation evaluated by describing the presence or absence of multiorgan abnormality (defined as MRI abnormalities involving two or more organs including the lungs) at baseline and after 12 weeks (+4 weeks) after IMP/Placebo: 1. The composite score based on relative difference in myocardial extracellular volume, myocardial T1, liver cT1, renal T1, and lung parenchymal signal intensity heterogeneity index post-treatment will be used. Exploratory objectives using the bioresource: 1. Inflammatory profile measured using blood (up to 100 ml) and urine (up to 100 ml) samples obtained at up to four time points: baseline, after 8 weeks (+/-2 weeks) of treatment/placebo, end of treatment/placebo at 12 weeks (+2 weeks) and 12 weeks (+2 weeks) after treatment/placebo 2. A subset of serum, plasma, whole blood, cells and urine samples will be subject to multi-omic assays to analyse the effect of treatment vs placebo on putative inflammatory biomarkers in the blood and urine, and their association with outcomes. This may include, but is not limited to, measurement of proteins, gene expression (mRNA), metabolites, cell populations and lipids related to the inflammatory response and other biological processes (for example, tissue damage and repair). 3. DNA will be analysed using either genome-wide microarray or next-generation sequencing (targeted, whole exome or whole genome) approaches to identify whether specific genetic variants, or combinations thereof, are associated with treatment response and outcomes 4. Stool samples will be collected for virus detection and other analyses at baseline, end of treatment/placebo at 12 weeks and 12 weeks after treatment/placebo. Ethics approval required West Midlands - Edgbaston Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 23/WM/0234 10.1186/ISRCTN46454974 2022-003211-29 1006298 CPMS: 60222, 0862 2022-003211-29 1006298 60222 0862 Double-blind randomized placebo-controlled parallel-group trial Interventional Randomised controlled trial Treatment 2026-07-31T00:00:00.000Z United Kingdom England Scotland University Hospitals of Leicester NHS Trust

Glenfield Hospital Groby Road

Leicester England LE1 5WW Guy's & St Thomas Hospital

Westminster Bridge Road

London England SE1 7EH 5LD99@2.16.840.1.113883.2.1.3.2.4.18.48 Kings College Hospital

Denmark Hill

London England SE5 9RS NIHR University College London Hospitals Clinical Research Facility

University College London Hospitals NHS Foundation Trust 4th Floor 170 Tottenham Court Road

London England W1T 7HA CRF11@2.16.840.1.113883.2.1.3.8.1.2 Oxford University Hospitals NHS Foundation Trust

John Radcliffe Hospital Headley Way Headington

Oxford England OX3 9DU RTH@2.16.840.1.113883.2.1.3.2.4.18.48 Sheffield Teaching Hospitals NHS Foundation Trust

Northern General Hospital Herries Road

Sheffield England S5 7AU RHQ@2.16.840.1.113883.2.1.3.2.4.18.48 Cambridge University Hospitals NHS Foundation Trust

Addenbrookes Hospital Hills Road

Cambridge England CB2 0QQ University Hospitals Birmingham NHS Foundation Trust

Queen Elizabeth Hospital Mindelsohn Way Edgbaston

Birmingham England B15 2GW RRK@2.16.840.1.113883.2.1.3.2.4.18.48 Glasgow Royal Infirmary

84 Castle Street

Glasgow Scotland G4 0SF G107H@2.16.840.1.113883.2.1.3.8.2.16.2 Manchester University Hospitals NHS Foundation Trust

Wythenshawe Hospital Southmoor Road Wythenshawe

Manchester England M23 9LT Northern Care Alliance NHS Foundation Trust

Salford Royal Hospital Stott Lane Eccles

Salford England M6 8HD Cardiff and Vale University Health Board

Clinical Research Facility University Hospital of Wales

Cardiff Wales CF14 4XW North Bristol NHS Trust

Clinical Research Centre Southmead Hospital Southmead Road Westbury-on-trym

Bristol England BS10 5NB University Hospitals Coventry and Warwickshire

Research & Development, WISDEM Research, Diabetes, Endocrinology & Metabolism University Hospitals Coventry & Warwickshire NHS Trust WISDEM Centre Clifford Bridge Road

Coventry England CV2 2DX Patient 1. Age ≥18 years old and ≤80 years old 2. Clinical diagnosis of COVID-19 at least 3 months prior to consent. Patient-reported positive test is acceptable 3. Patient does not feel fully recovered at recruitment after COVID-19 (response no or unsure to “do you feel fully recovered from your COVID-19”) 4. CRP >5 mg/L persistently raised after contracting COVID-19 and prior to randomisation 5. Euroqol EQ5D-5L utility index ≤0.90 units prior to randomisation 6. Reasonable understanding of the English language assessed by the research team (i.e. able to understand the risks of taking part in the trial and complete the measurements including the patient-reported outcome measures) Mixed 18 Years 80 Years All 152 0 Current exclusion criteria as of 16/01/2025: 1. Other comorbidity indicating survival at one year from consent is unlikely 2. Active malignancy or on treatment for malignancy 3. Unable or unwilling to provide written consent 4. Inability to comply with protocol-directed procedures and assessments 5. Current immunosuppression therapy including oral corticosteroids 6. Prior use of the trial drug within 3 months of consent (including intra-venous Tocilizumab for acute COVID). 3 months is five-half lives of tocilizumab 7. Involvement in other trials involving an IMP either concurrently or within four months of consent - to allow washout. This includes medications prescribed for acute COVID studies. 8. Previous adverse event to tocilizumab, either a severe allergic reaction or deranged liver function tests 9. Hepatic transaminases greater than three times the upper limit of normal 10. Low neutrophil (below 2 x 109/L) or low platelet levels (below 100 x 10e3/μL) 11. Signs of active infection 12. Receipt of live vaccine within 3 months or planning a live vaccine during the trial period. Most COVID vaccines are not live. 13. Pregnancy or breastfeeding, or planning a pregnancy during the trial period or unable or unwilling to meet the contraception criteria (see below) 14. Latent TB: to be excluded with IGRA testing and if positive exclude and refer for treatment as per national guidelines. 15. New diagnosis or on treatment for HIV 16. Past history of diverticulitis 17. Significant alcohol or substance misuse 18. History of clinically significant hypersensitivity reaction or significantly deranged liver function tests with other medication 19. Hepatitis B 20. Exclude Hepatitis C if untreated: on testing antibody positive and detectable viral load. If antibody positive, but viral load negative compatible with previous infection only participant can be included. 21. Supervised exercise rehabilitation programme including exercise training, or other rehabilitation therapy for example fatigue management or breathing retraining lasting for a minimum of 4 sessions within three months of consent or planned to occur during the trial period 22. New medication for Long Covid symptoms started within six weeks of consent 23. No new weight management medication to start within three months of consent or during the trial period, for example glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors _____ Previous exclusion criteria: 1. Other comorbidity indicating survival at one year from consent is unlikely 2. Active malignancy or on treatment for malignancy 3. Unable or unwilling to provide written consent 4. Inability to comply with protocol-directed procedures and assessments 5. Current immunosuppression therapy including oral corticosteroids 6. Prior use of the trial drug within 3 months of consent (including intra-venous Tocilizumab for acute COVID). 3 months is five-half lives of tocilizumab 7. Involvement in other trials involving an IMP either concurrently or within four months of consent - to allow washout. This includes medications prescribed for acute COVID studies. 8. Previous adverse event to tocilizumab, either a severe allergic reaction or deranged liver function tests 9. Hepatic transaminases greater than three times the upper limit of normal 10. Low neutrophil (below 2 x 109/L) or low platelet levels (below 100 x 10e3/μL) 11. Signs of active infection 12. Receipt of live vaccine within 3 months or planning a live vaccine during the trial period. Most COVID vaccines are not live. 13. Pregnancy or breastfeeding, or planning a pregnancy during the trial period or unable or unwilling to meet the contraception criteria (see below) 14. Latent TB: to be excluded with IGRA testing and if positive exclude and refer for treatment as per national guidelines. 15. New diagnosis or on treatment for HIV 16. Past history of diverticulitis 17. Significant alcohol or substance misuse 18. History of clinically significant hypersensitivity reaction or significantly deranged liver function tests with other medication 19. Hepatitis B 20. Exclude Hepatitis C if untreated: on testing antibody positive and detectable viral load. If antibody positive, but viral load negative compatible with previous infection only participant can be included. 21. Supervised exercise rehabilitation programme within three months of consent or planned to occur during the trial period 2024-02-01T00:00:00.000Z 2025-10-31T00:00:00.000Z Long COVID Infections and Infestations Tocilizumab/placebo subcutaneously for 12 weeks Dosage: 162 mg subcutaneous injection. Frequency of administration: body weight <100 kg 162 mg fortnightly/body weight ≥100 kg 162 mg weekly for 12 weeks. Details of the randomisation process: Participants will be allocated to treatment groups using a mixed minimisation/randomisation procedure, designed to maintain balance with respect to: 1. Study site (1-15) 2. EQ5D-5L UI (<0.70 / ≥0.70) 3. CRP level (≤20 mg/L / >20 mg/L) 4. Participation in the MRI sub-study (Yes/No) 5. Acute admission/tocilizumab status (non-hospitalised/hospitalised, no tocilizumab/hospitalised, with tocilizumab) All patients included in the trial be assigned a unique trial number to identify the participant throughout the trial. Randomisation using a web-based randomisation system will be provided by Glasgow CTU. The research staff at sites will provide the trial ID number and minimisation information and, if eligible, the randomisation group will be allocated. Blinded new participant randomisation e-mail confirmations will be sent to the research nurse(s), investigator and pharmacy staff as required. In addition, the randomisation notification will be sent electronically to the Interactive Web Response System (IWRS) supplier, with details of the trial ID number and randomisation group to allow drug supply management at site. Information may be shared back to the Glasgow CTU server, from the IWRS system, to allow for cross-checking between systems. Drug Phase II Tocilizumab Research data will be shared with bona fide researchers in different organisations, including those in other countries or in commercial organisations. Access to data will be managed through the Trial Management Group (TMG) and formal application requests will be submitted to the TMG by researchers requesting data. Once permission has been granted by the TMG data will be released to collaborators. Data will be labelled with a unique study number in place of any identifiable data (pseudonymised). Contractual agreements will be put in place prior to any sharing of data. Some trial data (anonymised questionnaire data) will be suitable for sharing for research. Available on request

