31401365 true The effect of Music Medicine on postoperative pain and anxiety in patients with lung cancer undergoing thoracic surgery The aim of the study was to investigate the effect of music listening (Music Medicine) on postoperative pain and anxiety in patients with lung cancer undergoing thoracic surgery. Secondary objectives were to investigate its effects on perceived stress, vital signs, additional analgesic use and Substance P levels. Background and study aims Surgery is a common treatment for lung cancer, but many patients experience pain, anxiety, and stress during their recovery. Medicines can help manage these symptoms, but additional non-drug approaches may also be beneficial. Listening to music has been suggested as a simple and inexpensive way to improve wellbeing and reduce discomfort in patients undergoing medical treatment. This study aims to investigate whether listening to relaxing music after thoracic surgery can reduce pain and anxiety in patients with lung cancer. The study also examines the effects of music on stress levels, vital signs, the need for additional pain medication, and levels of a substance involved in pain signalling called Substance P. Who can participate? Adults aged 18 to 75 years with lung cancer who are undergoing thoracic surgery and are able to speak Greek can take part. What does the study involve? Participants are allocated to one of two groups. Both groups receive standard postoperative care and medication. In addition, participants in the intervention group listen to 30 minutes of pre-recorded relaxing instrumental music through headphones once a day during their hospital stay, starting on the first day after surgery. Participants in the control group rest during the same period but do not listen to music. Researchers assess pain, anxiety, stress levels, blood pressure, heart rate, and the use of additional pain medication. Levels of Substance P are also measured in participants receiving the music intervention. The results are compared to determine whether music listening improves recovery after surgery. What are the possible benefits and risks of participating? Participants who listen to music may experience reduced pain, anxiety, or stress during their recovery. The findings may help improve supportive care for patients recovering from lung cancer surgery. Risks are expected to be minimal, although some participants may find listening to music through headphones uncomfortable or may not enjoy the selected music. Participants in the intervention group also undergo blood sampling to measure Substance P levels. Where is the study run from? The study is run at the Theagenio Cancer Hospital of Thessaloniki – Thoracic Oncology Surgery Department, Thessaloniki, Greece. When is the study starting and how long is it expected to run for? The study started recruiting participants in December 2025 and recruitment ended in March 2026. The study was completed in March 2026. Who is funding the study? The study is investigator-initiated and investigator-funded. The sponsor is Cyprus University of Technology. Who is the main contact? Dr Maria Chochou, mariachochou@gmail.com. Postoperative pain a Visual Analogue Scale (VAS) baseline preoperatively and daily at 15:30 and 16:30 from postoperative day 1 until the day before hospital discharge Postoperative state anxiety State subscale of the State-Trait Anxiety Inventory (STAI-S) Baseline preoperatively and daily between 15:30 and 16:30 from postoperative day 1 until the day before hospital discharge Perceived stress the Perceived Stress Scale (PSS-10) baseline preoperatively and on the day of hospital discharge Additional postoperative analgesic use data recording of whether each participant received at least one additional dose of analgesic medication the postoperative period until hospital discharge Vital signs, including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (pulse), standard methods baseline preoperatively and daily between 15:30 and 16:30 from postoperative day 1 until the day before hospital discharge Serum Substance P levels Enzyme-linked immunosorbent assay (ELISA) in the intervention group a daily time points before and after the music listening intervention from postoperative day 1 until the day before hospital discharge Ethics approval required Scientific Council and Board of Directors of Theagenio Cancer Hospital of Thessaloniki

2 Alexandrou Simeonidi Street

Thessaloniki Greece 54639 16/29.05.2025 10.1186/ISRCTN31401365 Interventional Non-randomized controlled trial Open (masking not used) Active Parallel Supportive care Not applicable 2026-03-22T00:00:00.000Z Greece Theagenio Cancer Hospital of Thessaloniki – Thoracic Oncology Surgery Department

2 Alexandrou Simeonidi Street

Thessaloniki Greece 54639 false 1. Patients diagnosed with lung cancer 2. Patients undergoing thoracic surgery via thoracotomy or video-assisted thoracoscopic surgery (VATS) 3. Aged 18 to 75 years 4. Able to speak Greek Mixed 18 Years 75 Years All 30 30 1. Hearing impairment (e.g. requiring the use of a hearing aid) 2. Unwillingness to participate in the study 3. Postoperative complications requiring repeat surgery 2025-12-05T00:00:00.000Z 2026-03-18T00:00:00.000Z Postoperative pain and anxiety in patients with lung cancer undergoing thoracic surgery Cancer Participants were allocated to either an intervention group or a control group using a non-randomized design. Both groups received standard postoperative care and pharmacological treatment. Participants in the intervention group additionally listened to 30 minutes of pre-recorded classical, soft, relaxing instrumental music without vocals, with a tempo of 60–80 beats per minute. Music listening was conducted once daily between 15:30 and 16:30, starting on the first postoperative day and continuing until the day before hospital discharge. Participants listened through headphones and were allowed to adjust the volume. Participants in the control group received standard postoperative care without music listening. During the corresponding assessment period, they followed the same resting conditions as the intervention group but did not listen to music and did not undergo blood sampling for Substance P measurement. Outcomes were assessed before and after the intervention/rest period during the postoperative period. Behavioural Not expected to be made available 8403b652-3fd5-418a-8d6b-21c073311832 8dd2cca9-19e8-4584-890d-c6d1c865fa1c 87344a77-6439-4b3d-961e-5501fb893dc4 No Maria Chochou Public Scientific Principal investigator

Tenedou 44 4th floor

Thessaloniki Greece 54453 +306943473583 mariachochou@gmail.com Public Cyprus University of Technology https://ror.org/05qt8tf94 Non-commercial Investigator initiated and funded 78134142 true Impact of periodontitis on occult lymph node metastasis and prognosis in early-stage non-small cell lung cancer PERIO-NSCLC To investigate the impact of periodontitis on occult lymph node metastasis and prognosis in early-stage non-small cell lung cancer Background and study aims Non‑small cell lung cancer (NSCLC) is one of the most common cancers worldwide with the highest death rates. With increasing public health awareness and the widespread adoption of lung cancer screening, the incidence of early‑stage NSCLC has risen considerably in recent years. Surgery remains the cornerstone of treatment for early‑stage NSCLC, and lymph node dissection is the standard surgical procedure. Unfortunately, about 5%–15% of patients with early‑stage NSCLC have occult lymph node metastasis, defined as the involvement of lymph nodes that was not detected before surgery. Patients with occult nodal metastases have a significantly worse prognosis than those without, indicating that they may require more extensive and aggressive treatment. Periodontal (gum) disease is one of the most common oral conditions in the general population, with a prevalence as high as 70% in individuals aged over 65 years, and it is a leading cause of tooth loss in the elderly. Several studies have shown that moderate‑to‑severe periodontitis is significantly associated with an increased risk of lung cancer. Cell and animal experiments have demonstrated that periodontitis‑associated microbiota (bacteria), particularly Porphyromonas gingivalis, can promote lung cancer progression, suggesting that periodontitis may be linked to poor prognosis in NSCLC patients. However, to date, no observational study in patient populations has directly investigated the association between periodontitis and occult lymph node metastasis in early‑stage NSCLC. Therefore, this study aims to evaluate the impact of periodontitis on occult lymph node metastasis and prognosis in patients with early‑stage NSCLC. Who can participate? Patients aged 18–90 years with early‑stage NSCLC that is clinically staged as T1–2N0M0 (meaning the tumour is confined to the lung with no evidence of lymph node or distant spread) who have undergone surgical removal of the tumour (wedge resection, segmentectomy, or lobectomy) by robotic‑assisted, video‑assisted, or open chest surgery, and the pathology result must confirm NSCLC. What does the study involve? This is a prospective observational study, meaning we will not assign any additional medical treatment or intervention beyond routine clinical care. Instead, we will observe and collect information from participants who have already been diagnosed with early‑stage non‑small cell lung cancer and have undergone surgery. The following information is collected and analysed: patient characteristics, cancer outcomes, and survival outcomes. What are the possible benefits and risks of participating? The risks of participating are very low. Because the study does not involve any experimental drugs, medical devices, or changes to patient standard clinical care, there are no physical risks related to medical interventions. The findings may benefit future patients by determining the impact of periodontitis on occult lymph node metastasis and prognosis. Where is the study run from? 1. Shanghai Chest Hospital (China) 2. The Affiliated Lihuili Hospital of Ningbo University (China) 3. The First Affiliated Hospital of Shaoyang University (China) 4. The First Affiliated Hospital of Ningbo University (China) 5. Putuo District People’s Hospital (China) When is the study starting and how long is it expected to run for? September 2026 to June 2032 Who is funding the study? 1. Shanghai Chest Hospital (China) 2. National Natural Science Foundation of China (82573557) 3. Natural Science Foundation of Shanghai (24ZR1464400) 4. Key R&D projects of Zhejiang Province (2024C03277SD2) Who is the main contact? Dr Hanbo Pan, docpanhanbo@163.com Occult lymph node metastasis pathological confirmation 1 month after surgery Recurrence-free survival the date of surgery to the first occurrence of tumor recurrence or all-cause death, whichever came first, 5 years after surgery Cumulative incidence of recurrence the time from surgery to tumor recurrence/metastasis, with patients censored at death if no recurrence occurred during follow-up, 5 years after surgery Overall survival the interval from surgery to death from any cause 5 years after surgery The presence of high-risk components pathological confirmation 1 month after surgery Ethics approval required Institutional Review Board of Shanghai Chest Hospital

241 Huaihai West Road, Xuhui District

Shanghai China 200030 IS25212 10.1186/ISRCTN78134142 Observational Cohort study 2032-09-30T00:00:00.000Z China false 1. Aged 18–90 years, male or female 2. Eastern Cooperative Oncology Group (ECOG) performance status 0–1 3. Clinical staging of pulmonary tumour as T1–2N0M0 4. Radiologically pure solid nodule, or nodule with a solid component proportion >50% 5. Underwent robotic‑assisted, video‑assisted thoracoscopic, or conventional open wedge resection, segmentectomy, or lobectomy, with pathology confirmed as primary non‑small cell lung cancer (NSCLC) 6. Underwent systemic or lobe-specific lymph node (LN) dissection that meets the criteria of R0 resection 7. Willing to undergo a basic oral examination to assess the status and severity of periodontitis 8. Willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures Mixed 18 Years 90 Years All 4500 0 1. Pathological diagnosis other than NSCLC, or malignant tumour of undetermined type, or benign lesion 2. Receipt of any preoperative neoadjuvant therapy 3. Incomplete clinical staging evaluation, including no preoperative chest CT or contrast‑enhanced brain MRI, no PET‑CT performed for lesions with a solid component > 1 cm, or no biopsy for suspected mediastinal lymph node metastasis indicated by PET‑CT 4. LN retrieval extent or surgical quality did not meet the criteria for R0 resection 5. Withdrawal of informed consent and discontinuation from the study 2026-09-21T00:00:00.000Z 2027-06-30T00:00:00.000Z The association of periodontitis with occult lymph node metastasis and prognosis in early-stage (T1-2N0M0) non-small cell lung cancer Cancer The following variables were collected and analysed: 1. Patient baseline characteristics, including age, gender, body mass index (BMI), smoking status, comorbidities, ECOG performance, FEV1% (forced expiratory volume in one second percentage), preoperative carcinoembryonic antigen (CEA), radiographic type, tumor location, clinical stage, and surgical approach 2. Pathological findings, including tumor differentiation degree, histologic subtype, pathological T descriptor, pathological N descriptor, residual tumor status, and lymph node dissection. 3. Survival outcomes, including 5-year recurrence-free survival (RFS), overall survival (OS), and cumulative incidence of relapse (CIR) Other The dataset analyzed in this study would be available upon proper request and approval from the Institutional Review Board of Shanghai Chest Hospital. Available on request f662549b-b72e-4c12-864e-e48b8fee4c34 bb940e87-a5f4-4231-924a-02fae16bda93 380ba3d9-5fb2-4ee2-946d-c9047cb859f4 6de83966-d8c8-4223-b98c-559500cafa93 b58a17f7-e812-4425-829a-64b2e6cc1410 d5d17c43-9b06-4419-94df-f7cadd4b2093 849ef408-56ed-4dbe-94df-1e9557247ddd Yes Hanbo Pan https://orcid.org/0000-0001-5880-2573 Scientific Public

No. 241 Huaihai West Road, Xuhui District

Shanghai China 200030 +86 (0)15058486839 docpanhanbo@163.com Public Qingquan Luo https://orcid.org/0000-0003-4098-9477 Principal investigator

241 Huaihai West Road, Xuhui District

Shanghai China 200030 +86 (0)13003247676 luoqingquan@hotmail.com Public Shanghai Chest Hospital https://ror.org/03fjc3817 Non-commercial Shanghai Chest Hospital http://dx.doi.org/10.13039/501100008837 National Natural Science Foundation of China http://dx.doi.org/10.13039/501100001809 Natural Science Foundation of Shanghai Municipality http://dx.doi.org/10.13039/100007219 Key R&D projects of Zhejiang Province 16053507 true Feasibility of home urine collection for lung health check (P4-LHC) P4-LHC The main objective of P4-LHC is to explore the feasibility of a home-collection urine kit to improve engagement in Targeted Lung Health Checks. Secondary objectives: 1. To assess if those who failed to respond to the original Lung Health Check invitations re-engage when provided with a urine collection kit; to help design a larger study to assess the utility of GAGome biomarkers to identify high-risk individuals for cancer screening. 2. To assess if any of those who were identified as low-risk for lung cancer as part of the Lung Health Check are instead considered high-risk using the GAGome test; to help decide how best to design a larger study comparing the two different risk assessments. 3. To assess if any of those who were identified as high-risk for lung cancer as part of the Lung Health Check are also considered high-risk using the GAGome test; to help decide how best to design a larger study to determine if the GAGome test might help identify those most at risk, potentially speeding up lung cancer diagnosis for those currently requiring a follow-up low-dose CT scan. 4. To provide data that will allow statisticians to model how the urine GAGome test might be best deployed to have a significant impact on the speed of cancer diagnosis and, hence, improved outcomes. Background and study aims Early detection of lung cancer (e.g., using low-dose CT screening, as in the NHS Targeted Lung Health Check [TLHC]) saves lives. However, this is currently only used for those considered high risk based on questionnaire-based risk scores dominated by age and smoking. Also, the thought of having to have a scan can be off-putting. An independent measure of cancer risk can be provided by molecules (glycosaminoglycans [GAGs]) found in urine; these can be provided as home-use kits (where people send a urine sample by post) and may also identify high-risk people who have not smoked as much (currently not offered a low-dose CT scan). This is a feasibility study run by the University of Liverpool to determine if those who are currently invited for the NHS TLHC (aged 55 to 74 years with any history of smoking) will provide home urine samples, whether or not they have responded to their TLHC invite, and (if they responded) whether they are either high- or low-risk by current risk scores. The data generated by this feasibility study will be used to design larger studies of a suitable size to determine if the GAG biomarkers will aid early cancer detection, improve on current cancer risk scores, and ultimately help save lives. Who can participate? People who are currently invited for the NHS TLHC (aged 55 to 74 years with any history of smoking) What does the study involve? Invites will be sent by Liverpool University Biobank, who will also receive the urine samples up to February 2026. Those who have not, so far, accepted their TLHC invite will be encouraged to do so, and it is hoped that this novel approach for home sample collection will inspire them to engage. Part of each sample will be sent to a Swedish company (Elypta AB) that is funding the study and will measure the GAG biomarkers. What are the possible benefits and risks of participating? Participants who engage with the lung cancer screening program may benefit. Participants will not get their results (as the tests have not been fully validated yet), and they will not be used to change treatment (participants will continue with their usual care). As an observational study, there is no significant risk to participants. Where is the study run from? The University of Liverpool (UK) When is the study starting and how long is it expected to run for? August 2025 to October 2026 Who is funding the study? Elypta AB (Sweden) Who is the main contact? Prof. John Field, j.k.field@liverpool.ac.uk Re-engagement in the NHS Lung Cancer Screening Programme updated recruitment data to Lung Cancer Screening (LCS) 6 months from initial recruitment invite GAGome biomarker quantitative high-performance liquid chromatography (HPLC) following end of recruitment Ethics approval required North West - Greater Manchester East Research Ethics Committee

