Ebermannstadt, Germany

RDC Biomarker Study

Background The proposed research will focus on Rapid Diagnostic Centres (RDCs) already established across multiple sites in England. Since 2019-2020, RDCs, have begun rolling out nationally across all cancer alliances. They are a single point of access for cancer diagnostics to allow personalised and rapid diagnosis of patients presenting with non-specific but concerning symptoms of cancer (NSCS). Cancer patients with NSCS typically have a longer interval in primary care to referral and have more advanced disease once a diagnosis is made, yet approximately 50% of cancer patients present with NSCS. These patients are poorly served by existing cancer referral pathways which can be circuitous when a clear pattern of symptoms is not present. The objectives of RDCs are to: - Support earlier and faster cancer diagnosis - Create increased capacity through more efficient diagnostic pathways - Deliver a better, personalised diagnostic experience for patients - Reduce unwarranted variation in referral for, access to and in the reliability of relevant diagnostic tests RDCs Limitations Although patients seen in RDCs are presumed to receive faster diagnosis and treatment, there is still very little known about how their vague symptoms developed over time and how these are linked to underlying health conditions, diagnosis, health outcomes and RDC effectiveness. Most RDC patients will not have cancer. Therefore, accurate and rapid triage will be essential and depend upon improved methods of risk stratification and cancer detection. There is both a significant need and opportunity to integrate quantitative research into RDCs to develop and validate novel diagnostic assays, and risk scores based on this unique population of patients. These patients both represent a primary care community, but the enriched cancer prevalence within RDCs could be utilised to facilitate more efficient biomarker development. Rationale Developing pathways to streamline care in this population group is important not only due to the importance of timely detection and treatment, but most patients in these pathways both with and without cancer are more likely to be from more deprived backgrounds or prone to being less engaged with healthcare provision. The implementation specification from NHS England highlights the need for RDCs to tackle health inequalities in their roll out. This study will allow us to generate a sample set and database to examine the potential to: i) discover high risk groups in RDC populations and ii) to detect cancer-specific signals in symptom profiling data; routine clinical and imaging data; and blood and non-blood biomarker tools. The primary aims focus on using descriptive analysis, to identify the following: 1. The number and clinical traits of Benign versus Malignant Diagnoses 2. The number and clinical traits of cancer subtypes (e.g. lung vs ovarian or other cancer) The primary aims also focus on describing how the variability between participants can delineate cancer versus benign pathology using molecular; germline risk, symptom-profiling; and clinical data from each of the four main work packages, independently or in combination using AI-based multi-parametric analysis of these traits: Descriptive analyses will provide feasibility data to develop and validate models using i) Peripheral blood and non-blood (e.g. breath and saliva) molecular signatures that can delineate between cancer and benign pathology. ii) Patient 'symptome' signatures delineating between cancer and benign pathology. iii) Digital health record signature from routinely collected clinical electronic health record (EHR) and/or imaging data and/or the 'standard' RDC dataset that delineate between cancer and benign pathology. iv) Risk stratification tools (e.g. epidemiological and genetic/PRS) that inform risk of cancer in RDC attendees and primary care. Patient Selection Overall, we expect an initial sample size of 1000 patients that will allow several exploratory analyses and simple model development/validation (in distinct datasets) within an observational platform study design. The target recruitment will be increased by the Trial Steering Group (TSG) if new relevant assays are identified, and extended funding is secured. This is supported by previous work which suggests that 1000 patients are more than sufficient to identify candidate biomarkers for further studies, it is a pragmatic approach and is not the result of power calculations. A target goal will be for 75% of cancer cases to have histological confirmation i.e. ground truth of final diagnosis to help power diagnostic accuracy and reliability for any future use of histopathological data Patients recruited will be removed from analysis where ground truth cannot be established by the time of completion of initial investigations or a period of clinical surveillance (not to exceed 12 months of surveillance after initial diagnostic pathway completed). The local Principal Investigator (PI), or members of the delegated clinical care team at participating trusts (e.g. Consultant