Study website Migrated from study website field

0296c127-81b8-4de1-a9d5-c0e6f024091c 4e87b8e9-db27-4602-bc2d-fae594ac8c33 5bf39197-9403-4e2a-93ba-0ed92af126ba 4838028d-8a2f-4cb0-b89d-b2426a5f269b Yes Statistical Analysis Plan ISRCTN46454974_SAP_v1_0_09June2026.pdf e251b8ef-7ede-4474-8077-3d64c2b1f1e4 true application/pdf 456464 8cbfcee40221999be60e4fd8d82bcad9 Victoria Harris Scientific

NIHR Leicester Biomedical Research Centre - Respiratory Department of Infection, Immunity and Inflammation Glenfield Hospital Groby Road

Leicester United Kingdom LE3 9QP +44 (0)116 250 2670 phosp-i@leicester.ac.uk Public Rachael Evans Principal investigator

Groby Road

Leicester United Kingdom LE3 9QP +44 (0)116 0300 030 1573 phosp-i@leicester.ac.uk Public University of Leicester University/education https://ror.org/04h699437 Non-commercial Genentech Roche 14643179 true Circulating tumour DNA guided Adaptive BRAF and MEK Inhibitor therapy DyNAMIc Current study objectives as of 01/10/2025: Adaptive therapy relies on the competition between drug-sensitive and drug-resistant subclones to control overall tumour growth. It aims to stabilise tumour burden by allowing a significant population of treatment-sensitive cells to survive, which suppresses the proliferation of the less fit, resistant populations. 1. Patients will have circulating tumour DNA (ctDNA) response upon re-introduction of encorafenib plus binimetinib following the first drug holiday. 2. Encorafenib plus binimetinib therapy using adaptive scheduling based on ctDNA level will improve the time to progression, reduce toxicity and enhance quality of life compared to continuous dosing in patients with stage III unresectable or stage IV melanoma. Objectives: To assess whether tumours respond to the re-introduction of encorafenib plus binimetinib following the first period of stopping the drugs. The researchers will do this by measuring the amount of circulating tumour DNA (ctDNA) in the plasma we obtained from the patients' blood samples, which are taken every 2 weeks. Using data from the main objective, they intend to develop a guideline based on the ctDNA levels, to inform doctors when the adaptive treatment should stop and re-start. The researchers compare the ctDNA results from the two arms to identify the average time it takes for participants to respond to the treatment, how long they may remain stable for, or for the disease to worsen. The time it may take for participants' cancer to worsen (known as progression), will be measured at 6, 12 and 15 months from commencing treatment. Also, the median time to the death of participants will be compared between the two arms. The researchers will also calculate the number of cycles of adaptive therapy participants on arm B completed, and use this information to establish the average. Measurements of quality of life between the participants on both arms will also be compared, as will any reactions from taking the drugs. Lastly, the researchers will measure the time it takes for the lab to provide the ctDNA result after receiving the blood sample. Previous study objectives: Adaptive therapy relies on the competition between drug-sensitive and drug-resistant subclones to control overall tumour growth. It aims to stabilise tumour burden by allowing a significant population of treatment-sensitive cells to survive, which suppresses the proliferation of the less fit, resistant populations. 1. Patients will have circulating tumour DNA (ctDNA) response upon re-introduction of encorafenib plus binimetinib following the first drug holiday. 2. Encorafenib plus binimetinib therapy using adaptive scheduling based on ctDNA level will improve the time to progression, reduce toxicity and enhance quality of life compared to continuous dosing in patients with stage III unresectable or stage IV melanoma. Objectives: To assess whether tumours respond to the re-introduction of encorafenib plus binimetinib following the first period of stopping the drugs. The researchers will do this by measuring the amount of circulating tumour DNA (ctDNA) in the plasma we obtained from the patients' blood samples, which are taken every 2 weeks. Using data from the main objective, they intend to develop a guideline based on the ctDNA levels, to inform doctors when the adaptive treatment should stop and re-start. The researchers compare the ctDNA results from the two arms to identify the average time it takes for participants to respond to the treatment, how long they may remain stable for, or for the disease to worsen. The time it may take for participants' cancer to worsen (known as progression), will be measured at 6, 12 and 15 months from commencing treatment. Also, the median time to the death of participants will be compared between the two arms. The researchers will also calculate the number of cycles of adaptive therapy participants on arm B completed, and use this information to establish the average. Measurements of quality of life between the participants on both arms will also be compared, as will any reactions from taking the drugs. Lastly, the researchers will measure the time it takes for the lab to receive blood and provide the ctDNA result. Background and study aims Encorafenib and binimetinib given in combination is a standard of care treatment in the UK for late-stage cutaneous melanoma, a skin cancer that starts in the cells that produce skin pigmentation. 'Late stage’ means it can't be surgically removed or has spread. The treatment is taken daily. Resistance to the treatment can develop after about 12-15 months. During this period, the treatment will kill the less resistant cells, meaning the tumour has a greater proportion of cells that are resistant to the treatment. This study aims to investigate if the patient having breaks in their treatment allows the less resistant cells to continue to grow, this would result in a tumour with a lower proportion of resistant cells, making the tumour as a whole less resistant to the treatment, and increasing the time it takes for the disease to progress. A blood test that measures the amount of tumour DNA circulating in the patient's blood (known as ctDNA) will be conducted every 2 weeks to check if the cancer cells are still present, and if they are becoming active. The result of this test will allow doctors to monitor the activity of the tumour and judge when to pause and resume treatment. This treatment is called adaptive therapy. Who can participate? Patients aged 18 years and over with late-stage cutaneous melanoma What does the study involve? Participants are randomly allocated to receive either the standard, daily treatment or adaptive therapy. Patients will receive their allocated treatment until their cancer progresses or there is no longer clinical benefit from taking it, they or their doctor withdraw them from the study, or until the study ends, whichever happens first. As well as the fortnightly visits to the hospital, patients will be required to complete questionnaires to assess their quality of life. These will be completed before their treatment starts, after 4 weeks of treatment, every 12 weeks from when they start treatment and if their cancer progresses or they stop treatment. What are the possible benefits and risks of participating? Participants will delay the commencement of their treatment until all screening and baseline procedures have been completed, which may result in them starting treatment a little later than they would if they were receiving it as routine care. However, if either the patient or treating clinician is of the opinion that this delay would be detrimental to the patient, treatment will commence immediately. Some CT and/or PET-CT scans may be extra to those given as routine care. CT scans use ionising radiation, which may cause cancer many years or decades after exposure. However, the chances of this occurring in the patients recruited to this study are extremely small. Some CT scans require a contrast dye to be used, which may cause bruising or swelling around the injection site. Rarely do some people have an allergic reaction to the dye. Patients with disease in their limbs will undergo PET-CT scans. Patients may get a small bruise or swelling around the area where they inject the radioactive tracer (dye). There is also a risk that the tracer may leak outside of the vein, which may cause swelling and pain in the limb. Rarely, some patients have an allergic reaction to the tracer. Some patients will need to undergo an MRI scan. Being placed into the scanner can make some people feel claustrophobic. Participants will be asked to undergo extra