3rd Floor, Barlow House 4 Minshull Street

Manchester United Kingdom M1 3DZ 24/NW/0283 10.1186/ISRCTN16053507 344969 344969 Observational Cohort study 2026-10-01T00:00:00.000Z United Kingdom England Liverpool Heart and Chest Hospital NHS Foundation Trust

Thomas Drive

Liverpool England L14 3PE RBQ@2.16.840.1.113883.2.1.3.2.4.18.48 true Prior invitation to the Cheshire and Merseyside NHS Lung Cancer Screening Programme (at the time called Targeted Lung Health Check [TLHC]) as identified by Liverpool Heart and Chest Hospital Mixed 55 Years 75 Years All 1000 231 1. Not included in the NHS Targeted Lung Health Check recruitment or opted out of NHS data sharing 2. Unable to provide consent 2025-08-15T00:00:00.000Z 2026-02-27T00:00:00.000Z Lung cancer Cancer NHS staff in the TLHC at Liverpool Heart and Chest Hospital will identify 1000 subjects for the University of Liverpool to approach for the study. The chosen subjects represent three major groups for which important questions remain: 1. TLHC non-responders: 500 randomly selected from those who have not yet responded to the TLHC invite (two letters and a phone call); with unknown risk (unless they subsequently engage with TLHC, as is hoped). 2. TLHC low-risk responders: 250 randomly selected from those who are low risk for lung cancer according to TLHC risk scores (and therefore not currently invited for an LDCT scan). 3. TLHC high-risk responders: 250 randomly selected from those who are high risk for lung cancer and are offered a TLHC low-dose CT scan. Liverpool University Biobank will securely receive the personal details (name, address and Liverpool Heart and Chest Hospital [LHCH] subject ID); store them in a secure database; create their own Liverpool University Biobank (LUB) Subject ID; and produce a personalised package for each subject approached consisting of: 1. An introductory leaflet (one page) with invite letter on the back (specific to the subject group) 2. A participant information sheet (two pages) 3. A Colli-Pee urine home collection kit (CE-marked kit including how-to-use instructions, a funnel device and a storage tube with lid) 4. A pre-addressed, pre-paid postage kit (to return the urine sample and the consent form) Access to information and further help will be available online (via QR codes providing access to Immersive Reader-enabled webpages or translation for those with English as a second language) or provided by telephone. Having read the provided information, P4-LHC participants will complete the consent form, provide a urine sample with the easy-to-use kit, and return both in the envelope provided. On receipt of the urine samples, the Liverpool University Biobank (LUB) will update its database to record consent and sample receipt and produce sample ID numbers for each subject. Two tubes will be stored in the LUB freezers (at -80°C) prior to shipment to Elypta AB labs. The three remaining tubes will be stored in LUB freezers (at -80°C). Additional data will be supplied by NHS TLHC staff to LUB (and shared anonymously with study researchers), for the 1000 subjects approached and for the population from which those 1000 subjects have been selected (representing those eligible for TLHC in a specific geographical catchment). The data would include age, sex, IMD decile, whether they responded to the TLHC, whether they were high or low risk for lung cancer (with % risk score from LLPv2 and PLCOm2012), whether they received a TLHC low-dose CT scan, and whether they were diagnosed with lung cancer by the TLHC. The urine samples received by Elypta AB (the Swedish company that developed the GAGome test) will be analysed for the glycosaminoglycans that make up the GAGome score. The anonymous data will be jointly analysed by the University and Elypta researchers. In this feasibility study the GAGome scores are not shared with the participants. Other Not expected to be made available b1c3aeeb-8e2f-4c45-a124-4c74e38d3763 d16ac6d8-8263-4742-bdc3-df6a8d9004f7 04b454e7-5860-4724-a1bb-842309d40773 9c079fd9-6339-47af-a7e9-96382aa26490 No John Field https://orcid.org/0000-0003-3951-6365 Principal investigator Scientific

The University of Liverpool Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular & Integrative Biology, The William Duncan Building, 6 West Derby Street

Liverpool United Kingdom L7 8TX +44 (0)151 794 9001 j.k.field@liverpool.ac.uk Public Michael Davies Public

The University of Liverpool Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular & Integrative Biology, The William Duncan Building, 6 West Derby Street

Liverpool United Kingdom L7 8TX +44 (0)151 794 9105 michael.davies@liverpool.ac.uk Public University of Liverpool https://ror.org/04xs57h96 Non-commercial Elypta AB Sweden 62918594 true A Cancer Research UK Phase I/IIa open-label, dose escalation and expansion trial of HMBD-001 (an anti-HER3 monoclonal antibody) given intravenously as a single agent and in combination in patients with advanced HER3-positive solid tumours Primary Objectives: 1. To propose a recommended dose and schedule for Phase II evaluation (RP2D) of HMBD-001 as a single agent 2. To establish the maximum tolerated dose or maximum administered dose of HMBD 001 in patients with advanced HER3 positive solid tumours 3. To assess the safety and tolerability profile of HMBD-001 in patients with advanced HER3 positive solid tumours 4. To establish a recommended dose and schedule of HMBD-001 to be given with the selected combination agent(s) 5. To assess the safety and tolerability profile of HMBD-001 in combination with selected agent(s) in the chosen expansion tumour types 6. To evaluate preliminary evidence of anti-tumour activity of HMBD-001 in combination in the chosen expansion tumour types Secondary Objectives: 1. To evaluate the preliminary anti-tumour activity of HMBD-001 when given as a single agent 2. To characterise the pharmacokinetic (PK) profile or determine limited PK parameters of HMBD-001 when given as a single agent and in combination 3. To evaluate the preliminary anti-tumour activity of HMBD-001 when given as a single agent and in combination 4. To determine progression free survival and overall survival in the selected tumour types Background and study aims This clinical trial is evaluating a drug called HMBD-001, a type of targeted cancer drug called a monoclonal antibody. It works by finding a protein on cancer cells called HER3, which is found in high numbers in some types of cancers including those that contain fusions in a gene called NRG1. By attaching itself to this HER3, it may then work to kill the cancer cells or to stop them from growing. The main aims are to find out the best dose of HMBD-001 that can be given to patients alone and in combination with other anti-cancer agents, more about the potential side effects of HMBD-001 and how they can be treated, and what happens to HMBD-001 inside the body and how it affects cancer cells. Part A is a ‘dose escalation’ phase where small groups of patients will receive increasing doses of HMBD-001 on its own (as a single agent) to find the safest dose that best targets cancer cells. Part B is a ‘dose expansion’ phase where larger groups of patients with specific cancer types that are known to have high levels of the protein HER3 or that have a confirmed NRG1 gene fusion will receive the highest doses of HMBD-001 considered to be safe as monotherapy from Part A in combination with other anti-cancer drugs that are already licensed for use. In Part B Arm 1, patients will receive HMBD-001 in combination with enzalutamide. Enzalutamide is a drug used to treat prostate cancer. Prostate cancer is known to be sensitive to androgens (hormones associated with male characteristics), and enzalutamide blocks the action of androgens by limiting the binding of androgens to androgen receptors. This slows the growth of prostate cancer cells and may kill them. Who can participate? Part A: Patients aged 16 years and over with advanced solid tumours or with a NRG1 fusion rearrangement or HER amplification. Part B: Patients aged 18 years and over with metastatic castration-resistant prostate cancer (mCRPC) confirmed as HER3 positive with no PTEN loss or with a NRG1 fusion rearrangement. What does the study involve? There are two parts to this trial, a dose escalation part and a dose expansion part. In the dose escalation part of the trial, the first few patients joining have a low dose of HMBD-001. If they don’t have any serious side effects, the next few patients have a higher dose. This process continues until the doctors find the best dose to give to patients to target cancer cells. In the dose expansion part, patients with mCRPC will receive the highest dose of HMBD-001 considered to be safe found in Part A as well as enzalutamide. Blood samples will be taken to find out what happens to HMBD-001 in the body and to check how HMBD-001 is working. What are the possible benefits and risks of participating? This is the first time that HMBD-001 is being used in humans. The possible direct benefit is that study drug may help treat the patient's cancer, although the chances of this are unknown. The trial may reveal information which may help improve the treatment for patients with cancer in the future. The information we have on potential side effects is based on laboratory tests and experience with similar drugs which have been given to patients. Possible side effects include: • feeling or being sick • diarrhoea • changes to your heartbeat • changes to the levels of magnesium or potassium in your blood • a drop in red blood cells causing tiredness and breathlessness • liver changes • skin rash • tiredness (fatigue) • fertility problems Where is the study run from? Cancer Research UK When is the study starting and how long is it expected to run for? The trial started recruiting in November 2021 and completed in September 2025. Who is funding the study? Cancer Research UK Who is the main contact? Cancer Research UK Centre for Drug Development; drugdev@cancer.org.uk https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-hmbd-001-for-solid-cancers-that-have-spread 1. Number of patients who experienced Dose Limiting Toxicities (DLTs) (Part A) DLTs graded for severity using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0, measured by count of patients per arm. [Time Frame: From first dose onwards until completion of Cycle 1 (28 days)] 2. Number of patients who experienced DLTs (Part B Arm 1) DLTs graded for severity using the NCI CTCAE v5.0, measured by count of patients per arm. [Time Frame: From first dose of combination therapy onwards until completion of Cycle 1 (28 days)] 3. Number of adverse events (AEs) by arm considered to be at least possibly related to HMBD-001 (Part A and Part B Arm 1) Number of AEs related to HMBD-001 given as a single agent and in combination with enzalutamide, graded according to NCI CTCAE v5.0. [Time Frame: From the date of written informed consent until the end of the safety follow-up period (maximum [max] 42 weeks per patient)] 4. Number of Grade 3, 4 and 5 AEs by arm considered to be at least possibly related to HMBD-001 (Part A and Part B Arm 1) Number of Grade 3, 4 and 5 AEs related to HMBD-001 given as a single agent and in combination with enzalutamide, graded according to NCI CTCAE v5.0. [Time Frame: From the date of written informed consent until the end of the safety follow-up period (max 42 weeks per patient)] 5. Overall response rate (ORR) within six cycles of HMBD-001 (Part B Arm 1) Proportion of patients who achieve a best response of complete response (CR) or partial response (PR), based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 and/or Prostate Cancer Working Group 3 (PCWG3) Criteria as applicable, within six cycles of HMBD-001 in combination with enzalutamide. [Time Frame: From baseline radiological disease assessment until 28 days after last dose of HMBD-001 (max 36 weeks per patient)] 1. ORR within six cycles of HMBD-001 (Part A) Proportion of patients who achieve a best response of CR or PR, based on RECIST v1.1 and/or PCWG3 Criteria as applicable, within six cycles of HMBD-001 monotherapy. [Time Frame: From baseline radiological disease assessment until 28 days after last dose of HMBD-001 (max 32 weeks per patient)] 2. Maximum observed serum concentration (Cmax) of HMBD-001 (Part A and Part B Arm 1) Cmax of HMBD-001 in serum, analysed via enzyme linked immunosorbent assay (ELISA). Not all patients will be analysed at all timepoints. [Time Frame: Up to 31 timepoints from first dose until 28 days after the last dose of HMBD-001 (max 28 weeks per patient)] 3. Minimum observed serum concentration (Cmin) of HMBD-001 (Part A and Part B Arm 1) Cmin of HMBD-001 in serum, analysed via ELISA. Not all patients will be analysed at all timepoints. [Time Frame: Up to 31 timepoints from first dose until 28 days after the last dose of HMBD-001 (max 28 weeks per patient)] 4. Area under the serum concentration-time curve (AUC) of HMBD-001 (Part A and Part B Arm 1) AUC of HMBD-001, analysed via ELISA. Not all patients will be analysed at all timepoints. [Time Frame: Up to 31 timepoints from first dose until 28 days after the last dose of HMBD-001 (max 28 weeks per patient)] 5. Terminal elimination half-life (t½) of HMBD-001 (Part A and Part B Arm 1) t½ of HMBD-001 in serum, analysed via ELISA. Not all patients will be analysed at all timepoints. [Time Frame: Up to 31 timepoints from first dose until 28 days after the last dose of HMBD-001 (max 28 weeks per patient)] 6. Steady state volume of distribution of HMBD-001 in serum (Part A and Part B Arm 1) Volume of distribution of HMBD-001 in serum at steady state, analysed via ELISA. Not all patients will be analysed at all timepoints. [Time Frame: Up to 31 timepoints from first dose until 28 days after the last dose of HMBD-001 (max 28 weeks per patient)] 7. Total body clearance of HMBD-001 (Part A and Part B Arm 1) Total body clearance of HMBD-001 measured in serum, analysed via ELISA. Not all patients will be analysed at all timepoints. [Time Frame: Up to 31 timepoints from first dose until 28 days after the last dose of HMBD-001 (max 28 weeks per patient)] 8. ORR within 8 and 16 weeks of commencing HMBD-001 (Part A and Part B Arm 1) Proportion of patients achieving a best response of CR or PR, according to RECIST v1.1 and/or PCWG3 Criteria as applicable, within 8 and 16 weeks of commencing HMBD-001 as monotherapy and in combination with enzalutamide. [Time Frame: From baseline radiological disease assessment up to 16 weeks post first HMBD-001 administration (max 24 weeks per patient)] 9. Disease control rate within six cycles of HMBD-001 (Part A and Part B Arm 1) Proportion of patients achieving a best response of CR, PR or stable disease (SD), based on RECIST v1.1 and/or PCWG3 Criteria as applicable, within six cycles of HMBD-001 as monotherapy and in combination with enzalutamide. [Time Frame: From baseline radiological disease assessment up to 28 days post last HMBD-001 administration (max 36 weeks per patient)] 10. Duration of response (Part A and Part B Arm 1) The median duration in days from the first observation of a CR or PR, according to RECIST v1.1 and/or PCWG3 Criteria as applicable, until either progressive disease (PD) or death from any cause, in patients with a confirmed CR or PR. [Time Frame: From the date of first recorded response until 24 months after the last enrolled patient's first dose of HMBD-001 (max 48 months per patient)] 11. Duration of clinical benefit (Part A and Part B Arm 1) The median duration in days from the first administration of HMBD-001 until either PD or death from any cause, in patients who achieve a CR, PR, or SD for at least 24 weeks, according to RECIST v1.1 and/or PCWG3 Criteria as applicable. [Time Frame: From the date of first recorded response until 24 months after the last enrolled patient's first dose of HMBD-001(max 48 months per patient)] 12. Progression free survival (Part B Arm 1) The median duration in days from first dose of HMBD-001 to death from any cause or PD according to RECIST v1.1 and/or PCWG3 Criteria as applicable. [Time Frame: From first dose of HMBD-001 until 24 months after the last enrolled patient's first dose of HMBD-001 (max 48 months per patient)] 13. Overall survival (Part B Arm 1) The median time from first dose of HMBD-001 to death from any cause. [Time Frame: From first dose of HMBD-001 until 24 months after the last enrolled patient's first dose of HMBD-001 (max 48 months per patient)] Ethics approval required London Surrey Borders Research Ethics Committee

Skipton House, 80 London Road

London United Kingdom SE1 6LH 21/LO/0477 10.1186/ISRCTN62918594 2020-005891-36 298897 NCT05057013 CPMS: 49816, CRUKD/22/002 NCT05057013 2020-005891-36 298897 49816 CRUKD/22/002 Interventional Non-randomized controlled trial Open (masking not used) Active Parallel Treatment Not applicable Treatment 2025-09-10T00:00:00.000Z United Kingdom England Royal Marsden NHS Foundation Trust

-

London England SM2 5PT Churchill Hospital

-

Oxford England OX3 7LE Freeman Hospital

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Newcastle England NE7 7DN The Christie NHS Foundation Trust

-

Manchester England M20 4BX Patient false 1. Written (signed and dated) informed consent and be capable of co-operating with HMBD-001 administration and follow-up. 2. Part A: Monotherapy Dose Escalation Histologically confirmed advanced or metastatic solid tumours resistant or refractory to conventional treatment, or for which no conventional therapy exists or is not considered appropriate by the Investigator or is declined by the patient. Patients with tumour types known to overexpress HER3 including: • Bladder cancer • Triple negative breast cancer • Castration-resistant prostate cancer • Cervical cancer • RAS wild type colorectal cancer • Endometrial cancer • Gastric cancer • Hepatocellular carcinoma • Melanoma • Non-small cell lung cancer • Oesophageal cancer • Ovarian cancer • Pancreatic cancer • Squamous cell cancers of the head and neck Patients with a confirmed existing NRG1 fusion rearrangement or HER amplification will also be considered eligible. Part B Arm 1: HMBD-001 and Enzalutamide Combination • Histologically confirmed metastatic castration-resistant prostate adenocarcinoma without neuroendocrine differentiation or small-cell features • Serum testosterone concentration ≤50 ng/dL sustained by medical or surgical castration • Patients must have progressive disease prior to study enrolment. • PSA at screening >1 ng/mL • Confirmed high HER3 expression • Absence of PTEN loss • Patients with confirmed existing NRG1 fusion rearrangement will also be considered eligible. 3. Life expectancy of at least 12 weeks. 4. Eastern Cooperative Oncology Group performance status of 0 or 1. 5. Haematological and biochemical indices within the protocol specified ranges. 6. Patients with advanced prostate cancer must have castrate levels of testosterone and have received a next generation hormonal agent (at least one of abiraterone, enzalutamide, apalutamide or darolutamide). 7. Part A: Aged 16 years or over at the time consent is given. 8. Part B Arm 1: Aged 18 years or over at the time consent is given. Mixed 16 Years 110 Years All 81 25 1. Radiotherapy (except for palliative reasons), chemotherapy, endocrine therapy (with the exceptions of life-long hormone suppression such as luteinising hormone-releasing hormone [LHRH] agents in prostate cancer and patients that are being re-screened for the trial who are continuing to receive enzalutamide, having previously responded to enzalutamide during Cycle 0), immunotherapy or investigational medicinal products (IMPs) during the previous 4 weeks before first dose of IMP. 2. Patients with ongoing toxic manifestations of previous treatments greater than NCI CTCAE Grade 1. Exceptions apply. 3. Patients with symptomatic brain or leptomeningeal metastases should be excluded. Exceptions apply. 4. Women of child-bearing potential (or are already pregnant or lactating). Exceptions apply. 5. Male patients with partners of child-bearing potential. Exceptions apply. 6. Major surgery from which the patient has not yet recovered. 7. At high medical risk because of non-malignant systemic disease including active uncontrolled infection. 8. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus infection. Patients with previous hepatitis C exposure but no current infection are eligible to participate. 9. Known or suspected hypersensitivity reaction to previous biological therapy that in the opinion of the Investigator is a contraindication for their participation in this study. 10. Concurrent congestive heart failure, prior history of ≥ Class II cardiac disease (New York Heart Association), clinically significant cardiac ischaemia or clinically significant cardiac arrhythmia. Patients with significant cardiovascular disease as defined in the protocol are excluded. 11. Active autoimmune disease. Exceptions apply. 12. Patients receiving doses of prednisolone 10 mg daily (or equipotent doses of other corticosteroids) within 7 days prior to the first dose of study drug are not eligible unless administered as pre-medication. 13. Patients having received a live vaccination within 4 weeks prior to first dose of HMBD-001. 14. Is a patient or plans to participate in another interventional clinical trial, whilst taking part in this Phase 1/2a trial of HMBD-001. Participation in an observational trial or interventional clinical trial which does not involve administration of an IMP and which would not place an unacceptable burden on the patient in the opinion of the Investigator and Medical Advisor would be acceptable. 15. Any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial. 16. Current or prior malignancy which could affect safety or efficacy assessment of the IMP or compliance with the protocol or interpretation of results. Patientts with curatively-treated non-melanoma skin cancer, non-muscle-invasive bladder cancer, or carcinomas-in-situ are generally eligible. Part B Arm 1: HMBD-001 and Enzalutamide Combination. 17. Patients receiving warfarin or coumarin-like anti-coagulants. 18. History of seizures or other risk factors for the development of seizures e.g. prior history of stroke, brain injury, brain metastases, leptomeningeal disease. 19. Patients with hypersensitivity to enzalutamide or any of the excipients. 20. Patients who have received prior enzalutamide or other next generation hormonal agent that has been stopped due to toxicities or intolerance or required a dose reduction during administration due to toxicity or intolerance. 2021-10-07T00:00:00.000Z 2024-08-19T00:00:00.000Z Bladder Cancer Triple Negative Breast Cancer Castration-resistant Prostate Cancer (metastatic) Cervical Cancer RAS Wild Type Colorectal Cancer Endometrial Cancer Gastric Cancer Hepatocellular Carcinoma Melanoma Non-small Cell Lung Cancer Oesophageal Cancer Ovarian Cancer Pancreatic Cancer Squamous Cell Cancers of the Head and Neck Cancer This is an open label, multi-centre, first in human, Phase I/IIa adaptive design trial with initial single patient intrapatient dose escalation followed by inter-patient dose escalation to determine the recommended Phase II dose (RP2D) of HMBD-001 as a single agent. The clinical trial's two parts consist of: Part A (the dose escalation phase), and Part B (the dose expansion phase). In Part A, patients with advanced solid tumours will receive HMBD-001 diluted in 0.9% sodium chloride, administered once a week as a 120-minute intravenous (IV) infusion. The starting dose will be 150 mg. Each cycle of HMBD-001 will consist of 28 days with no break in between and patients may continue for up to six cycles. If the patient is showing benefit, they may continue beyond six cycles. In Part B, patients with metastatic castration-resistant prostate cancer (mCRPC) confirmed as HER3 positive with no PTEN loss or with a NRG1 fusion rearrangement will receive the HMBD-001 recommended Phase 2 dose (RP2D) as determined in Part A, diluted in 0.9% sodium chloride and administered once a week as a 120-minute IV infusion, in combination with enzalutamide administered at a fixed dose of 160 mg once daily, in 28-day cycles with no break between cycles. Prior to commencing combination therapy, patients may receive one 28-day cycle of enzalutamide monotherapy to confirm that their disease does not respond to enzalutamide alone. HMBD-001 may be administered for up to six cycles; enzalutamide may be continued until disease progression or unacceptable toxicity. Drug Phase I/II HMBD-001 Data from this trial and the final clinical study protocol will be submitted to a public registry and will be available immediately following publication, with no end date. Individual deidentified patient data that underlie the results reported will be shared with researchers whose proposed use of the data is approved by a review committee of the Sponsor. All requests made within 5 years from the end of trial will be considered; requests made subsequently will be considered where possible. Requests should be submitted to drugdev@cancer.org.uk. Available on request Results Basic results see attached file ISRCTN62918594_BasicResults_12Aug2026.pdf (added 01/09/2026)

ffeef156-c094-4c52-a8d3-a22c2a7ade0a 41c66c04-3ce0-4eb9-add8-090592ec2947 c2dd8cf0-1b7d-4a86-b847-05da1ec5bc13 0b1c5226-42c9-4d52-9638-c082bb04aef5 69a1ab93-7d0c-4f79-ae62-790c46e4948b Yes Basic results ISRCTN62918594_BasicResults_12Aug2026.pdf 05eff96a-5483-44b1-9990-40e0b9b13da8 true application/pdf 430405 2fa71efacf1cb0b504b2f9eec11f6715 Protocol file ISRCTN62918594_Protocol_V7.0_04Aug2026.pdf e412df5f-718c-441e-b2cf-ddd290769329 true application/pdf 4520080 ab7c0821c9e7cd0382d06b402724ae29 Johann De Bono Principal investigator

Royal Marsden NHS Foundation Trust

Surrey United Kingdom SM2 5PT +44 0208 722 4029 Johann.DeBono@icr.ac.uk Public Derrick Spencer-Briggs Scientific

2 Redman Place

London United Kingdom E20 1JQ +44 030 0123 1022 drugdev@cancer.org.uk Public Lesley McGuigan Public

2 Redman Place

London United Kingdom E20 IJQ +44 030 0123 1022 drugdev@cancer.org.uk Public Cancer Research UK Charity https://ror.org/054225q67 Non-commercial Cancer Research UK 18632261 true CanBenefit 3: Implementation of tailored wellbeing advice as standard care among people diagnosed with lung cancer CanBenefit 3 Primary objectives: 1. To assess the proportion of eligible patients receiving a referral, and the proportion accepting referral within the evaluation period 2. To assess levels of engagement with the programme via the Rehab Guru platform and/or number of workout sessions completed 3. To assess the safety of the programme through patient-reported symptoms and recording of adverse events in routine clinical and cancer rehabilitation service documentation during the 6-month programme period 4. To assess the acceptability of the programme and referral pathway among patients and staff, using qualitative process evaluation interviews and service user feedback surveys 5. To assess the ability to obtain routinely collected data for analysis and data quality at baseline, 3, 6 and 12 months via routine NHS medical records and cancer rehabilitation service documentation Secondary objectives: To describe changes in patient health status from baseline to 6 months in order to determine the potential impact of a cancer rehabilitation service on changes in the following: 1. Clinical outcomes (cancer treatment completion rates) 2. Physical function (cardiovascular endurance, muscular strength and endurance) 3. Service user patient-reported outcomes (cancer-specific quality of life, breathlessness scores) 4. Physical activity, nutrition, and sleep behaviours via service user feedback surveys Background and study aims Lung cancer can affect physical fitness, quality of life, and the ability to complete cancer treatment. Although rehabilitation and wellbeing support may help people manage the effects of cancer and its treatment, access to these services is often limited. CanBenefit 3 aims to evaluate whether a personalised cancer rehabilitation service can be successfully integrated into routine NHS lung cancer care. The study will assess referral rates, patient engagement, acceptability, and the feasibility of collecting routine outcome data, while also exploring potential effects on physical function, wellbeing, and cancer treatment outcomes. Who can participate? Patients aged 18 years and over diagnosed with lung cancer who are eligible for referral to the cancer rehabilitation service at participating NHS Trusts. Eligibility will be determined by the clinical team according to the study protocol and local service criteria. What does the study involve? Clinicians will identify eligible patients during routine care and refer them to an exercise physiologist. Patients who choose to attend will receive an initial assessment and a personalised exercise and wellbeing programme delivered primarily through the Rehab Guru platform, with paper-based options available if preferred. Follow-up appointments will take place at about 3 and 6 months. Routine clinical and patient-reported outcome data will be collected at these appointments and from medical records up to 12 months after referral. Some patients and staff may also be invited to take part in a one-off interview to share their experiences of the service. What are the possible benefits and risks of participating? Participants may benefit from receiving personalised exercise and wellbeing support tailored to their needs. The information collected may help improve rehabilitation services for people with lung cancer in the future. The risks are expected to be low and are similar to those associated with routine rehabilitation services, such as temporary muscle soreness, fatigue, breathlessness, or minor exercise-related injury. Programmes are tailored to individual needs and monitored by trained professionals to minimise risks. Where is the study run from? The study is coordinated by researchers at Hull York Medical School, University of Hull, and supported by the Hull Health Trials Unit. It is delivered through participating NHS Trusts across Yorkshire, England. When is the study starting and how long is it expected to run for? October 2026 to September 2028 Who is funding the study? Yorkshire Cancer Research (YCR) (UK) Who is the main contact? Dr Cynthia Forbes, Cindy.Forbes@hyms.ac.uk Plain English summary under review with external organisation 1. Referral uptake: Proportion of eligible patients referred to and accepting referral to the cancer rehabilitation service, measured using service referral and attendance records during the 12-month study period. 2. Programme engagement: Engagement with the rehabilitation programme, measured using Rehab Guru log-ins, exercise completion records and appointment attendance over 6 months. 3. Acceptability and feasibility: Acceptability, safety and feasibility of the rehabilitation service, measured using qualitative interviews, service user feedback surveys, clinical records and implementation data throughout the study period. 1. Cancer treatment outcomes: treatment completion and delivery measured from medical records from baseline to 12 months. 2. Physical function measured using handgrip strength, standing balance, timed up and go (TUG), 30-second sit-to-stand (SPPB), bioelectrical impedance analysis (BIA) and the Australian Karnofsky Performance Scale (AKPS) at baseline, 3 months and 6 months. 3. Quality of life and nutritional status measured using EQ-5D-5L, EQ-VAS and Patient-Generated Subjective Global Assessment (PG-SGA) at baseline, 3 months and 6 months 4. Physical activity measured using the Short Questionnaire to Assess Health Enhancing Physical Activity (SQUASH), measured at baseline, 3 months and 6 months 5. Capability, opportunity and motivation for physical activity, measured using three COM-B/TDF-informed items at baseline, 3 months and 6 months 6. Sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI) at baseline, 3 months and 6 months 7. Healthcare utilisation measured using healthcare contacts recorded in medical records from baseline to 12 months 8. Survival measured using date and cause of death recorded in clinical records from baseline to 12 months Ethics approval required