biopsies, but can still participate if they choose not to. The study will be active at hospitals for a period of 3 years. Depending on when a participant commences treatment, they may be involved for between 1 day and 3 years. However, with the exception of the extra visits for blood sampling (explained below), the majority of procedures are as they would receive as part of standard care. Those participants on adaptive therapy will have one 28-day cycle of treatment before it is then withheld, however, the frequency that blood samples are taken to monitor their health and safety will be increased to every 14 days from the standard 28 days. To allow for accurate comparison of results, this increased frequency will also be implemented for participants on the standard treatment too. Although this increase in blood sampling will require more frequent visits to the hospital, it also allows for a 100% increase in the amount of monitoring the participant will receive compared to normal care. All extra visits to the hospital have been mapped to match those for the standard of care as much as possible. Women of childbearing potential will be required to undergo extra pregnancy tests as part of the screening procedure and again at the end of their treatment or when the study ends. This test will be done with a urine sample; however, a blood sample may be required if there is a problem with the urine test. Extra monitoring may also be used if their doctor thinks it is necessary. In addition to those taken as part of routine care, a biopsy (sample) of the tumour will be taken before the patient commences treatment, about 6 weeks later, and again if they relapse. Participants on adaptive therapy will receive stop/start therapy, which may cause them anxiety. They will be reassured that they will be monitored for signs of progression twice as often as they would be normally and, if their ctDNA levels show signs of increasing beyond a pre-determined threshold, they will be advised to immediately recommence the treatment using the 'reserve pack' of tablets they will have been issued. Where is the study run from? University of Liverpool (UK) When is the study starting and how long is it expected to run for? May 2022 to September 2027 Who is funding the study? Jon Moulton Charity Trust (UK) Who is the main contact? DyNAMIc Trial Manager, dynamic_study@liverpool.ac.uk https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-using-blood-test-monitor-guide-treatment-melanoma-dynamic Maximal reduction in percentage mutant copies/ml (ctDNA mutant BRAF copies/ml of plasma) from baseline 2 TAB level upon restart of drugs following first drug off period. Measured longitudinally throughout the study. Current key secondary outcome(s) as of 09/06/2026: 1. ctDNA mutant BRAF copies/ml of plasma. Measured longitudinally throughout the study. 2. Maximal response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) using RECIST v1.1 criteria. Measured from Baseline 1 until RECIST progression/clinical deterioration. 3. Percentage of participants who have experienced disease progression or death. Progression Free Survival, defined as time from randomisation to progression (RECIST v1.1 and in Arm B defined as progression whilst on targeted therapy unless stopped due to toxicity/choice). Measured continuously throughout the study. 4. Time to clinical deterioration. Defined as either the point of progression (defined as per RECIST v1.1) or in participants treated beyond progression, at the time of clinically determined deterioration, defined at the discretion of the treating clinician, specifically due to progression of the underlying cancer. Measured continuously throughout the study. 5. Overall survival, defined as time from randomisation until death from any cause. Measured continuously throughout the study. 6. Overall survival, defined as time from randomisation until death from melanoma. Measured continuously throughout the study. 7. Number of adaptive therapy cycles completed. Measured longitudinally throughout the study. 8. Median duration of adaptive therapy cycles. Measured longitudinally throughout the study. 9. Percentage of ctDNA results reported within 5 days from sample receipt into the laboratory. Measured longitudinally throughout the study. 10. EORTC QLQ-C30 and PRO-CTCAE. Measured longitudinally throughout the study. 11. Adverse Events and Serious Adverse Events defined by CTCAE version 5. Measured continuously throughout the study. 12. Number and location of sites of progression. At disease progression on imaging _____ Previous secondary outcome measures as of 01/10/2025: 1. ctDNA mutant BRAF copies/ml of plasma. Measured longitudinally throughout the study. 2. Maximal radiological response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) using RECIST v1.1 criteria. Measured from Baseline 1 until RECIST progression/clinical deterioration. 3. Percentage of participants who have experienced disease progression or death. Progression Free Survival, defined as time from randomisation to progression (RECIST v1.1 and in Arm B defined as progression whilst on targeted therapy unless stopped due to toxicity/choice). Measured continuously throughout the study. 4. Time to clinical deterioration. Defined as either the point of progression (defined as per RECIST v1.1) or in participants treated beyond progression, at the time of clinically determined deterioration, defined at the discretion of the treating clinician, specifically due to progression of the underlying cancer. Measured continuously throughout the study. 5. Overall survival, defined as time from randomisation until death from any cause. Measured continuously throughout the study. 6. Overall survival, defined as time from randomisation until death from melanoma. Measured continuously throughout the study. 7. Number of adaptive therapy cycles completed. Measured longitudinally throughout the study. 8. Median duration of adaptive therapy cycles. Measured longitudinally throughout the study. 9. Percentage of ctDNA results reported within 5 days from sample receipt into the laboratory. Measured longitudinally throughout the study. 10. EORTC QLQ-C30 and PRO-CTCAE. Measured longitudinally throughout the study. 11. Adverse Events and Serious Adverse Events defined by CTCAE version 5. Measured continuously throughout the study. 12. Number and location of sites of progression on imaging. At disease progression on imaging _____ Previous secondary outcome measures: 1. Optimised thresholds of percentage reduction in ctDNA mutant BRAF copies/ml as a measure of response to stop drugs and the percentage and/or minimum increase in BRAF mutant copies/ml as a decision to restart drugs, measured longitudinally throughout the study 2. Maximal radiological response (complete response [CR]/partial response [PR]/stable disease [SD]/progressive disease [PD]) to therapy in Arm A vs Arm B measured using RECIST (v1.1) criteria 3. Progression-free survival (PFS) defined as the time from randomisation to radiological progression (RECIST v1.1 and in Arm B defined as radiological progression whilst on targeted therapy unless stopped due to toxicity/choice) on Arm A vs Arm B 4. PFS defined as time from randomisation to radiological progression (RECIST v1.1 and in Arm B defined as radiological progression whilst on targeted therapy unless stopped due to toxicity/choice) at 6, 12 and 15 months on Arm A vs Arm B 5. Overall survival (OS) defined as the time from randomisation until death in Arm A vs Arm B 6. Number of adaptive therapy cycles completed, recorded longitudinally throughout the study 7. Median duration of adaptive therapy cycles, measured using completed adaptive therapy date longitudinally throughout the study 8. Number and location of sites of disease progression, recorded continuously throughout the study 9. Percentage of ctDNA results provided within 5 working days from sample receipt into CBC, recorded longitudinally throughout the study 10. Maximal reduction in ctDNA mutant BRAF copies/ml for each adaptive cycle, recorded longitudinally throughout the study 11. Rise in ctDNA mutant BRAF copies/ml during drug off period for each patient, recorded longitudinally throughout the study 12. Incidence of CTCAE all grade adverse events in Arm A vs Arm B defined by CTCAE version 5 continuously throughout the study 13. Quality of life measured using EORTC QLQ-C30 and PRO-CTCAE longitudinally throughout the study The study is expected to last for 3 years, analyses of the secondary endpoints will commence once the trial ends. Ethics approval required London - Chelsea Research Ethics Committee