10.1186/ISRCTN18632261 367879 CPMS: 74811, RA/2024/R2/117 367879 74811 RA/2024/R2/117 Non-randomized study Interventional Non randomised study Treatment 2028-09-30T00:00:00.000Z United Kingdom England 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 York and Scarborough Teaching Hospitals NHS Foundation Trust

York Hospital Wigginton Road

York England YO31 8HE RCB@2.16.840.1.113883.2.1.3.2.4.18.48 false 1. Adults aged 18 years or older 2. Lung cancer, any stage, any type 3. Receiving any combination of chemotherapy, radiotherapy, and targeted therapy alongside surgery (if applicable) 4.Patients being treated curatively, palliatively, or with best supportive care Mixed 18 Years 100 Years All 300 0 Any condition or circumstance which, in the opinion of the clinician, would make referral to the service inappropriate. This includes: 1. An unstable or acute medical condition (for example severe uncontrolled symptoms, unresolved pulmonary embolism, or decompensated heart failure), as determined by the participating clinical team 2. An underlying severe chronic condition or disease where systemic anti-cancer treatment is not considered appropriate by the treating oncologist 2026-10-01T00:00:00.000Z 2027-09-30T00:00:00.000Z Lung cancer Cancer This is a multi-centre feasibility study taking place in two NHS Trusts across Yorkshire. It aims to deliver a tailored cancer rehabilitation service embedded within existing NHS cancer services. The study will explore whether this service can be delivered and how it may influence outcomes and quality of life for people with lung cancer. Patients will be identified by their direct clinical team at any stage after diagnosis and referred to an NHS Trust exercise physiologist (EP). The EP will send referral letters to consecutively referred patients, with approximately 300 patients referred over the study period. If the referral is accepted, patients will attend appointments with the EP at baseline, 3 months and 6 months. At these appointments, a personalised home-based exercise programme will be created and adapted based on their needs using a secure online platform (Rehab Guru). At each appointment, information will be collected as part of routine care. This includes details about cancer diagnosis and treatment, body measurements (such as height, weight and BMI), physical function (such as strength and mobility), and questionnaires on quality of life, sleep, lifestyle, and wellbeing. Patients may also complete short symptom rating scales (for example, pain, fatigue, breathlessness, and mood). 12-month outcome data will be recorded within NHS Trust systems and the Rehab Guru platform as part of routine care. At the end of the study, a pseudonymised dataset will be securely transferred to the University of Hull Data Safe Haven for analysis, with fully anonymised datasets derived for reporting where appropriate. Patients will take part in the programme as part of routine NHS care. The study will use pseudonymised data collected through this service to understand how well it works in practice. Some patients (including those who accept or decline the service) and healthcare professionals may be invited to take part in a one-off interview to share their experiences. Those who take part in interviews will be given a Participant Information Sheet and asked to provide informed consent. Behavioural The datasets generated and/or analysed during the current study will be available upon reasonable request from the chief investigator (Dr Cynthia Forbes; Cindy.Forbes@hyms.ac.uk). Requests will be considered on a case-by-case basis and must be consistent with the study objectives and relevant ethical approvals. Only fully anonymised data will be shared. Data will become available following publication of the main study results and will be retained for a minimum of five years after study completion. Access will be subject to applicable legal, ethical and governance requirements, including data protection legislation and institutional policies. Available on request 17ea30af-03c6-4d34-92f9-43d5f318db09 742dc53a-c661-4b5d-b1f5-34c9f0db519e e9813087-c99b-45fc-9579-8ef06a8cfbee 34376f49-e106-4970-a6ad-de8f3f92eb98 Yes Buse Apel https://orcid.org/0000-0002-4191-6782 Scientific Public

Hull York Medical School 3rd floor, Allam Medical Building University of Hull

Hull United Kingdom HU6 7RX +44 (0)1482463505 buse.apel@hyms.ac.uk Public Cynthia Forbes https://orcid.org/0000-0002-3259-1832 Principal investigator

Hull York Medical School 3rd floor, Allam Medical Building University of Hull

Hull United Kingdom HU6 7RX +44 (0)1482 463741 Cindy.Forbes@hyms.ac.uk Public University of Hull Hospital/treatment centre https://ror.org/04nkhwh30 Non-commercial Yorkshire Cancer Research http://dx.doi.org/10.13039/100011703 52550559 true Expression of CUG2, βIGH3 (TGFBI), and TGF-β in bronchoscopic biopsy specimens of lung cancer patients: predictive value for metastasis and differential diagnosis from other thoracic malignancies — a pilot study 1. To evaluate the diagnostic accuracy of CUG2, βIGH3 (TGFBI), and TGF-β gene expression in bronchoscopic biopsy specimens for predicting metastatic status at the time of lung cancer diagnosis (primary objective). 2. To assess the utility of CUG2, βIGH3 (TGFBI), and TGF-β expression for differential diagnosis of primary lung cancer from other thoracic malignancies. 3. To examine correlations between biomarker expression levels and clinical variables including age, smoking history, PET/CT stage, and overall survival. 4. To evaluate the prognostic significance of biomarker expression for overall survival using Kaplan-Meier and Cox regression analyses. 5. To compare biomarker expression across histopathological subtypes (squamous cell carcinoma, adenocarcinoma, and small cell lung cancer). Background and study aims Lung cancer is one of the most common and deadly cancers worldwide. When patients are first diagnosed, doctors need to know whether the cancer has spread (metastasized) to other parts of the body, and whether the tumor in the chest is a primary lung cancer or a cancer that has spread from elsewhere. This information is critical for choosing the right treatment. This study investigates whether three proteins — CUG2, βIGH3 (also called TGFBI), and TGF-β — measured in tissue samples taken during a bronchoscopy (a routine procedure where a thin flexible tube is passed into the airways to take small tissue samples) can help answer these questions. Who can participate? Adults aged 18 years or older who are undergoing diagnostic bronchoscopy for suspected lung cancer or suspected spread of another cancer to the chest. Patients must have a confirmed tissue diagnosis and adequate biopsy sample quality for laboratory analysis. What does the study involve? Participants undergo routine diagnostic bronchoscopy as part of their standard clinical care. A small additional portion of the biopsy sample obtained during this procedure is used for laboratory analysis. Gene expression levels of three biomarkers (CUG2, βIGH3/TGFBI, and TGF-β) are measured using a technique called quantitative PCR (qPCR). No additional procedures, medications, or interventions are administered. Cancer spread (metastatic status) is determined by PET/CT scan as part of routine staging. What are the possible benefits and risks of participating? There are no direct benefits or risks to participants from this study. The biopsy is performed as part of standard diagnostic care. The biomarker measurements are performed on existing tissue samples and do not require any additional procedures. Results are not used to guide individual patient treatment in this study. Where is the study run from? Süleyman Demirel University Faculty of Medicine, Department of Pulmonology, Turkey. When is the study starting and how long is it expected to run for? January 2019 to June 2022 Who is funding the study? Süleyman Demirel University Scientific Research Projects Coordination Unit, Turkey. Who is the main contact? Dr. Önder Öztürk, Süleyman Demirel University Faculty of Medicine, Department of Pulmonology, Turkey, dronderozturk@gmail.com Diagnostic accuracy of CUG2 expression for predicting metastatic status at diagnosis area under the receiver operating characteristic curve with 95% confidence interval derived by bootstrap resampling (2000 iterations), with optimal cut‑off determined by Youden Index and corresponding sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy reported a single time point at diagnostic fiberoptic bronchoscopy between January 2018 and January 2022 Diagnostic accuracy and cut-off validation for biomarkers ROC curve analysis: AUC with 95% CI by bootstrap resampling (2000 iterations); optimal cut-off by Youden Index; sensitivity, specificity, PPV, NPV at optimal cut-off. Mann-Whitney U test for between-group comparison; rank-biserial correlation for effect size; and, ROC curve analysis: AUC with 95% CI by bootstrap resampling (2000 iterations); sensitivity, specificity, PPV, NPV at Youden-optimal cut-off a single time point at diagnosis (January 2018 – January 2022) Correlation analysis Spearman rank correlation coefficient (ρ) with two-sided p-value; point-biserial correlation for biomarker vs. metastatic status (binary variable), a single time point at diagnosis (January 2018 – January 2022) Survival analysis (prognosis) Kaplan-Meier survival curves; log-rank test (χ²) for between-group comparison; median OS with 95% CI; 1-year OS rate. Univariate Cox proportional hazards regression: hazard ratio (HR) with 95% CI.5.Kruskal-Wallis H test for overall between-subtype comparison; Dunn post-hoc test with Bonferroni correction for pairwise comparisons, a single time point at diagnosis (January 2018 – January 2022) Ethics approval required Süleyman Demirel University Faculty of Medicine Clinical Research Ethics Committee

Süleyman Demirel Üniversitesi Tıp Fakültesi Dekanlığı Morfoloji Binası İdari Ofisler 2. Kat Doğu Kampüsü Çünür

Isparta, Merkez, Türkiye 32260 239 10.1186/ISRCTN52550559 TDK-2019-6958 TDK-2019-6958 Observational Prospective observational diagnostic accuracy study 2022-06-20T00:00:00.000Z Türkiye false 1. Adult patients aged 18 years or older 2. Undergoing diagnostic fiberoptic bronchoscopy (FOB) for suspected primary lung cancer or suspected thoracic involvement by an extrapulmonary malignancy 3. Histopathologically confirmed diagnosis from bronchoscopic biopsy specimen 4. Adequate RNA yield from biopsy specimen (A260/A280 ratio 1.7–2.0) 5. Written informed consent obtained prior to enrollment Mixed 18 Years 99 Years All 49 57 1. Benign histology on bronchoscopic biopsy specimen 2. Insufficient RNA yield from biopsy specimen (A260/A280 ratio outside 1.7–2.0 range) 3. Non-evaluable biomarker measurements 4. Duplicate patient records 5. Age under 18 years 6. Refusal to provide written informed consent 2019-01-01T00:00:00.000Z 2022-01-01T00:00:00.000Z Lung cancer; thoracic malignancy; lung neoplasms; bronchoscopic biopsy; metastasis; differential diagnosis Cancer This is a prospective observational diagnostic accuracy study. No intervention was administered to participants. Index test: Quantitative real-time PCR (qPCR) measurement of CUG2, βIGH3 (TGFBI), and TGF-β gene expression using the 2^−ΔΔCt method with β-actin as reference gene, performed on RNA extracted from bronchoscopic biopsy specimens obtained during routine diagnostic fiberoptic bronchoscopy. Reference standard: Metastatic status determined by PET/CT imaging and thoracic CT in accordance with the 8th edition TNM classification; histopathological diagnosis confirmed from bronchoscopic biopsy specimens. Non-randomised. Participants were assigned to study groups (primary lung cancer vs. other thoracic malignancies; metastatic vs. non-metastatic) based on histopathological diagnosis and PET/CT findings at the time of diagnostic bronchoscopy, not by randomisation. Other Not expected to be made available

0beb6c18-cae7-4633-abeb-043022e4392a 79d99bc2-4c6d-4133-8543-9dbb13b1b8ef 26234fb5-5766-4600-9e54-e6b046a84b8b No Statistical Analysis Plan 49667_SAP_v1.0_01June2026.pdf 44a4141e-6626-4951-8bd7-e416e3196af9 true application/pdf 113882 f4c358ee7ad11c632525acc99e3edb08 Onder Ozturk https://orcid.org/0000-0001-8570-2172 Principal investigator Scientific Public

Department of Pulmonology, Faculty of Medicine, Süleyman Demirel University

Isparta, Merkez Türkiye 32200 +905322677973 dronderozturk@gmail.com Public Süleyman Demirel University https://ror.org/04fjtte88 Non-commercial Süleyman Demirel Üniversitesi http://dx.doi.org/10.13039/501100004935 15819396 true A Cancer Research UK Phase I/IIa trial of KJ-103 given as monotherapy and alongside standard of care pembrolizumab in participants with advanced solid tumours Primary Objectives: Monotherapy Dose Escalation (module A): 1. To propose a dose for expansion of KJ-103 that can be given safely in participants with advanced cancers. 2. To make an assessment on how safe and tolerable KJ-103 is in participants with advanced cancers. Safety Run-In and Randomised Efficacy Assessment With SoC Pembrolizumab (Module B): 1. To make an assessment on how safe and tolerable KJ-103 is when given alongside standard of care (SoC) pembrolizumab in participants with advanced cancers. 2. To document preliminary anti-tumour activity of KJ-103 is when given alongside SoC pembrolizumab Monotherapy Dose Expansion (Module C): 1. To document preliminary anti-tumour activity of KJ-103 in participants with advanced cancer. Secondary Objectives: Module A: 1. To document preliminary anti-tumour activity of KJ-103 in participants with advanced cancer. 2. To characterise the pharmacokinetic (PK) profile of KJ-103 in participants with advanced cancer Module B: 1. To propose a dose for expansion of KJ-103 when given alongside SoC pembrolizumab that can be given safety in participants with advanced cancers. 2. To further document preliminary antitumour activity of KJ-103 is when given alongside SoC pembrolizumab 3. To determine limited PK parameters of KJ 103 given alongside SoC pembrolizumab in participants with advanced cancer. Module C: 1. To further document preliminary anti-tumour activity of KJ-103 in participants with advanced cancer. 2. To make a further assessment on how safe and tolerable KJ-103 is in participants with advanced cancers. 3. To determine limited PK parameters of KJ 103 in participants with advanced cancers. Background and study aims Researchers are testing a new drug called KJ-103 in people with advanced solid tumours. This is the first time KJ-103 is being given to humans. The main aims of the trial are to find out: 1. The safest dose of KJ-103 to give to people 2. How the drug behaves in the body 3. Whether KJ-103 is effective on its own or when combined with another cancer treatment called pembrolizumab, which is already used as standard care for some cancers. KJ-103 is a type of drug called a monoclonal antibody. It works by attaching to a protein called TROP2, which is found on the surface of certain cancer cells. KJ-103 also binds to a receptor on immune cells (called the Fc receptor, found on macrophages and natural killer cells). By doing this, KJ-103 acts like a bridge between cancer cells and immune cells, helping the immune system to recognise and destroy cancer cells. We hope this will make the immune cells in your body more active against cancer, but we cannot be sure if it will work at this stage. Who can participate? Patients aged 16 years and over with advanced solid tumours What does the study involve? The trial is divided into different parts (called modules): Module A: KJ-103 will be given on its own at different dose levels to small groups of participants to find the safest dose. Module B: KJ-103 will be tested together with pembrolizumab. First, researchers will check the safety of the combination. Then, participants will be randomly assigned to receive either KJ-103 plus pembrolizumab or pembrolizumab alone. Module C: Once the best dose is found, more participants will receive KJ-103 on its own to learn more about its effects. KJ-103 is given by an intravenous (IV) infusion. Treatment is organised into cycles of 21 days. Participants may receive up to 12 cycles, and if they continue to benefit, they may receive up to 22 additional cycles. This trial will help researchers understand if KJ-103 can be safely combined with pembrolizumab and whether it can help treat advanced cancers. What are the possible benefits and risks of participating? KJ-103 is a new drug that has never been given to humans before. Possible risks and benefits are based on laboratory tests and experience with similar drugs but there is not yet any information about the effects of KJ-103 in humans. Participants in the trial will be monitored closely to find out the effects of KJ-103, and the trial has been carefully designed to keep participants safe. Where is the study run from? Cancer Research UK When is the study starting and how long is it expected to run for? June 2026 to September 2029 Who is funding the study? 1. Cancer Research UK 2. Kisoji Biotechnology Inc. (Canada) Who is the main contact? 1. Dr Christian Ottensmeier, christian.ottensmeier@nhs.net 2. Rashida Teladia, rashida.teladia@cancer.org.uk https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-kj-103-pembrolizumab-cancer-spread 1. Dose for expansion determined following review of all clinically relevant data, including but not limited to toxicity, efficacy, PK and pharmacodynamic (PD) data. Evaluation of this endpoint will occur when all clinically relevant data in Module A have been reviewed by the sponsor, chief investigator and principal investigators. 2. Nature and frequency of dose-limiting toxicities (DLTs). DLTs are defined and assessed according to specific criteria in the trial protocol. Evaluation of this endpoint will occur when sufficient participants in Module A have completed the DLT observation period (first 21 days of administration). 3. Frequency of adverse events (AEs) considered at least possibly related to KJ 103 and number of Grade 3, 4 and 5 AEs considered at least possibly related to KJ-103. AEs, including relatedness, seriousness and severity (graded according to NCI-CTCAE v5.0), will be assessed by the Investigator. AEs will be collected from the date of informed consent until 10 weeks after the last administration of KJ-103 (or at least 4 months after the last dose of pembrolizumab for participants in Module B) or until the participant starts another anti-cancer therapy in Modules A and B. 4. Progression-free survival (PFS): defined as the time from the first dose of the trial intervention to the first occurrence of disease progression, as determined by the Investigator using RECIST V1.1, or death from any cause during the trial, whichever occurs first. Participants who are alive with no recorded progression at the time of analysis will be censored at the date of the scan when they were last recorded with an evaluable measure that was not progression. This endpoint will be evaluated at the end of trial for participants in Module B. 5. Objective response rate (ORR): defined as the percentage of participants who achieve complete response (CR) or partial response (PR) according to RECIST V1.1. This endpoint will be evaluated at the end of trial for participants in Module C. 1. ORR. This endpoint will be evaluated at the end of the trial for participants in Modules A and B. 2. Clinical benefit rate (CBR): defined as the percentage of participants who achieve CR, PR, or stable disease (SD) according to RECIST V1. This endpoint will be evaluated at the end of trial for participants in Modules A and C. 3. Duration of response (DoR): defined as the period from the date of initial CR or PR until the date of progressive disease or death from any cause, whichever occurs first. DoR will be evaluated in the subset of participants with measurable disease at baseline who have achieved an objective response according to RECIST V1.1. This endpoint will be evaluated at end of trial for participants in Modules A and C. 4. PK parameters for KJ-103, including Cmax and Cmin for all participants, and total exposure (AUC), clearance, volume of distribution, and terminal elimination half-life for participants in Module A. Additional PK parameters may be determined as appropriate. Samples for PK analysis will be taken at up to 23 timepoints for participants in Modules A, B and C. 5. Dose for expansion of KJ-103 given alongside SoC pembrolizumab, determined following review of all clinically relevant data, including but not limited to toxicity, efficacy, PK and PD data. Evaluation of this endpoint will occur when all clinically relevant data in the safety run-in of Module B have been reviewed by the sponsor, chief investigator and principal investigators, and at the end of Module B. 6. Nature and frequency of DLTs. DLTs are defined and assessed according to specific criteria in the trial protocol. Evaluation of this endpoint will occur when sufficient participants in the safety run-in of Module B have completed the DLT observation period (first 21 days of administration) and all relevant data have been collected, and at the end of Module B 7. Time to response (TTR): defined as the time from the first dose of any trial drug to the date of the first documented CR or PR according to RECIST V1.1. This endpoint will be evaluated at end of trial for participants in Module B and C. 8. Disease control rate (DCR) at 18 weeks: defined as the proportion of participants with best overall response of CR, PR or SD per RECIST V1.1 assessed at 18 weeks after the first dose of KJ-103. This endpoint will be evaluated at the end of trial for participants in Module C. 9. PFS. This endpoint will be evaluated at end of trial for participants in Module C. 10. Frequency of AEs considered at least possibly related to KJ 103 and the number of Grade 3, 4 and 5 AEs considered at least possibly related to KJ-103. AEs, including relatedness, seriousness and severity (graded according to NCI-CTCAE v5.0), will be assessed by the Investigator. AEs will be collected from the date of informed consent until 10 weeks after the last administration of KJ-103 or until the participant starts another anti-cancer therapy in Module C. Ethics approval required North East- York Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 26/NE/0012 10.1186/ISRCTN15819396 1012337 CPMS: 71033, CRUKD/26/001 1012337 71033 CRUKD/26/001 Interventional Randomized controlled trial Open (masking not used) Dose comparison Parallel Treatment Not applicable 2029-09-01T00:00:00.000Z United Kingdom England Clatterbridge Cancer Centre

Clatterbridge Hospital Clatterbridge Road

Wirral England CH63 4JY RJR62@2.16.840.1.113883.2.1.3.2.4.18.48 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 Barts Health NHS Trust

St Bartholomew's Hospital, West Smithfield

London England EC1A 7BE Royal Free Hospital

Pond Street

London England NW3 2QG false Core Inclusion Criteria: 1. Written (signed and dated) informed consent and capable of co-operating with investigational medicinal product (IMP) administration and follow-up. 2. Histologically and/or cytologically confirmed diagnosis of advanced (incurable locally recurrent or metastatic) solid tumour (please refer to the specific inclusion criteria for each of the Modules for further details on tumour types). 3. At least 1 measurable target lesion, according to RECIST V1.1. Lesions which have previously received definitive radiotherapy can only be considered target lesions if there has been radiological disease progression since the completion of prior radiotherapy. 4. Eastern Cooperative Oncology Group performance status of 0–1 5. Haematological and biochemical indices within the ranges shown below. These measurements should be performed to confirm the participant’s eligibility to take part in the trial. 5.1. Haemoglobin (Hb) ≥90 g/L. Hb must be independent of transfusional support within last 14 days prior to testing 5.2. Absolute neutrophil count (ANC) ≥1.5 × 10e9/L (ANC must be independent of growth factor support within last 14 days prior to testing) 5.3. Platelet count ≥100 × 10e9/L must be independent of transfusional support within last 14 days prior to testing 5.4. Total bilirubin ≤1.5 × upper limit of normal (ULN); if known Gilbert syndrome: total bilirubin ≤3 × ULN 5.5. Alanine aminotransferase and aspartate aminotransferase ≤5 × ULN 5.6. Calculated creatinine clearance (using the Cockcroft & Gault formula) ≥50 mL/min 6. Aged 16 years or over at the time consent is given. 7. Patient must be able and willing to provide the following fresh tumour biopsy samples: 7.1. Pre-treatment biopsy – mandatory from participants in all Modules unless a fresh biopsy is not feasible due to a significant clinical risk. In such cases the suitability of an archival biopsy must be agreed between the investigator and the sponsor prior to enrolment. Use of an archival biopsy will not be allowed in Module A ‘backfill’ participants. 7.2. On-treatment biopsy in cohorts where this is mandated (Module A 'backfill' participants and all participants in Module B). Inclusion Criteria Specific for Module A (KJ-103 monotherapy dose escalation): 1. Documented radiological disease progression during or after their most recent line of anti-cancer therapy; have received 1 or more prior lines of systemic SoC anti-cancer therapy in the advanced setting for their respective cancer indication and are suitable for entry into a clinical trial in the opinion of the investigator. 2. Histologic or cytologic documentation of disease*: 2.1. HNSCC 2.2. Breast cancer 2.3. NSCLC 2.4. Urothelial carcinoma *Other types can be considered Inclusion Criteria Specific for Module B (KJ-103 given alongside pembrolizumab): 1. No local or systemic prior anti-cancer therapy given in the recurrent/metastatic disease setting. Histologic or cytologic documentation of squamous cell cancer of the oral cavity, oropharynx, larynx or hypopharynx, which is recurrent/metastatic or locally advanced and not amenable to local treatment with curative intent. 2. PD-L1 status known (combined positive score ≥1). Inclusion Criteria Specific for Module C (KJ-103 monotherapy dose expansion): 1. Documented radiological disease progression during or after their most recent line of anti-cancer therapy; have been previously treated with at least 1 and no more than 2 lines of systemic SoC anti-cancer therapy in the recurrent/metastatic setting and are suitable for entry into a clinical trial in the opinion of the Investigator. 2. Histologic or cytologic documentation of squamous cell cancer of the oral cavity, oropharynx, larynx or hypopharynx, which is recurrent/metastatic or locally advanced and not amenable to local treatment with curative intent. Mixed 16 Years 100 Years All 133 0 1. Previous treatment with anti-cancer therapies within the following timeframes: 1.1. Cytotoxic chemotherapy, mAbs, and/or small molecule tyrosine kinase inhibitors within 2 weeks prior to C1D1, or 5 half-lives, whichever is shorter. 1.2. Any investigational cancer treatment within 4 weeks prior to Cycle 1 Day 1 (C1D1) or 5 half-lives, whichever is shorter. 1.3. Radiation therapy (except for palliative reasons), within 2 weeks prior to C1D1. 1.4. Endocrine therapy (except when given for conditions other than malignant disease; e.g., thyroid replacement for hypothyroidism, hydrocortisone for cortisol deficiency/panhypopituitarism) 1.5. Participants with prior TROP2-targeted therapy are allowed 2. Co-administration of anti-cancer therapies other than those specified in this trial (with the exception of lifelong hormone suppression such as luteinising hormone releasing hormone agonists/analogues in prostate cancer). 3. Ongoing toxic manifestations of previous treatments greater than CTCAE Grade 1 (other than alopecia of any grade or Grade 2 peripheral neuropathy). Exceptions to this are any clinical stable AEs, which in the opinion of the Investigator should not exclude the patient. 4. Stroke or transient ischemic attack within 6 months prior to Screening. 5. Any central nervous system (CNS) metastases (unless the participant had local therapy and is asymptomatic and radiologically stable for at least 4 weeks prior to the first dose of KJ-103 [or pembrolizumab] and has been off steroids for the last 7 days prior to the first dose of KJ-103 or pembrolizumab [except for ≤10 mg prednisolone daily (or steroid equivalent)]). * Note: For participants with a history of CNS involvement, or a clinical suspicion of CNS involvement, brain imaging should be performed during Screening. 6. Women who are pregnant or breastfeeding (or planning to breastfeed). 7. Women of childbearing potential. Those participants who are not already pregnant or breastfeeding (or planning to breastfeed) are eligible, provided they have a negative highly sensitive serum pregnancy test within 7 days before enrolment and agree to follow the trial’s contraceptive requirements. 8. Male participants with partners of childbearing potential. Those participants who agree to follow the trial’s contraceptive guidance are eligible. 9. Major surgical procedure within 4 weeks of C1D1 or plans to undergo a major surgical procedure during the course of the trial. *Note: Procedures that are considered to be minimally invasive (e.g., peripherally inserted central catheter lines and/or port placements or minor biopsy procedures) will be exceptions. 10. At high medical risk because of non-malignant systemic disease, including active uncontrolled infection (defined as symptoms, signs, or radiographic) of bacterial, viral, or fungal or unknown aetiology requiring systemic therapy within 14 days of C1D1. A minimum 7-day washout prior to C1D1 must be observed for any antibiotic use. Participants with clinical and/or laboratory evidence of persistent infection must be excluded. Patients with previous HCV exposure but no current infection are eligible to participate. 11. Known to be serologically positive for the following: 11.1. HIV 11.2. HBsAg 11.3. HBcAb. Participants with a positive HBcAb test followed by a negative hepatitis B virus DNA test at Screening may be enrolled. 11.4. Hepatitis C virus antibody test. Participants with a positive HCV antibody test followed by a negative HCV RNA test at Screening may be enrolled. 12. Receiving or planning to receive systemic treatment with steroids or other immunosuppressive agents during the trial or having received such treatment within 4 weeks of C1D1. Exceptions: 12.1. Topical (≤20% of the skin surface area), ocular, intra-articular, intranasal, or inhalation corticosteroids. 12.2. Physiologic doses of corticosteroids (≤10 mg prednisolone daily [or steroid equivalent]) are permitted. 13. Hypersensitivity to any of the ingredients/excipients in the relevant trial drug(s). Participants with a known or suspected history of hypersensitivity reaction to previous biological therapy that, in the Investigator’s opinion, is a contraindication are excluded from this trial. 14. Has evidence of interstitial lung disease (such as idiopathic pulmonary fibrosis) or active pneumonitis of any aetiology. For further details, please refer to protocol for full exclusion criteria 2026-06-16T00:00:00.000Z 2029-02-27T00:00:00.000Z Advanced solid tumour types which are known to have a high frequency of TROP2 positivity (e.g., head and neck squamous cell carcinoma [HNSCC], urothelial, breast cancer, non-small cell lung cancer [NSCLC]) Cancer In the monotherapy dose escalation (Module A), KJ-103 will be administered in escalating doses (multiple participant cohorts consisting of 3–6 participants). Participants will receive KJ-103 intravenously once every week in cycles of 21 days. The starting dose will be 3 mg/kg. In the safety run-in of Module B, up to 2 dose levels of KJ-103 (IMP) will be explored alongside SoC pembrolizumab (non-IMP). The doses and schedule of KJ-103 will be determined based on data from Module A. In the randomised efficacy assessment in combination with pembrolizumab of Module B, participants will be randomised 2:1 (using an electronic data capture [EDC] system) to either receive KJ-103 with SoC pembrolizumab or SoC pembrolizumab alone. KJ-103 will be administered alongside SoC pembrolizumab at the suitable dose level identified in the safety run-in of Module B. In the monotherapy dose expansion (Module C), participants will receive KJ-103 as an intravenous infusion at a dose and schedule that will be determined based on data from Module A. All participants may receive KJ-103 for up to 12 cycles. An additional 22 cycles of treatment may be agreed upon for participants with continued benefit. Participants will be followed up for safety for at least 10 weeks after the last administration of KJ-103 (or at least 4 months after the last dose of pembrolizumab) or until the participant starts another anticancer therapy. Participants will continue to be followed up for efficacy and survival until the end of the trial. Biological/Vaccine Phase I/II KJ-103 The datasets generated during and/or analysed during the current trial are available from the corresponding author on reasonable request Available on request e475ebcb-7ada-4034-805a-773205381413 24643765-ce2f-4722-98a6-a956ebddaf38 c5c7b7b9-2b1c-40c2-a414-9a16169df52f c7dcd4e7-6c1c-4e28-8e13-f971769cb55c ea338cab-6e25-41f1-a200-364f80d573f6 09d08b1e-5375-4f7b-9b9d-dfe0067764f4 Yes Rashida Teladia Scientific Public