REC London Centre, 2 Redman Place, Stratford

London United Kingdom E20 1JQ 22/LO/0453 10.1186/ISRCTN14643179 1004759 CPMS: 55327, CFTSp175 1004759 55327 CFTSp175 Randomized parallel-arm proof-of-concept study Interventional Randomised controlled trial Treatment 2027-09-30T00:00:00.000Z United Kingdom England Scotland Wales Addenbrookes

Addenbrookes Hospital Hills Road

Cambridge England CB2 0QQ NV504@2.16.840.1.113883.2.1.3.2.4.18.48 Guys Hospital

Guys Hospital Great Maze Pond

London England SE1 9RT NV515@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Preston Hospital

Sharoe Green Lane Fulwood

Preston England PR2 9HT Freeman Hospital

Freeman Road High Heaton

Newcastle upon Tyne England NE7 7DN Queens Medical Centre

Nottingham University Hospital Derby Road

Nottingham England NG7 2UH 5N896@2.16.840.1.113883.2.1.3.2.4.18.48 John Radcliffe Hospital

Headley Way Headington

Oxford England OX3 9DU RDU5A@2.16.840.1.113883.2.1.3.2.4.18.48 Christie Hospital

Wilmslow Road

Manchester England M20 4BX RM582@2.16.840.1.113883.2.1.3.2.4.18.48 Clatterbridge Cancer Centre

65 Pembroke PLACE

Liverpool England L7 8YA B5N6N@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Marsden Hospital

Royal Marsden Hospital Downs Road

Surrey England SM2 5PT Southampton

Southampton General Hospital Tremona Road

Southampton England SO16 6YD NV163@2.16.840.1.113883.2.1.3.2.4.18.48 Velindre Cancer Centre

Velindre Road

Cardiff Wales CF14 2TL RQFH5@2.16.840.1.113883.2.1.3.2.4.18.48 The Royal Marsden Hospital

Fulham Road

London England SW3 6JJ W5Z3P@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Bournemouth Hospital

Castle Lane East

Bournemouth England BH7 7DW RBD44@2.16.840.1.113883.2.1.3.2.4.18.48 Beatson West of Scotland Cancer Centre

1053 Great Western Road

Glasgow Scotland G12 0YN G517H@2.16.840.1.113883.2.1.3.8.2.16.2 Royal Free Hospital