2 Redman Place

London United Kingdom E20 1JQ +44 (0)300 123 1022 Rashida.Teladia@cancer.org.uk Public Christian Ottensmeier Principal investigator

Clatterbridge Road

Birkenhead United Kingdom CH63 4JY +44 (0)7879485676 christian.ottensmeier@nhs.net Public David Gear Public Scientific

Centre for Drug Development, 2 Redman Place

London United Kingdom E20 1JQ +44 (0)300 123 1022 David.Gear@cancer.org.uk Public Cancer Research UK https://ror.org/054225q67 Non-commercial Cancer Research UK http://dx.doi.org/10.13039/501100000289 Kisoji Biotechnology Inc. 70717445 true A Modular Cohort-Based Precision-Prevention Trial of neoantigen-targeting vaccines to prevent cancer in individuals at risk of recurrent or new non-small cell lung cancer (NSCLC) and other cancers LungVax Primary objective: To determine the safety and immunogenicity (magnitude) of ChAdOx2 LungVax Secondary objectives: 1. Assessment of longer-term safety and tolerability of ChAdOx2 LungVax 2. To determine the immunogenicity (breadth) of ChAdOx2 LungVax 3. Assessment of longer-term immunogenicity of ChAdOx2 LungVax Background and study aims Lung cancer is the most common cause of cancer death that society faces. It kills almost 35,000 people every year in the UK. Although it is one of the most lethal cancers, it is also one of the most preventable because it takes a long time for lung cancer to develop and there are clear risk factors. We now know that the earliest changes in persistent smokers are subtle changes to the cells lining their lungs and airways. The first are mutations to genes contained within these cells. Cells which contain mutated genes send out distress signals like flags displayed by a ship in danger. These short protein flags are called neoantigens. The immune system recognises most cells bearing these neoantigen “flags” and kills them. However, the immune system sometimes does not recognise or kill these ‘flag-waving’ cells. As a result, cells can survive, develop more mutations, and grow to become lung cancer over years or even decades. Eventually, these tumours cause symptoms like a cough or shortness of breath and can be seen on an X-ray or CT scan. The vaccine (ChAdOx2 LungVax) “teaches” the immune system to recognise and kill every cell that carries these neoantigens, preventing them from developing into lung cancer. Who can participate? The trial will assess the safety and effectiveness of ChAdOx2 LungVax in two distinct sets of high cancer risk individuals. The first set are individuals who have recently had curative surgery for early-stage non-small cell lung cancer (NSCLC). The second set are individuals who are participating in the NHS Lung Cancer Screening Programme - who are at elevated risk of NSCLC and other cancers, but have not had a cancer diagnosis. What does the study involve? Participants will be vaccinated with ChAdOx2 LungVax four times over an 18-month period. What are the possible benefits and risks of participating? Benefits: Not provided at time of registration Risk: ChAdOx2 LungVax has not been given to human subjects before Minimisation of risk: ChAdOx2 LungVax, is a replication-deficient simian adenovirus ChAdOx2 vector expressing 22 LungVax hotspot mutations and the NYESO-1 and MUC1 cancer antigens. The ChAdOx2 vector is derived from simian adenovirus ChAd68. The ChAdOx2 vector is replication-deficient as the E1 gene region, essential for viral replication, has been deleted. Because of the E1 deletion, the virus can only propagate in cells expressing E1 functions, and thus virus is unable to replicate within vaccinated animals or humans. To ensure overall participant safety: the first participant in Cohort 1 will be enrolled at least 48 hours before subsequent participants, enabling Day0 - Day2 adverse events to be assessed before dosing of the next participant. Provided there are no safety concerns, as assessed by the Trial Management Group (TMG) a further two participants will be vaccinated at least 1 hour apart. The trial TMG will perform a comprehensive safety evaluation of Cohort 1, 28 days after the last participant has received their initial vaccination. If less than 4 Dose Limiting Toxicities are observed in Cohort 1, we will then commence enrolment into Cohort 2. Risk: Administering LungVax Minimisation of risk: Assessment of Haemoglobin, white cell count with differential count (neutrophils and lymphocytes) and platelets will be completed prior to administration of ChAdOx2 LungVax. No potential drug reactions are known for ChAdOx2 LungVax. ChAdOx2 LungVax is unlikely to interfere directly with the cytochrome P450-mediated metabolism of other drugs. There are no human or animal data regarding overdose of ChAdOx2 LungVax and no non-clinical single or repeat dose toxicology studies have been performed. Should an overdose occur, participants should be carefully monitored, and management should be supportive and tailored to symptoms as they arise. Any participant who inadvertently receives a higher dose than intended should be monitored closely, managed with appropriate supportive care until recovery and followed up expectantly. Management of overdose should include monitoring for toxicity, general supportive measures including monitoring of symptoms and haematological parameters, and treatment provided based on any signs or symptoms experienced. Risk: There is a risk associated with additional research blood sample collection; blood samples could cause pain, bruising or bleeding. Risk minimisation: The trial will be conducted at a hospital with expertise in the treatment and diagnosis of NSCLC to ensure the highest standard of care for participants. The trial has undergone a risk assessment involving the operational team, oncology consultants, nursing team, and statistician. The trial set-up has also involved patient involvement, with 3 members from a PPI group who have lived experience of cancer. Meetings have been held to review the participant pathway through the trial, and also discuss the sampling schedule and visit burden, in addition to patient-facing documentation, their input has tailored how the trial is presented to potential participants . These PPI members will also sit on the Trial Management Group and Trial Steering Committee. Burden: Attending trial visits at the investigator site . This may be a particular burden to participants in Cohort 2 - as they are not under post-surgical surveillance, they may need to visit the hospital solely for trial visits. Burden minimisation: Investigator sites will be informed to align trial visits to when participants are already visiting the hospital (where possible) and to inform participants of the dates of upcoming trial visits as early as possible, to allow maximum notice. The burden of attending trial visits is clearly explained in the participant information sheet and will be explained during the screening trial visit, allowing potential participants can understand what is involved if they consent to take part. If the investigator site can facilitate, participants will be informed that a family/friend can attend trial visits with them for support. Reasonable travel expenses will also be reimbursed as per local policy. Where is the study run from? University of Oxford (UK) When is the study starting and how long is it expected to run for? June 2026 to December 2030 Who is funding the study? Cancer Research UK CRIS Cancer Foundation Who is the main contact? octo-lungvax@oncology.ox.ac.uk 1. Number and severity of adverse events (AEs) within the DLT evaluable period (28 days after first vaccination at D0) within each cohort. Measured using vaccine-emergent AEs or clinically significant laboratory changes (per CTCAE v6.0) or changes in vital signs within each cohort 2. Magnitude of vaccine antigen specific cellular immunogenicity using peripheral-blood mononuclear cells (PBMCs) (e.g. for Interferon gamma (IFNγ) enzyme-linked immunospot (ELISpot) assay). Measured at Day 0 and Day 14 1. Total number and severity of AESIs and SAEs in each cohort (within and outside the DLT evaluable period), comprising treatment - emergent AESIs and SAEs. Measured at 24 months after vaccination at Day 0 or Early Withdrawal Visit (EWV) 2. Breadth of vaccine antigen specific immune responses defined as the number of peptides/peptide pools targeted by vaccine specific T cells at peak response (spot-forming units (SFUs)/million PBMCs) relative to negative control in each assay. Measured at Day 0 and Day 14 3. Cellular immunogenicity (as above for primary end point). Measured during the 24-month follow-up and at 24 months after vaccination at Day 0 4. Responses to vaccine antigens restricted by Human leukocyte antigens (HLA) alleles, e.g. using ELISpot (and/or intracellular cytokine assays) against selected peptide antigens. Measured during the 24-month follow-up and at 24 months after vaccination at Day 0 Ethics approval required Wales Research Ethics Committee 1 Cardiff

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

Cardiff United Kingdom CF11 9AB 26/WA/0090 10.1186/ISRCTN70717445 1013101 CPMS: 55929, OCTRU428 1013101 55929 OCTRU428 Interventional Non-randomized controlled trial Open (masking not used) Uncontrolled Single Safety Not applicable 2030-12-31T00:00:00.000Z United Kingdom England 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 true Cohort 1: 1. Age ≥18 years. 2. Histological confirmation of NSCLC. 3. Curative surgery in keeping with NICE guidelines for stage IA or IB NSCLC ≤ 3 months of D0. 4. Post-operative imaging confirming no active cancer (within 3 months/≤90 (+/- 7) days of Day 0). 5. Laboratory parameters (tested during screening period and results obtained prior to vaccine administration) within the ranges specified in the protocol. 6. For participants of childbearing potential only (as defined by protocol section 5.1): willing to use effective contraception for the duration of the study and a negative pregnancy test on the days of screening and vaccination. 7. Willing and able to comply with the protocol scheduled visits and investigations for the duration of the trial. Cohort 2: 1. Age 55–74 years inclusive, in accordance with NHS Lung Cancer Screening Programme eligibility. 2. Participating in NHS Lung Cancer Screening Programme with recent (within 3 months/≤90 (+/- 7) days of Day 0) low dose CT scan/or other imaging confirming no active cancer or suspicion of cancer. 3. Haemoglobin (Hb), white cell count (WCC) and platelets (tested during screening period, prior to vaccine administration) within the normal ranges specified (local lab ranges). 4. For participants of childbearing potential only (as defined by protocol section 5.1): willing to use effective contraception for the duration of the study and a negative pregnancy test on the days of screening and vaccination. 5. Willing and able to comply with the protocol scheduled visits and investigations for the duration of the trial. Mixed 18 Years 74 Years All 40 0 Cohort 1: 1. Positive surgical margins or incomplete resection (R2 macroscopic resection on post-operative pathological assessment). 2. Other/active malignancy or cancer requiring systemic treatment within the past 2 years apart from non-melanomatous skin cancer, stage 0 melanoma in situ, breast ductal carcinoma in situ (DCIS), polyps and in situ cervical cancer. Or, other new or recurrent cancer diagnosed previously that is currently being treated or maintained in remission (including by hormonal therapy). 3. Prior, or eligible for, neoadjuvant or adjuvant treatment. 4. Currently pregnant or breast-feeding. 5. Prior history of thromboembolic events such as myocardial infarction, angina, cerebrovascular accident/TIA/stroke, pulmonary embolus or deep vein thrombosis. 6. History of heparin-induced thrombocytopenia and thrombosis (HITT or HIT type 2). 7. Active autoimmune disease. e.g. Crohn’s disease, rheumatoid arthritis. 8. Confirmed active diagnosis of known high-risk infections (e.g., Human Immunodeficiency Virus) (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or syphilis infection, tuberculosis and Creutzfeldt-Jacob disease) unless participant case is of a particular scientific interest and agreed in advance with CI or delegate. 9. Any significant or uncontrolled disease or condition that, in the clinical judgment of the treating physician, is likely to interfere with evaluation of trial treatment, interpretation of participant safety or trial results, prevent the participant from complying with any aspect of the protocol or that may put the participant at unacceptable risk. 10. Live or live-attenuated vaccine administered less than 14 days before the first ChAdOx2 LungVax vaccination (Day 0). 11. Any disorder that is clinically relevant to the participants current health or vaccine response, as judged by the investigator, including known primary or secondary immunodeficiencies, ongoing immunosuppressive therapy, or laboratory evidence of immune compromise. 12. Severe hypersensitivity (≥Grade 3) to ChAdOx1-containing vaccines and/or any of their excipients. 13. Prior administration of ChAdOx2 vaccine. 14. Severe allergy to eggs or any previous vaccination. 15. Current participation in another interventional clinical trial involving the administration of an investigational medicinal product. Cohort 2: 1. Active malignancy or cancer requiring systemic treatment within the past 2 years apart from non-melanomatous skin cancer, stage 0 melanoma in situ, breast ductal carcinoma in situ (DCIS), polyps and in situ cervical cancer. Or, other new or recurrent cancer diagnosed previously that is currently being treated or maintained in remission (including by hormonal therapy). 2. Currently pregnant or breast-feeding. 3. Prior history of thromboembolic events such as myocardial infarction, angina, cerebrovascular accident/TIA/stroke, pulmonary embolus or deep vein thrombosis. 4. History of heparin-induced thrombocytopenia and thrombosis (HITT or HIT type 2). 5. Active autoimmune disease. e.g. Crohn’s disease, rheumatoid arthritis. 6. Confirmed active diagnosis of known high-risk infections (e.g., Human Immunodeficiency Virus) (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or syphilis infection, tuberculosis and Creutzfeldt-Jacob disease) unless participant case is of a particular scientific interest and agreed in advance with CI or delegate. 7. Any significant or uncontrolled disease or condition that, in the clinical judgment of the treating physician, is likely to interfere with evaluation of trial treatment, interpretation of participant safety or trial results, prevent the participant from complying with any aspect of the protocol or that may put the participant at unacceptable risk. Active autoimmune disease. e.g. Crohn’s disease, rheumatoid arthritis. 8. Live or live-attenuated vaccine administered less than 14 days before the first ChAdOx2 LungVax vaccination (Day 0). 9. Any disorder that is clinically relevant to the patient’s current health or vaccine response, as judged by the investigator, including known primary or secondary immunodeficiencies, ongoing immunosuppressive therapy, or laboratory evidence of immune compromise. 10. Severe hypersensitivity (≥Grade 3) to ChAdOx1-containing vaccines and/or any of their excipients. 11. Prior administration of ChAdOx2 vaccine. 12. Severe allergy to eggs or any previous vaccination. 13. Current participation in another interventional cancer clinical trial involving the administration of an investigational medicinal product. 2026-06-01T00:00:00.000Z 2027-03-31T00:00:00.000Z Surgically resected stage 1A/1B non small cell lung cancer Cancer This phase of the LungVax trial includes two cohorts. Both cohorts will receive the intervention, ChAdOx2 LungVax, via intramuscular injection at a dose of 5 x 10^10 vp on day (D)0 and D28, month (M)12 and M18. Both cohorts will be followed up for 2 years post first vaccination to record longer term toxicity and immunogenicity Cohort 1 will recruit 20 patients who have undergone successful (R0/R1) surgical resection for Stage 1A/1B NSCLC within 3 months of surgery. These participants will be followed up for 2 years post first vaccination to record longer term toxicity and immunogenicity during which time they will undergo 6-monthly CT chest, abdomen and pelvis imaging to exclude new or recurrent cancers. Cohort 2 will involve 20 individuals drawn from the NHS Lung Cancer Screening Programme, who have been identified as being at elevated risk of NSCLC and other cancers. These participants would have undergone a low-dose CT assessment or other imaging, within 3 months prior to enrolment, that has excluded the presence of cancer. These participants will also undergo a low-dose CT scan at approximately 24 months after the baseline (screening) scan, in line with routine imaging and current standard of care within the NHS Cancer screening Programme. Drug Phase I ChAdOx2 LungVax Data sharing statement to be made available at a later date a5f585bf-d870-49d7-8f7b-65b7d8bf531d 6fa16aef-52bd-401f-a946-0e7dcbdcf62d c1a97ade-5aaf-4e41-b576-db9a9cef874a 44c2b195-1397-4f95-b1e7-f9bb1388efee 3949d79a-9a7c-4d6c-a368-1b1619a19e7b 96374a37-2264-4b46-8699-27e4e12cbbce No Mariam Jamal-Hanjani Scientific

72 Huntley Street

London United Kingdom WC1E 6DD - octo-lungvax@oncology.ox.ac.uk Public Maise Al Bakir Principal investigator

1 Midland Road

London United Kingdom NW1 1AT - octo-lungvax@oncology.ox.ac.uk Public - Oncology Clinical Trials Office Public

Old Road Campus Research Building (ORCRB), Roosevelt Drive, Headington

Oxford United Kingdom OX3 7DQ +44 1865 617420 octo-lungvax@oncology.ox.ac.uk Public University of Oxford https://ror.org/052gg0110 Non-commercial Cancer Research UK CRIS Cancer Foundation http://dx.doi.org/10.13039/501100023479 14753723 true A phase 1, dose-escalation, open-label study, evaluating the safety and tolerability of ZI-MA4-1, a TCR-NK cell therapy, in HLA A*02:01 positive patients with inoperable, locally advanced, or metastatic MAGE-A4 expressing solid malignancies ZIMA-101 Primary objective: To evaluate the safety and tolerability of ZI‑MA4‑1 when administered to human leukocyte antigen (HLA)-A*02:01 positive participants with advanced solid tumour malignancies expressing melanoma‑associated antigen (MAGE)‑A4 Secondary objective: Safety: 1. To determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of ZI-MA4-1 2. Long term safety 3. To identify the minimum biologically active dose (MBAD) Efficacy: 1. To evaluate the efficacy of ZI-MA4-1 in HLA-A*02:01 positive participants with MAGE-A4 expressing solid malignancies Pharmacokinetics: 1. Evaluation of persistence of ZI-MA4-1 in the blood Background and study aims This study will recruit patients with the following cancer indications: ovarian cancer, squamous non-small cell lung cancer, synovial sarcoma and head and neck cancer, with inoperable locally advanced or metastatic solid tumours. Currently, these patients have a poor prognosis and a relatively short overall survival. There is a lack of meaningful, effective therapies available that improve the outcome for these patients. The treatment being investigated in this study is ZI-MA4-1, an allogeneic cell therapy product. This is the first time ZI-MA4-1 will be administered to humans. The study is planned to consist of two parts (A and B). Part A includes up to four dose escalation cohorts and aims to identify the maximum tolerated dose of ZI-MA4-1 and give insight into the recommended Phase 2 dose (RP2D). Part B consists of an expansion cohort and is designed to further evaluate the RP2D identified in Part A across one or more indications. The study procedures and eligibility criteria will be the same for participants in Parts A and B, except for the dose level of ZI-MA4-1. Who can participate? Adult patients aged with inoperable locally advanced or metastatic solid tumours. What does the study involve? All participants will receive ZI-MA4-1 administered via IV infusion 3 times per 33-day treatment cycle at their assigned dose. It is planned that all participants in the study will get a minimum of one treatment cycle and up to a maximum of two treatment cycles. Prior to receiving ZI-MA4-1, participants will be given fludarabine and cyclophosphamide to temporarily reduce lymphocytes in the body (lymphodepletion). The total duration for participation is approximately 5 years & 2 months. What are the possible benefits and risks of participating? The possible benefit of participating is unknown. It is not known if taking part in this study will improve patients' condition and there is no guarantee of any such improvement. It is possible that the study medication may address the underlying cause or some symptoms of their cancer. However, it is not known for how long any benefit may last and any benefit may not be long-lasting or permanent. This is the first time the study medication (ZI-MA4-1) has been given to humans, so the risks are unknown. ZI-MA4-1 is a cell therapy. Different types of similar treatments have been used before to treat cancer. Some of the known side effects from this type of treatment are: • Cytokine release syndrome • Confusion, dizziness, or headaches, or (in rare cases) neurological damage • Feeling or being sick, and loss of appetite • Tiredness • Changes to the levels of certain substances in your blood. Risks associated with lymphodepletion include: • High chance of infection due to the reduction in white blood cells (neutropenia) • Feeling tired, weak and breathless due to a reduction in red blood cells (anaemia) • Bruising, bleeding gums or nosebleeds due to a reduction in the platelets (thrombocytopenia), which help blood clot • Fever Other study procedure risks include: - biopsy risks (pain or discomfort where the sampling tool enters) - blood sample risks (minor pain, bleeding, and/or bruising) - CT scan risks (feeling unwell due to contrast dye) Where is the study run from? Zelluna Immunotherapy AS When is the study starting and how long is it expected to run for? May 2026 to December 2032 Who is funding the study? Zelluna Immunotherapy AS Who is the main contact? Medical and Product Information Enquiry, ctinfo@zelluna.com Safety and tolerability of ZI-MA4-1 from baseline through end of study visit clinical assessments and adverse event reporting recorded in the eCRF, including dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-related adverse events (TRAEs), assessed baseline through Day 28 and throughout the study up to 5 years Ethics approval required North East – York Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 26/NE/0005 10.1186/ISRCTN14753723 1013415 CPMS: 71922 1013415 71922 Interventional N/A: single arm study Open (masking not used) Uncontrolled Single Treatment Not applicable Efficacy Safety 2032-12-01T00:00:00.000Z United Kingdom England 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 The Royal Marsden NHS Foundation Trust

Fulham Road

London England SW3 6JJ RPY@2.16.840.1.113883.2.1.3.2.4.18.48 false Pre-Screening Inclusion Criteria 1. Participant has signed the Pre-Screening ICF 2. Participant is HLA-A*02:01 positive (assessed by the hospital’s own laboratory vendor) 3. Participant’s tumour(s) show expression of the MAGE-A4 protein of ≥30% tumour cells at ≥2+ intensity (assessed by sponsors central lab) 4. Participant meets, or is expected to comply with all Screening Inclusion Criteria Screening Inclusion Criteria (Part A and Part B) 5. Participant must be capable of giving signed informed consent as described in Section 10.3 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 6. 18 to ≤75 years of age, at the time of signing the informed consent. 7. Histopathological or cytological diagnosis of inoperable Locally Advanced or Metastatic malignant disease: ovarian cancer, squamous non-small cell lung cancer (NSCLC), synovial sarcoma or head and neck cancer. 8. No approved therapy with demonstrated clinical benefit is indicated or available to treat the patients, or the patient is intolerant of or has refused standard of care therapy. Patients should not have been withdrawn from any treatment (considered necessary for the clinical management of the patient) with the only purpose being fulfilling the study eligibility criteria. 9. Patients must have documented imaging confirmed disease progression while on or within 6 months after the end of the most recent therapy. 10. Patients must have received ≥2 prior lines of cancer therapy except for patient with synovial sarcoma for whom ≥1 prior lines of cancer therapy are required. 11. Patients have measurable disease according to RECIST v1.1 criteria. 12. An ECOG PS of 0 or 1 with no deterioration over the previous 2 weeks, and an anticipated life expectancy of >3 months following lymphodepletion. 13. Adequate haematological, renal, and hepatic function within 7 days of the start of lymphodepletion 14. Patients must not have evidence of rapidly progressive disease that would preclude patient from completing at least 1 cycle of ZI-MA4-1 treatment. The lymphodepletion regimen comprises cyclophosphamide and fludarabine which are teratogenic and may impair fertility, appropriate contraception and pregnancy precautions are required. Contraceptive guidance is consistent with the respective Summaries of Product Characteristics (SmPCs) for cyclophosphamide and fludarabine. Contraceptive use by participants or participants’ partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies 15. Female participants are eligible to participate if they are not pregnant or breastfeeding, and one of the following conditions applies: o Participant is a woman of non‑childbearing potential (WONCBP) as defined in Section 13.1.1 OR o WOCBP must have negative pregnancy test and agree to use a highly effective contraceptive method Note: Breastfeeding is prohibited during treatment and for at least 6 months following the last dose of ZI‑MA4‑1. See Section 8.3.5 for pregnancy testing schedule. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated). 16. A WOCBP must have a negative hCG serum pregnancy test at screening and a negative urine/serum pregnancy test within 24 hours of lymphodepletion (requirements for pregnancy testing during and after the study are provided in Section 8.3.5). o If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. o The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 17. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 6 months after the last dose of ZI‑MA4‑1: o Refrain from donating sperm or fresh unwashed semen; AND in addition, either: - Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long‑term and persistent basis) and agree to remain abstinent; OR - Agree to use contraception/barrier as follows: Use a male condom when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. Female partners must use an additional highly effective contraceptive method with a failure rate of <1% per year as described in Section 13.1.2. 18. Able and willing to give consent for biopsy collection. An exception may be granted if the biopsy procedure poses a safety risk to the patient or if the lesion's location precludes the collection of tumour tissue; however, such an exception requires prior consultation with the sponsor Mixed 18 Years 75 Years All 39 0 Pre-Screening Exclusion Criteria 1. Participant currently meets, or is expected to meet, any of the Main Exclusion Criteria. Screening Exclusion Criteria (Part A and Part B) 1. Patients have received any prior cellular or gene therapy. 2. Receiving experimental investigational products within 4 weeks of lymphodepletion. 3. Recent therapies prior to lymphodepletion including: a. Within 4 weeks or 5 half‑lives (whichever is longer) of the start of lymphodepletion: biologic agents (such as monoclonal antibodies including marketed drugs), anti-cancer immunotherapy including monoclonal antibodies against PD-1 receptor or ligand. b. Within 4 weeks of lymphodepletion: Bone/soft tissue directed palliative radiotherapy, c. Within 3 weeks of lymphodepletion: Cytotoxic chemotherapy or loco-regional therapy, liver directed radiation therapy within 3 months. d. Within 2 weeks of lymphodepletion: Systemic corticosteroids, other types of radiotherapy not stated above, or any other immunosuppressive therapy. e. Any other therapy, which in the opinion of the investigator presents as a contra indication to lymphodepletion. f. Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) within 4 weeks or 5 half‑lives (whichever is longer) of the start of lymphodepletion in this study. 4. Residual toxicities ≥2 CTCAE grade due to prior therapy, that in the opinion of the investigator may interfere with study conduct. 5. Patients have had any other active malignancy besides the tumour under study within 3 years prior to screening except for in situ removal of basal cell carcinoma or adequately treated cervix carcinoma in-situ. 6. Active or documented history of autoimmune disease or any other diseases requiring immunosuppressive therapy or corticosteroid therapy (defined as >10 mg/day prednisone or equivalent). Physiological replacement, topical, and inhaled steroids are permitted. 7. Significant CNS disorders including Uncontrolled seizures and CNS metastases, within 3 months of enrolment. 8. Myocardial infarction, cardiac angioplasty or stenting, cardiac arrhythmia requiring medication, unstable angina, New York Heart Association Class II or greater congestive heart failure, cardiac atrial or ventricular lymphoma involvement, or other clinically significant cardiac disease within 6 months of enrolment. 9. Active fungal, bacterial viral, or other infection requiring intravenous antibiotic, antifungal, or antiviral medication within 7 days prior to lymphodepletion, including acute symptoms of COVID-19 infection or positive covid test. 10. Received or planned to receive a live vaccine ≤6 weeks before the planned start date of lymphodepletion. 11. Severe or uncontrolled medical condition (e.g., severe chronic obstructive pulmonary disease, interstitial lung disease , severe Parkinson’s disease, active inflammatory bowel disease) or psychiatric condition, which in the opinion of the investigator would interfere with study activities. 12. Active bleeding diatheses, including but not limited to therapeutic anticoagulation, and treatment with major surgery within 28 days before lymphodepletion (minor surgical procedures such as lymph node biopsy/excision or catheter placement are permitted). 13. Patients have significant immunosuppression 14. Known significant hepatic or biliary abnormalities. Active infection with hepatitis B (HbsAg positive), hepatitis C (anti-HCV positive). A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing. Patients that are HbsAg negative but hepatitis B core antibody positive must receive prophylaxis against viral reactivation prior to lymphodepletion therapy. If Hep B core positive and Ag negative then prophylaxis needed. 15. Any medical, psychological, or social condition, drug or alcohol abuse that would make it difficult for the patient to participate in the study and comply with the study procedures, restrictions, and requirements. History of allergic reactions to compounds chemically or biologically similar to cyclophosphamide, fludarabine or other agents used in the study 16. QTc > 450 msec for male participants or > 470 msec for female participants 17. Medical conditions, such as anti-coagulation, which is not suitable for reversal which, at the opinion of the investigator, preclude or make the patient a poor candidate for biopsy 18. Personal history of allergies or intolerance to local anaesthetic. 19. Recent treatment with immunosuppressive agents 20. Residual toxicities ≥2 Common Terminology Criteria for Adverse Events (CTCAE) grade due to prior therapy, that in the opinion of the investigator may interfere with study conduct  2026-05-15T00:00:00.000Z 2027-12-01T00:00:00.000Z Ovarian cancer, squamous non-small-cell lung cancer, synovial sarcoma, head and neck cancer. Cancer This is an open-label, first-in-human, Phase 1 dose-escalation study (3+3 design) evaluating the safety and tolerability of ZI-MA4-1, an allogeneic TCR-NK cell therapy, in patients with advanced solid tumours. There are no randomised treatment arms. All participants receive lymphodepleting chemotherapy consisting of cyclophosphamide (300 mg/m²/day) and fludarabine (30 mg/m²/day), administered intravenously prior to study treatment. ZI-MA4-1 is administered intravenously in three doses on Days 1, 4 and 8 of Cycle 1. Dose levels are evaluated sequentially in a 3+3 dose-escalation design to determine the maximum tolerated dose and/or recommended Phase 2 dose. An optional second treatment cycle may be administered following safety review. Participants are hospitalised during the dosing period for monitoring. The primary evaluation period includes a dose-limiting toxicity (DLT) assessment window through Day 28 of Cycle 1. Participants are subsequently followed for response and safety for up to 2 years after first dose, with long-term follow-up for up to 5 years. No randomisation is performed in this study. Drug Phase I ZI-MA4-1 Not expected to be made available ad2fbe2e-7618-4487-9b67-0abd70205370 f9609dfa-1679-4977-bd53-112f5a632528 c014b1bf-89ec-4ec4-8f1e-7d6e932265a6 0f7c7a5a-11f9-4d6e-9b39-857f3e110429 No Fiona Thistlethwaite https://orcid.org/0000-0002-4832-7008 Principal investigator