Pond Street

London England NW3 2QG RAL01@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Current key inclusion criteria as of 09/06/2026: At screening: 1. Written and informed consent obtained from the participant and agreement of the participant to comply with the requirements of the study 2. Histological confirmation of cutaneous melanoma, including acral 3. ≥18 years of age 4. Stage III un-resectable/ IV disease 5. Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT, or clinically accurately measurable (RECIST v1.1) 6. BRAF p.V600E/K/R/D mutation confirmed (exact point mutation must be known) 7. ECOG performance status 0/1/2 8. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs 9. Adequate organ function enabling safe administration of the study treatment 10. Women of childbearing potential participating in the study (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug 11. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 1 month 28 days following last dose of drug (either encorafenib or binimetinib) 12. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug (either encorafenib or binimetinib) Prior to randomisation: 13. BRAF ctDNA level of ≥7 copies/ml of plasma. (If there is a discrepancy between the screening and baseline 1 ctDNA TAB levels this should be discussed via the DyNAMIc trial team at the LCTC.) 14. Left Ventricular Ejection fraction (LVEF) ≥50% of ≥LLN by ECHO _____ Previous key inclusion criteria as of 01/10/2025: At screening: 1. Written and informed consent obtained from the participant and agreement of the participant to comply with the requirements of the study 2. Histological confirmation of cutaneous melanoma, including acral 3. ≥18 years of age 4. Stage III un-resectable/ IV disease 5. Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT (RECIST v1.1) 6. BRAF p.V600E/K/R/D mutation confirmed (exact point mutation must be known) 7. ECOG performance status 0/1/2 8. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs 9. Adequate organ function as defined below: 9.1. Haemoglobin ≥9 g/dL 9.2. White blood count ≥2 x 10^(9)/L 9.3. ANC ≥1.2 x 10(9)/L 9.4. Platelet count ≥75 x 10^(9)/L 9.5. Albumin ≥2.5 g/dL 9.6. Total bilirubinb ≤1.5 x ULN 9.7. AST or ALT ≤3 x ULN 9.8. Calculated creatinine clearance ≥30 ml/min 10. Women of childbearing potential participating in the study (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug 11. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 1 month 28 days following last dose of drug (either encorafenib or binimetinib) 12. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug (either encorafenib or binimetinib) At randomisation: 13. BRAF ctDNA level of ≥7 copies/ml of plasma 14. Left Ventricular Ejection fraction (LVEF) ≥50% of ≥LLN by ECHO _____ Previous key inclusion criteria: Patients eligible for the trial must comply with all of the following at randomisation: 1. Written and informed consent obtained from participant and agreement of participant to comply with the requirements of the study 2. Histological confirmation of cutaneous melanoma 3. ≥18 years of age 4. Stage III un-resectable/ IV disease 5. Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT, and CT or MRI (brain) scan (RECIST v1.1) 6. BRAF p.V600E/K/R mutation confirmed (exact point mutation must be known) 7. BRAF ctDNA TAB level of ≥15 copies/ml of plasma 8. ECOG performance status 0/1/2 9. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs 10. Adequate organ function as defined below: 10.1. Haemoglobin ≥9 g/dL 10.2. White blood count ≥2 x 10(9)/L 10.3. ANC ≥1.2 x 10(9)/L 10.4. Platelet count ≥75 x 10(9)/L 10.5. Albumin ≥2.5 g/dL 10.6. Total bilirubinb ≤1.5 x ULN 10.7. AST or ALT ≤3 x ULN 10.8. Calculated creatinine clearance ≥30 ml/min 10.9. Left Ventricular Ejection fraction (LVEF) ≥50% or ≥LLN by ECHO 11. Women of childbearing potential participating in the study (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug 12. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 1 month following last dose of drug (either encorafenib or binimetinib) 13. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug (either encorafenib or binimetinib) 14. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP participating in the study who are continuously not heterosexually active must still undergo pregnancy testing (as described in inclusion criterion 11) Mixed 18 Years 120 Years All 40 0 Current key exclusion criteria as of 09/06/2026: 1. Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥26 weeks following discontinuation of drugs) 2. BRAF wild-type malignant melanoma 3. Current evidence of active metastasis to the brain or leptomeninges (the designation of “active metastasis” should be determined by the local clinical care team in discussion with the DyNAMIc study team at LCTC if needed and informed by recent imaging.) 4. Any contraindication to treatment with Encorafenib or Binimetinib as per the local Summary of Product Characteristics 5. Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib 6. Current use of a prohibited medication as described in the protocol 7. History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study. Discussion via the DyNAMIc trial team at LCTC as to whether they can be included in the study is allowed and the outcome of the discussion will determine entry. 8. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient’s safety, obtaining informed consent, or compliance with study procedures 9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 10. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (as described in the protocol) 11. Prisoners or patients who are involuntarily incarcerated 12. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness _____ Previous key exclusion criteria as of 15/10/2025: 1. Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥26 weeks following discontinuation of drugs) 2. BRAF wild-type malignant melanoma 3. Current evidence of active metastasis to the brain or leptomeninges (patients with prior definitive treatment with immune therapy/radiotherapy (including SRS) or surgery), with no evidence of progression in the last 3 months, can be included 4. Any contraindication to treatment with Encorafenib or Binimetinib as per the local Summary of Product Characteristics 5. Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib 6. Current use of a prohibited medication as described in the protocol 7. History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study 8. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient’s safety, obtaining informed consent, or compliance with study procedures 9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 10. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption 11. Child-Pugh B or C liver disease 12. Coronary syndromes (including myocardial infarction within 6 months or unstable angina) 13. A history or evidence of current ≥Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of <50% 14. Treatment refractory hypertension defined as a blood pressure of systolic >150 mmHg and/or diastolic >95 mmHg on >3 occasions which cannot be controlled by anti-hypertensive therapy 15. Uncorrectable electrolyte abnormalities >CTCAE v5 Grade 1 (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline 1 QTC interval ≥480 msec) or taking medicinal products known to prolong the QT interval 16. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes) 17. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (as described in the protocol) 18. Prisoners or patients who are involuntarily incarcerated 19. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness _____ Previous key exclusion criteria as of 01/10/2025: Any patient meeting any of the criteria listed below at baseline will be excluded from study participation: 1. Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥6 months ≥26 weeks following discontinuation of drugs) 2. BRAF wild-type malignant melanoma 3. Current evidence of active metastasis to the brain or leptomeninges (patients with prior definitive treatment with immune therapy/radiotherapy (including SRS) or surgery), with no evidence of progression in the last 3 months, can be included 4. Any contraindication to treatment with Encorafenib or Binimetinib as per the local Summary of Product Characteristics 5. Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib 6. Current use of a prohibited medication as described in the protocol 7. History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study 8. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient’s safety, obtaining informed consent, or compliance with study procedures 9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 10. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption 11. Child-Pugh B or C liver disease 12. Coronary syndromes (including myocardial infarction within 6 months or unstable angina) 13. A history or evidence of current ≥Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of <50% 14. Treatment refractory hypertension defined as a blood pressure of systolic >150 mmHg and/or diastolic >95 mmHg on >3 occasions which cannot be controlled by anti-hypertensive therapy 15. Uncorrectable electrolyte abnormalities >CTCAE v5 Grade 1 (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline 1 QTC interval ≥480 msec) or taking medicinal products known to prolong the QT interval 16. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes) 17. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (as described in the protocol) 18. Prisoners or patients who are involuntarily incarcerated 19. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness _____ Previous key exclusion criteria: Any patient meeting any of the criteria listed below at baseline will be excluded from study participation: 1. Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥6 months following discontinuation of drugs) 2. BRAF wild-type malignant melanoma 3. Metastasis to the brain or leptomeninges 4. Any contraindication to treatment with Encorafenib or Binimetinib as per the local Summary of Product Characteristics 5. Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib 6. Current use of a prohibited medication as described in the protocol 7. History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study 8. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient’s safety, obtaining informed consent, or compliance with study procedures 9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 10. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption 11. Child-Pugh B or C liver disease 12. Coronary syndromes (including myocardial infarction within 6 months or unstable angina) 13. A history or evidence of current ≥Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of <50% 14. Treatment refractory hypertension defined as a blood pressure of systolic >150 mmHg and/or diastolic >95 mmHg on >3 occasions which cannot be controlled by anti-hypertensive therapy 15. Uncorrectable electrolyte abnormalities >CTCAE v5 Grade 1 (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline QTC interval ≥480 msec) or taking medicinal products known to prolong the QT interval 16. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes) 17. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (as described in the protocol) 18. Prisoners or patients who are involuntarily incarcerated 19. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness 2024-11-29T00:00:00.000Z 2027-03-31T00:00:00.000Z Cutaneous melanoma Cancer Malignant melanoma of skin, unspecified Current interventions as of 01/10/2025: Randomisations are processed using an online system. Both arms use encorafenib (450 mg once daily) plus binimetinib (45 mg twice daily) which are both administered orally. Arm A is standard of care (SOC) for the condition and, in line with the licence, both drugs are given continuously until progression occurs or when there is no longer clinical benefit from taking the treatment, or when the treatment ends. Arm B is adaptive treatment. This means the treatment is stopped and re-started as guided by the amount of circulating tumour DNA (ctDNA) in a patient’s bloodstream; treatment on this arm will also cease upon progression or when there is no longer clinical benefit from taking the treatment, or when the treatment ends. When ‘on-treatment’, patients on arm B will receive the SOC dose of both drugs. All participants on arm B will commence with one SOC cycle of both drugs before switching to being ‘off-treatment’. The levels of ctDNA is known as the Tumour Activity Burden (TAB). The ctDNA TAB provides guidance on the resistance levels of the tumour. Pre-defined ctDNA TAB threshold levels are used to indicate when treatment should stop/re-start. These levels will be assessed and reviewed during the trial. All participants, regardless of treatment arm, will provide blood samples for ctDNA TAB analysis every 2 weeks up to progression. Once progression occurs, all participants will be followed up every 3 months until the end of the study, withdrawal or death. Previous interventions: Randomisations are processed using an online system. Both arms use encorafenib (450 mg once daily) plus binimetinib (45 mg twice daily) which are both administered orally. Arm A is standard of care (SOC) for the condition and, in line with the licence, both drugs are given continuously until relapse occurs. Arm B is adaptive treatment. This means the treatment is stopped and re-started as guided by the amount of circulating tumour DNA (ctDNA) in a patient’s bloodstream; treatment on this arm will also cease upon relapse. When ‘on-treatment’, patients on arm B will receive the SOC dose of both drugs. All participants on arm B will commence with one SOC cycle of both drugs before switching to being ‘off-treatment’. The levels of ctDNA is known as the Tumour Activity Burden (TAB). The ctDNA TAB provides guidance on the resistance levels of the tumour. Pre-defined ctDNA TAB threshold levels are used to indicate when treatment should stop/re-start. These levels will be assessed and reviewed during the trial. All participants, regardless of treatment arm, will provide blood samples for ctDNA TAB analysis every 2 weeks up to progression. Once relapse occurs, all participants will be followed up every 3 months until the end of the study, withdrawal or death. Drug Phase II Encorafenib, binimetinib Data sharing statement to be made available at a later date Protocol