The Christie NHS Foundation Trust Wilmslow Road, Withington

Manchester United Kingdom M20 4BX Protected Medical and Product Information Enquiry . Public Scientific

Ullernchausséen 64

Oslo Norway 0379 - ctinfo@zelluna.com Public Zelluna Immunotherapy AS Commercial Zelluna Immunotherapy AS 11668189 true SEARCH: Screening for Early detection of second cancers After Radiotherapy and Chemotherapy for Hodgkin lymphoma . Implementing and evaluating lung cancer screening for high-risk Hodgkin lymphoma survivors within the NHS national lung cancer screening programme SEARCH The primary objective of the SEARCH study is to determine the proportion of lung cancers detected at an early stage (stage I–II) among high‑risk Hodgkin lymphoma (HL) survivors who meet PLCO‑HL risk criteria and undergo low‑dose CT (LDCT) screening within an adapted NHS Lung Cancer Screening Programme pathway. Secondary objectives are to: 1. Describe lung cancer screening outcomes, including cancer detection rate, stage distribution, histological subtype, false‑positive and false‑negative rates, incidental findings, and rates of curative‑intent treatment. 2. Compare the performance of lung cancer risk prediction models (PLCO‑HL, PLCOm2012 and LLPv2) in HL survivors, including measures of predictive accuracy and calibration. 3. Assess participation, feasibility and acceptability of the screening pathway at each stage (invitation, lung health check, LDCT, optional saliva sampling and patient‑reported outcomes). 4. Evaluate health inequalities in access, engagement and screening outcomes across demographic and socioeconomic groups. 5. Assess feasibility and operational delivery of implementing a PLCO‑HL risk‑adapted screening pathway across multiple NHS Cancer Alliances. 6. Undertake a health‑economic evaluation, including cost‑effectiveness, cost per early‑stage cancer detected, quality‑adjusted life years (QALYs) gained and return on investment. 7. Assess environmental impact, including carbon emissions associated with screening and emissions potentially avoided through earlier diagnosis. Exploratory objectives include evaluating enhancements to lung cancer risk prediction using additional clinical variables, assessing the performance of emerging risk models, and exploring the contribution of polygenic risk scores to lung cancer risk stratification in HL survivors. Background and study aims People who have been treated for Hodgkin lymphoma in the past have a higher risk of developing lung cancer later in life. This increased risk is mainly due to the radiotherapy and chemotherapy they received as part of their earlier cancer treatment. Lung cancer in this group is often found late, when it is harder to treat, because there is currently no dedicated screening programme for Hodgkin lymphoma survivors. The SEARCH study aims to find out whether offering a low‑dose CT (LDCT) lung scan to higher‑risk survivors is practical, acceptable, and effective within the NHS. The study also aims to understand how best to identify people at higher risk, how people feel about being invited, and whether screening is equally accessible to everyone. Who can participate? Adults aged 45–74 years who: previously had classical Hodgkin lymphoma, completed their treatment at least 3 years ago, have a history of smoking, and are well enough to undergo lung cancer treatment if anything is found. People must also be able to give informed consent. What does the study involve? Participation happens in several steps: Invitation – Potential participants are identified through NHS records and invited by text message. Initial telephone assessment – A screening nurse checks eligibility and explains the study. Lung Health Check (LHC) – A short appointment (usually by phone or video) where the participant gives consent, answers health questions, and has their personal lung cancer risk calculated. Low‑dose CT scan – People found to be at higher risk are offered an LDCT scan at an NHS hospital or mobile unit. Results and follow‑up – Scan results are sent by post or phone using standard NHS processes. Questionnaires – Participants complete short questionnaires at the start, 3 months, and 6 months to understand their experiences. Some participants may also be invited to optional interviews or to give a saliva sample. What are the possible benefits and risks of participating? Possible benefits: The LDCT scan may detect early signs of lung cancer, when treatment is more successful. Participants may feel more informed about their lung health. The study will help the NHS decide whether to offer screening widely to Hodgkin lymphoma survivors. Possible risks or burdens: Low‑dose CT scans involve a small amount of radiation. The scan may detect findings that need further tests. Some people may feel anxious before or after receiving results. The study team minimises these risks through national safety procedures and clear information before, during and after the scan. Where is the study run from? The study is sponsored by The University of Manchester and delivered by NHS Lung Health Check teams across participating NHS Cancer Alliances in England. When is the study starting and how long is it expected to run for? The study is expected to begin in 2026 and run for approximately 2–3 years, including recruitment, scans, and follow‑up. Who is funding the study? The SEARCH study is funded by SBRI Healthcare (NHS Cancer Programme Innovation Call), with additional support from the NIHR Manchester Biomedical Research Centre. Who is the main contact? Professor Kim Linton Chief Investigator, SEARCH Study The University of Manchester kim.linton@macnhester.ac.uk Proportion of early stage (stage I–II) lung cancers detected among high risk Hodgkin lymphoma survivors lung cancer diagnosis and stage determined using routine NHS clinical records including radiological assessment, multidisciplinary team review, and histological confirmation where available, with staging classified using the TNM system and cancers identified through baseline and surveillance low dose CT scans baseline screening and during follow up for up to 12 months after screening Ethics approval required Health and Social Care Research Ethics Committee A (HSC REC A)

Office for Research Ethics Committees Northern Ireland (ORECNI) BSO, Floor 2, James House, 2-4 Cromac Avenue

Belfast United Kingdom BT7 2JD 26/NI/0059 10.1186/ISRCTN11668189 357604 357604 Interventional N/A: single arm study Open (masking not used) Historical Single Screening Not applicable 2027-06-01T00:00:00.000Z United Kingdom England Manchester University NHS Foundation Trust

Cobbett House, Oxford Road,

Manchester England M13 9WL University Hospital of North Midlands NHS Trust

Newcastle Road

Stoke-on -trent England ST4 6QG Doncaster and Bassetlaw Teaching Hospitals NHS Foundation Trust

Doncaster Royal Infirmary Armthorpe Road

Doncaster England DN2 5LT RP5@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Eye Infirmary - University Hospitals Plymouth NHS Trust

Derriford Hospital Derriford Road Derriford

Plymouth England PL6 8DH Z1I9N@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospital Southampton

Southampton University Hospital Tremona Road

Southampton England SO16 6YD NHS Cambridgeshire and Peterborough Integrated Care Board

Gemini House, Bartholemew's Walks, Cambridgeshire Business Park

Cambridge England CB7 4EA Harrogate and District NHS Foundation Trust

Harrogate District Hospital Lancaster Park Road

Harrogate England HG2 7SX The Royal Marsden Hospital Pathology Services

Royal Marsden Hospital Fulham Road Chelsea

London England SW3 6JJ false 1. Previous classical Hodgkin lymphoma treated with chemotherapy ± radiotherapy; no relapse or HL treatment within the past 3 years 2. Age 45–74 years at identification. 3. Ever‑smoker (current or former), with smoking history verified (typically ≥100 lifetime cigarettes or equivalent). 4. Able to undergo LDCT, including ability to lie flat and weight ≤200 kg 5. Medically fit for potential curative‑intent lung cancer treatment (i.e., not severely frail and not on palliative care pathways). 6. Capacity to give informed consent 7. Individuals with a prior thoracic CT within 24 months may participate if imaging meets study standards (still complete LHC, risk assessment, ePRO, etc.) Mixed 45 Years 74 Years All 4400 500 1. Never‑smokers: Individuals with no history of ever smoking 2. Lack of capacity to consent: Unable to provide informed consent at the time of enrolment 3. Incorrect lymphoma diagnosis: Any lymphoma other than classical Hodgkin lymphoma 4. History of lung cancer ≥24 months previously: Participants with a diagnosis of lung cancer occurring ≥24 months prior to identification 5. Unsuitable for LDCT scanning. Including: 5.1. Weight >200 kg 5.2. Unable to lie flat 5.3. Any physical, clinical, or technical contraindication preventing LDCT acquisition 6. Not medically fit for curative‑intent treatment. Including: 6.1. Severe frailty (eFI >0.36) 6.2. Registered on a palliative care register 6.3. Metastatic cancer with poor prognosis 6.4. Any comorbidity making curative treatment inappropriate 7. Self‑referrals from outside England: Individuals self‑referring from outside England are not eligible 2026-09-01T00:00:00.000Z 2027-05-01T00:00:00.000Z Lung cancer risk among survivors of classical Hodgkin lymphoma Cancer SEARCH is a multicentre, pragmatic, real‑world evaluation study integrating a risk‑adapted lung cancer screening pathway for high‑risk Hodgkin lymphoma (HL) survivors within the NHS Lung Cancer Screening Programme (LCSP). Eligible participants are identified through primary care searches and direct referrals across multiple NHS Cancer Alliances in England. Following an opt‑in invitation, participants attend a Lung Health Check (LHC) where informed consent is obtained and standardised data on demographics, clinical history and smoking behaviour are collected. Automated lung cancer risk assessment is performed using the investigational PLCO‑HL risk model alongside standard LCSP risk models (PLCOm2012 and LLPv2). Participants meeting predefined high‑risk thresholds are offered screening. Outcomes are evaluated using routinely collected NHS data and study‑specific assessments. Analyses are primarily descriptive, focusing on screening outcomes, feasibility, acceptability, health inequalities, and economic impact. Interventions The intervention is a risk‑based lung cancer screening pathway, comprising the following components: Risk assessment at Lung Health Check Participants undergo automated lung cancer risk assessment using PLCO‑HL in addition to standard LCSP risk models to identify those at elevated risk. Low‑dose CT (LDCT) screening Participants identified as high risk are offered a baseline LDCT scan delivered under standard NHS LCSP clinical governance. Image acquisition, reporting, nodule surveillance and referral pathways follow existing LCSP protocols. Clinical management of findings occurs entirely within routine NHS care. Follow‑up and outcome assessment Participants are followed for screening outcomes including lung cancer detection, stage at diagnosis, incidental findings and treatment outcomes, using routine NHS records and study data collection at defined follow‑up points. Patient‑reported outcomes (PROs) Participants complete questionnaires at baseline and follow‑up to assess acceptability, experience of screening, anxiety, quality of life and smoking behaviour. Optional saliva sampling (research component) Participants may optionally provide a saliva sample for genetic analysis. Samples are used for exploratory research purposes only, including genotyping and development of polygenic risk scores, and do not inform clinical decision‑making. Smoking cessation support All current smokers are offered brief smoking cessation advice and referral to NHS smoking cessation services in line with LCSP standards. The study does not involve investigational treatments. All imaging and clinical care are delivered through existing NHS pathways, with the intervention focused on risk‑based identification and targeted screening. Device Not Applicable PLCO-HL Not expected to be made available Protocol

7dbaec41-50cc-43c0-8697-6cd3965800e9 adf79d94-5b60-478f-8656-00de37e97230 33880990-0a5d-4aee-a5ee-65ed78123072 fa9e515f-efda-4de8-a70a-f733d6ea11d0 241e9f5f-ffe4-4160-84cf-41358dbc181d No Protocol file ISRCTN11668189_PROTOCOL_V0.7_02Jun2026.pdf 6389e06b-8687-4617-823d-a8d15fd4e7d4 true application/pdf 1604193 6f06597e3e34a7aa152dc232b7d8ed3b Tania Seale https://orcid.org/0000-0003-3791-5290 Public

Floor 6 Paterson Cancer Research Centre Division of Cancer Sciences, The University of Manchester

Manchester United Kingdom M20 4BX +44 7879779259 tania.seale@manchester.ac.uk Public Kim M Linton Scientific Principal investigator

University of Manchester, Oxford Road M13

Manchester United Kingdom M20 4BX +44 7789206562 kim.linton@macnhester.ac.uk Public University of Manchester https://ror.org/027m9bs27 Non-commercial SBRI Healthcare (NHS Cancer Programme Innovation Call) Manchester Biomedical Research Centre http://dx.doi.org/10.13039/100014653