e3f183e4-a274-4ab5-80fb-833fb7584999 df5e103c-3240-4ce0-af72-f940f1be88ad b30d0006-a1a4-4724-853a-0373b3be0528 da4ebc0e-91f8-4129-aa5c-8b5fdf53d436 e4447446-50cb-4d9a-9d5b-44cedd9000af No Protocol file 41841_PROTOCOL_v3.0.pdf 554dafb0-92b3-4ce0-8e97-0f032516655b true application/pdf 3178013 8ab6168325d7c5bfe12452a062639534 Protocol file ISRCTN14643179_Protocol_v4.0_27March2023.pdf 1936664c-5025-445d-822f-54e7fb7a58bc true application/pdf 1918956 dc05e9f6645a3d44b165ff97475adaba Protocol file ISRCTN14643179_Protocol_v5.0_21May2024.pdf 131f8a6c-84ad-41f8-9147-45157d4c17be true application/pdf 3224191 4989a3dcb2b36a8aec14de0343d55da8 Protocol file ISRCTN14643179_Protocol_v6.0_05March2025.pdf 636bc951-4736-4852-bce7-397bfbd1a181 true application/pdf 3223104 27e6dab3d55b57e69ae09bae8240400a Protocol file ISRCTN14643179_Protocol_v7.0_23June2025.pdf fdd89e40-59e4-400d-95fa-ab71ff7da848 true application/pdf 3316457 6730a0120688ba800d59bde40b6d3f26 Protocol file ISRCTN14643179 DyNAMIc_Protocol_V8.0 14Jan2026.pdf 9fe419c0-d703-4211-a814-2b08d9154fc7 true application/pdf 3428955 fd94b17de5266676cfe3456678268262 Paul Lorigan https://orcid.org/0000-0002-8875-2164 Scientific

University of Manchester The Christie NHS Foundation Trust Wilmslow Road

Withington United Kingdom M20 4BX - paul.lorigan@nhs.net Public Paul Lorigan Principal investigator

University of Manchester The Christie NHS Foundation Trust Wilmslow Road

Withington United Kingdom M20 4BX - paul.lorigan@nhs.net Public DyNAMIc Trial Manager Public

Liverpool Clinical Trials Centre Waterhouse Building 1-3 Brownlow Street

Liverpool United Kingdom L69 3GL - dynamic_study@liverpool.ac.uk Public The Christie NHS Foundation Trust Hospital/treatment centre https://ror.org/03v9efr22 Non-commercial Jon Moulton Charity Trust http://dx.doi.org/10.13039/501100023262 13390479 true Analysis of proton versus photon radiotherapy in oligodendroglioma and assessment of cognitive health APPROACH To assess the feasibility of recruitment to a randomised trial of proton beam therapy versus photon radiotherapy and whether there are early (2 years post-radiotherapy) signals of neurocognitive benefit with proton beam therapy compared to photon radiotherapy. The main aim will be to establish whether there is a long-term (5 years post-radiotherapy) neurocognitive benefit of proton beam therapy compared to photon radiotherapy. Background and study aims The study is called the APPROACH study. APPROACH stands for Analysis of Proton versus Photon Radiotherapy in Oligodendroglioma & Assessment of Cognitive Health. Oligodendroglioma is an uncommon brain tumour with an excellent outlook. Standard treatment involves surgery to remove as much tumour as possible, radiotherapy (RT) and then chemotherapy. RT helps stop the tumour from re-growing. Standard RT for adult patients in the UK uses photon RT. Photon RT is given as lots of small treatments on weekdays over about six weeks. This is the best way to control the tumour whilst minimising side effects in normal brain tissue. Unfortunately, photon RT for oligodendroglioma can cause long-term side effects. These can develop years after RT and can include memory problems and difficulties in processing information. These can have a negative impact on quality of life. Proton beam radiotherapy (PBT) is an advanced type of RT, also given on weekdays over about six weeks. It requires expensive technology but can reduce the dose of RT delivered to the normal brain, including parts of the brain used for memory and information processing. We do not know, however, if these lower doses result in fewer long-term side-effects. We do not expect any difference in controlling the growth of the tumour as the same dose of RT is given to the tumour whether photon RT or PBT is used. To do this we will compare the long-term side effects of photon RT or PBT for patients with oligodendroglioma. We want to find out which is the best treatment for patients with oligodendroglioma to reduce long-term side effects. Who can participate? Patients with oligodendroglioma from across the UK What does the study involve? Participants in our study will be randomly assigned (by computer) to receive photon RT or PBT, with an equal chance of either. We will gather information on long-term brain function, quality of life, other side effects and tumour control. As part of the study we will look at whether travelling to a distant RT centre is acceptable to patients. Patients receiving photon RT will have this at their local RT centre. PBT is only available in Manchester and London, so patients having PBT will need to stay in Manchester or London for the treatment period (accommodation is provided). To assess long-term side effects, we will monitor patients for five years after RT. This will involve: - Carrying out short practical tasks and memory assessments to measure brain function - Completing questionnaires about quality of life and work - Having Magnetic Resonance Imaging (MRI) scans to monitor the tumour - Having blood tests to track hormone levels- these can also be affected by RT We will also ask carers to complete questionnaires, to assess carer experiences. What are the possible benefits and risks of participating?: By taking part in this study, the researchers hope to understand better the effects of lower dose of RT delivered to healthy brain, if side effects can be reduced and how it may impact a patient's quality of life. This will help hospitals in choosing the best treatment for future patients diagnosed with oligodendroglioma. Participants have a risk of side effects in both the radiotherapy groups. Because RT is given over several weeks it can disrupt to day-to-day life for patients and carers, especially as this condition often involves people of working age who are not allowed to drive due to their diagnosis. Possible side effects of chemotherapy are tiredness, nausea, vomiting, taste changes, sore mouth or mouth ulcer, infections, bruising and bleeding, poor appetite, diarrhoea, constipation, abdominal pain, anaemia, skin changes and allergic reactions. Possible side effects from radiotherapy could include; tiredness, patchy hair loss, headaches, dizziness, swelling in the brain, nausea, vomiting, skin redness or irritation on the scalp, weakness, seizures and dry mouth or taste changes. Patient and Public Involvement (PPI) has played a key role in the study: patients and carers supported the research question and follow-up plan and advised on study design. At least three PPI representatives will sit on the Trial Management Group to ensure the patient voice is represented. The PPI group will have an active role throughout and will contribute to the final scientific report and in the dissemination of the findings, that will be shared with trial participants and the wider public. Where is the study run from? University of Leeds (UK) When is the study starting and how long is it expected to run for? January 2024 to July 2032 Who is funding the study? National Institute for Health and Care Research - Efficacy and Mechanism Evaluation Programme (NIHR) (UK) Who is the main contact? Dr Samantha Noutch, approach@leeds.ac.uk (UK) https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-looking-at-proton-beam-therapy-for-people-with-a-brain-tumour-called-oligodendroglioma Neurocognitive function (NCF) at 5 years measured using the standard neurocognitive test battery - EORTC core clinical trial battery composite (CTB COMP) during baseline and at 1, 3, 6, 12, 24, 36, 48 and 60 months post end of RT, as per standard follow-up schedules 1. Additional tests of neurocognitive function measured using the CNS Vital Signs test battery (Verbal Memory (VBM), Visual Memory (VIM), Finger Tapping (FTT), Symbol Digit Coding (SDC), Stroop Test (ST), Shifting Attention (SAT), Continuous Performance (CPT), Perception of Emotion (POET), On-Verbal Reasoning (NVRT), and the 4-part Continuous Performance (FPCPT)) at baseline, and 1, 12, 24, 36, 48 and 60 months post-RT 2. Health-Related Quality of Life (HRQoL) measured using the EORTC Quality of life questionnaire core 30 (QLQ-C30), QLQ-BN20, the EuroQol EQ-5D-5L, and Multidimensional Fatigue Inventory (MFI) questionnaire and the Hospital Anxiety and Depression Scale (HADS) at baseline, during the final week of RT and at 1, 3, 6, 12, 24, 36, 48, 60 months post-RT 3. Endocrinopathy measured using dynamic/static testing in blood for GH/IGF-1, FSH/LH/testosterone (males) and SHBG (males)/oestradiol (females), cortisol, T4/T3/TSH, and prolactin at baseline and at 6, 12, 24, 36, 48 and 60 months post-RT, as per standard of care 4. Treatment compliance measured using patient records with data on the treatment participants receive collected weekly during radiotherapy 5. Work and economic impact measured using the WPAI general health (WPAI: GH) questionnaire completed by the participant and their primary caregivers at baseline, during the final week of RT and at 1, 3, 6, 12, 24, 36, 48 and 60 months post-RT 6. Caregiver distress measured using the 30-item Caregiver Needs Screen completed by the participant’s primary caregiver at baseline, during the final week of RT and at 1, 3, 6, 12, 24, 36, 48, and 60 months post-RT 7. Early (acute) and late toxicity: acute toxicity period, defined from the start of RT to the 3 months post end of RT follow-up assessment, measured by clinician assessment each week of treatment during clinic and during the 1 and 3 month follow-up assessments; late toxicity period, defined as after 3 months until the final follow-up visit at 60 months, measured by clinician assessment during each of the follow-up visits and will be recorded at 6, 12, 24, 36, 48 and 60 months post start of radiotherapy treatment. Toxicities will also be recorded at each chemotherapy assessment. 8. Radiological tumour response meaured using MRI scans, performed at baseline, 3, 6, 12, 24, 36, 48 and 60 months post-RT, as per standard of care. Response will be evaluated based on the RANO criteria. Additional off-schedule MRI scans may be used in the case of suspected progression. 9. Progression-free survival (PFS), defined as the time from randomisation to the date of the first documented evidence of progression or death from any cause measured using response data evaluated by RANO at 3, 6, 12, 24, 36, 48 and 60 months post-RT. Additional unscheduled MRI scans may be used in the case of suspected progression. 10. Overall survival (OS), defined as the time from randomisation to the date of death from any cause collected at standard follow-up visits Ethics approval required North East - Newcastle North Tyneside 1 Research Ethics Committee

NHSBT Newcastle Blood Donor Centre, Holland Drive

Newcastle upon Tyne United Kingdom NE2 4NQ 22/NE/0232 10.1186/ISRCTN13390479 306432 CPMS: 54825 306432 54825 Multicenter interventional unblinded randomized controlled trial Interventional Randomised controlled trial Treatment 2032-07-17T00:00:00.000Z United Kingdom England Wales Addenbrookes

Addenbrookes Hospital Hills Road

Cambridge England CB2 0QQ NV504@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospital Bristol

Bristol Royal Infirmary Marlborough Street

Bristol England BS2 8HW RA7C1@2.16.840.1.113883.2.1.3.2.4.18.48 Charing Cross Hospital

Fulham Palace Road

London England W6 8RF RDU92@2.16.840.1.113883.2.1.3.2.4.18.48 The Christie

550 Wilmslow Road Withington

Manchester England M20 4BX RBV01@2.16.840.1.113883.2.1.3.2.4.18.48 Clatterbridge Cancer Centre

Clatterbridge Hospital Clatterbridge Road

Wirral England CH63 4JY RJR62@2.16.840.1.113883.2.1.3.2.4.18.48 Guy's & St Thomas Hospital

Westminster Bridge Road

London England SE1 7EH 5LE98@2.16.840.1.113883.2.1.3.2.4.18.48 Maidstone Hospital

Hermitage Lane

Maidstone England ME16 9QQ 5P925@2.16.840.1.113883.2.1.3.2.4.18.48 James Cook University Hospital

Marton Road

Middlesbrough England TS4 3BW RTDCR@2.16.840.1.113883.2.1.3.2.4.18.48 Queens Medical Centre

Nottingham University Hospital Derby Road

Nottingham England NG7 2UH 5N896@2.16.840.1.113883.2.1.3.2.4.18.48 Oxford University Hospitals

John Radcliffe Hospital Headley Way Headington

Oxford England OX3 9DU RGT2V@2.16.840.1.113883.2.1.3.2.4.18.48 Derriford Hospital

Derriford Road Derriford

Plymouth England PL6 8DH RH8D2@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospital Birmingham

Queen Elizabeth Hospital Edgbaston

Birmingham England B15 2TH RRJ24@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Marsden Hospital

Royal Marsden Hospital Downs Road

Sutton England SM2 5PT RVRD9@2.16.840.1.113883.2.1.3.2.4.18.48 St. Bartholomews Hospital

West Smithfield

London England EC1A 7BE RP405@2.16.840.1.113883.2.1.3.2.4.18.48 St James' University Hospital

Beckett Street

Leeds England LS9 7TF RQR13@2.16.840.1.113883.2.1.3.2.4.18.48 Singleton Hospital

Sketty Lane Sketty

Swansea Wales SA2 8QA 7A3C4@2.16.840.1.113883.2.1.3.2.4.18.48 University College London Hospital

235 Euston Road

London England NW1 2BU RAL79@2.16.840.1.113883.2.1.3.2.4.18.48 Velindre Cancer Centre

Velindre Road

Cardiff Wales CF14 2TL RQFH5@2.16.840.1.113883.2.1.3.2.4.18.48 Leicester Royal Infirmary

Infirmary Square

Leicester England LE1 5WW RFR0H@2.16.840.1.113883.2.1.3.2.4.18.48 Mount Vernon Hospital

Mount Vernon Road

Barnsley England S70 4DP RXG84@2.16.840.1.113883.2.1.3.2.4.18.48 Queens Hospital

Rom Valley Way

Romford England RM7 0AG RP425@2.16.840.1.113883.2.1.3.2.4.18.48 Patient 1. Histologically proven diagnosis of oligodendroglioma (ODG) with 1p19q co-deletion and isocitrate dehydrogenase (IDH) mutation 2. Randomisation must be performed within 28 days of the magnetic resonance imaging (MRI) that leads to the decision that radiotherapy (RT) is required at that point in time. Outside of 28 days, an updated MRI is required to serve as a contemporaneous baseline scan to assess response to further treatment. 3. Karnofsky Performance Status (KPS) ≥70%. 4. Adequate wound healing and recovery if recent surgery. 5. Suitable to complete baseline neurocognitive testing (No access to translated tests, can only be administered in English). 6. Patients of childbearing potential should be asked to confirm that they are not pregnant to confirm trial eligibility. Formal Pregnancy testing should be performed if there is any doubt as to pregnancy status or if felt appropriate, including in circumstances such as irregular periods, unprotected sexual intercourse since the last menstrual period, missed contraceptive pill or antibiotics during the last menstrual cycle or failure of barrier contraception. 7. Fertile participants, born male, must agree to practice methods of contraception that are considered medically acceptable for the duration of RT, adjuvant chemotherapy and for 6 months post-end of treatment if sexually active with a person of child-bearing potential. 8. Able to swallow oral medication. 9. Able to provide study-specific informed consent. 10. Age 25 or above at the point of starting RT treatment. 11. No known haematological, renal or hepatic impairments making PCV chemotherapy inappropriate Mixed 25 Years 110 Years All 246 0 1. Pregnancy (positive pregnancy test) or lactating. 2. Prior cranial or head and neck radiotherapy (RT). 3. Any previous chemotherapy for the treatment of oligodendroglioma (ODG). 4. Comorbid neurodegenerative diseases that influence neurocognitive function (NCF). 5. Severe active co-morbidity making patient unsuitable for RT and/ or adjuvant chemotherapy (e.g., uncontrolled diabetes, uncontrolled hypertension). 6. Leptomeningeal disease. 7. Spinal or infratentorial disease. 8. Another currently active malignancy or another malignancy within the last 3 years. 9. Any contra-indication to procarbazine, vincristine or lomustine including: coeliac disease; the rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption. 10. Any recognised genetic syndrome causing sensitivity to radiotherapy. 11. Patient unwilling/ unable to attend for follow up in the local radiotherapy centre. 12. Contraindication to MRI or gadolinium. 2024-01-17T00:00:00.000Z 2027-07-17T00:00:00.000Z Brain cancer, oligodendroglioma Cancer The APPROACH trial is a Phase III, multicentre trial. Patients will be recruited from 18-25 centres and randomised 1:1 between photon radiotherapy (RT) and proton beam therapy (PBT), delivered over approximately 6 weeks. Photon RT will be delivered at the local RT centre while PBT will be delivered at one of the two NHS PBT centres in the UK (The Christie or UCLH). Neurocognitive tests will be performed at baseline, one-month post-end of RT and annually for 5 years. Follow-up will also include clinical assessment, blood tests and brain imaging, as per standard follow-up protocols. Patient quality of life (QoL) and productivity questionnaires and caregiver questionnaires will also be performed throughout follow-up. Interim analyses will assess the feasibility of recruitment, and early efficacy at 2 years (i.e., signals of improved neurocognitive function (NCF) with PBT), and assess futility. The primary endpoint will be at 5 years. 246 patients (123 per arm) are required to detect a moderate effect size difference in NCF at 2 and 5 years between PBT and photon RT. The required sample size is 246 patients, recruited over 3.5 years. NCF is measured using Clinical Trial Battery Composite (CTB COMP) scoring, calculated from the mean of standardized z-scores for the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT)-A/B, and Controlled Oral Word Association (COWA). The sample size for NCF at 5 years is based on a two-sample t-test. A Cohen’s d of 0.5 is considered a moderate effect size; assuming a common standard deviation (SD) of 1 this effect size equates to a mean z-score of 0.5, and is deemed clinically relevant in this setting given that patients are typically young and of working age, so even small deteriorations will likely result in noticeable everyday issues. This is the same targeted difference in CTB COMP score adopted in the NRG-BN005 US PBT versus photon RT glioma study (NCT03180502). Based on a two-sample t-test with 5% two-sided significance and 90% power, 172 patients (86 per arm) are required to detect an effect size of 0.5. Assuming a 30% loss to follow-up at 5 years, 123 patients will be required per arm. Participants completing CNS vital sign tests will do this after face-to-face testing for the primary NCF endpoints, on a desktop computer or PC with a mouse, supervised by a research nurse or other qualified individual. Data on the treatment participants receive will be collected weekly during radiotherapy. Information will be recorded on the total dose of radiotherapy received (dose and fractions), the overall treatment time (i.e. time between start and end date), details of any interruptions to the radiotherapy and the reasons for these interruptions (i.e. toxicity or other). In the case of PBT, any fractions that are given as photon treatment instead of PBT (e.g. the result of PBT machine breakdown) will also be recorded. Adherence to the radiotherapy schedule will be defined as a participant that has completed their scheduled course of radiotherapy with no more than two treatment days of interruptions due to toxicity or any other reason. The number of chemotherapy cycles and doses delivered will also be recorded, along with details of any modifications (delays, dose reductions, omissions) to treatment and their associated reasons. Additional tests of neurocognitive function comprises the CNS vital sign tests to be assessment include: Verbal Memory (VBM), Visual Memory (VIM), Finger Tapping (FTT), Symbol Digit Coding (SDC), Stroop Test (ST), Shifting Attention (SAT), Continuous Performance (CPT), Perception of Emotion (POET), On-Veral Reasoning (NVRT), and the 4-part Continuous Performance (FPCPT). Participants will complete this after face-to-face testing for the primary NCF endpoints, on a desktop computer or PC with a mouse, supervised by a research nurse or other qualified individual. Treatment compliance measures include information recorded on the total dose of radiotherapy received (dose and fractions), the overall treatment time (i.e. time between start and end date), details of any interruptions to the radiotherapy and the reasons for these interruptions (i.e. toxicity or other). In the case of PBT, any fractions that are given as photon treatment instead of PBT (e.g. the result of PBT machine breakdown) will also be recorded. Adherence to the radiotherapy schedule will be defined as a participant that has completed their scheduled course of radiotherapy with no more than two treatment days of interruptions due to toxicity or any other reason. The number of chemotherapy cycles and doses delivered will also be recorded, along with details of any modifications (delays, dose reductions, omissions) to treatment and their associated reasons. The Work & economic impact, WPAI general health (WPAI:GH) will be completed by the participant and their primary Caregivers. The questionnaire includes six questions about employment, time off and productivity at work and during regular activities, assessing the impact due to overall health and symptoms. An additional health resource use questionnaire will collect patients’ utilisation of health services related to their brain cancer including NHS and primary health services, hospital based secondary care services and personal costs incurred. Personal costs incurred for caregivers will also be collected. The health recourse utilisation will be collected at baseline and annual follow-up. Caregiver distress (the 30-item Caregiver Needs Screen) will be completed by the participant’s primary caregiver. The questionnaire includes subscales for neurologic and oncologic symptoms, personal communication, communication with healthcare providers, resources and caregiver health. Early and late toxicity, including the acute toxicity period has been defined from start of RT to the 3 months post end of RT follow-up assessment. The late toxicity period will be defined as after 3 months until the final follow-up visits at 60 months. All radiotherapy and chemotherapy toxicities will be evaluated using the CTCAE criteria (V5.0) and include all ARs, SARs and RUSAEs. Tumor response will be evaluated based on the RANO criteria. Additional off-schedule MRI scans may be used in the case of suspected progression. Device Phase III Photon radiotherapy (RT), proton beam therapy (PBT) De-identified individual participant data datasets generated and/or analysed during the current study will be available upon request from the Clinical Trials Research Unit, University of Leeds (contact CTRU-DataAccess@leeds.ac.uk in the first instance). Data will be made available at the end of the trial, i.e. usually when all primary and secondary endpoints have been met and all key analyses are complete. Data will remain available from then on for as long as CTRU retains the data. CTRU makes data available by a 'controlled access' approach. Data will only be released for legitimate secondary research purposes, where the Chief Investigator, Sponsor and CTRU agree that the proposed use has scientific value and will be carried out to a high standard (in terms of scientific rigour and information governance and security), and that there are resources available to satisfy the request. Data will only be released in line with participants' consent, all applicable laws relating to data protection and confidentiality, and any contractual obligations to which the CTRU is subject. No individual participant data will be released before an appropriate agreement is in place setting out the conditions of release. The agreement will govern data retention, usually stipulating that data recipients must delete their copy of the released data at the end of the planned project. The CTRU encourages a collaborative approach to data sharing and believes it is best practice for researchers who generated datasets to be involved in subsequent uses of those datasets. Recipients of trial data for secondary research will also receive data dictionaries, copies of key trial documents and any other information required to understand and reuse the released datasets. The conditions of release for aggregate data may differ from those applying to individual participant data. Requests for aggregate data should also be sent to the above email address to discuss and agree on suitable requirements for release. Available on request 2026 Other publications in https://pubmed.ncbi.nlm.nih.gov/42743785/ (added 16/09/2026)

Added from spreadsheet

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Trial Coordinator Clinical Trials Research Unit Leeds Institute of Clinical Trials Research University of Leeds

Leeds United Kingdom LS2 9JT +44 (0)113 343 3275 approach@leeds.ac.uk Public Louise Murray https://orcid.org/0000-0003-0658-6455 Principal investigator

Level IV Bexley Wing Beckett Street

Leeds United Kingdom LS9 7TF - L.J.Murray@leeds.ac.uk Public Samantha Noutch Scientific

Leeds Institute of Clinical Trials Research (LICTR) Level 10, Worsley Building Clarendon Way University of Leeds

Leeds United Kingdom LS2 9NL +44 (0)113 343 1486 approach@leeds.ac.uk Public University of Leeds University/education https://ror.org/024mrxd33 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272