physicians, nurse specialists, clinical fellows or admin staff), will identify suitable patients via RDC clinic appointments, RDC multidisciplinary team (MDT) lists or by RDC service evaluations, supported where necessary by clinical informatics approaches (e.g. structured query language searches) or local research team. We estimate that each participating hospital will see approximately 20-50 new RDC patients per week, thus we expect that we could recruit large numbers of patients from a small number of RDCs. This estimation may evolve considering the number of participating sites, as well as the evolving nature of how RDCs are utilised, particularly given the impact of the COVID-19 pandemic on cancer diagnosis. Recruitment will be consecutive in the order in which patients are seen within each respective RDC. Allocation of participants to a particular sample type/assay will be pragmatic based on site geography/capability of the RDC at which the patient is recruited. Study Duration The study will end when complete outcome or surveillance data is available for all participants, or after 12 months following recruitment ± completion of clinical assessment of the last patient, whichever occurs sooner. This duration is necessary to ensure confirmation of diagnosis, or stability after discharge and therefore ground truth. It is expected that recruitment will complete within two years. Patient data and samples will be stored for a total of ten years. The ten-year duration of storage is necessary to allow us to utilise more advanced laboratory and data analysis techniques, which may become available with evolving technology. Newer approaches may require very large datasets, and this timeframe would allow for a protocol amendment for expansion of our data and further research to be performed as the field evolves. Upon completion of the study, we will establish a research database for future work and will store patient data for a total of ten years. Assessment of imaging data quality and integrity and suitability of research specimens for laboratory analysis will be contemporaneous to patient recruitment/sample receipt and ongoing thereafter. Analysis will typically be performed on patients with confirmed ground truth by biopsy or sufficient clinical surveillance if benign e.g. 12 months (see above) but scans performed after this period may be accessed if future relevant data become available. Enrolment and Consent Patient enrolment into the study will occur once consent is taken and eligibility criteria is met. A trial number will be allocated to each patient for the identification research samples. In most cases, patients will donate a blood specimen on one visit (Baseline). Where recurrent visits to the hospital for surveillance CT scans are made over a longer period, then up to 3 blood specimens will be collected in total with a minimum of 21 days between each research specimen collection or a treatment intervention. This will allow the consideration of evolution of the biomarker signal in question as a determinant of cancer presence or absence (using the logic that a given signal is likely to increase alongside tumour growth and therefore be easier to detect in comparison with samples from patients without malignancy). All participants are free to withdraw at any time from the protocol treatment without giving reasons and without prejudicing further treatment. The patient can request that any remaining samples donated are destroyed. All members of the delegated research team will ensure that patient confidentiality is maintained in compliance with the UK Data Protection Act 2018 and General Data Protection Regulation Patient Samples, Acquisition and Processing The laboratory manual will provide further details of the collection, processing, and storage of specimens. Study Oversite A Trial Steering Group (TSG) will meet on a regular basis to provide overall study oversight and clinical or scientific steer - particularly for academic/research considerations. In addition, a Trial Management Group (TMG) will meet quarterly to discuss patient recruitment, data collection, data management, data analysis, reporting for adverse events, and change management. The minutes of these meetings will be made available, and a rolling agenda will highlight any ongoing actions or concerns. In addition, the trial management team will provide day-to-day support for trial administration, including all rules and regulations concerning research studies in the UK. This includes: UK Policy Framework for Health and Social Care Research, Data Protection Act 2018 and UK General Data Protection Regulations Data Analysis and Statistical Considerations Statistical guidance and study design oversight will be provided by RM-ICR guided by the CI and Lead Statistician/Data Scientist and will be undertaken in partnership with academic partner institutions named in the protocol ± support from other academic centres. Data sharing agreements will be in place in each case. A full Data Analysis Plan will be assembled and ratified by the Trial Steering Group at its creation and on any subsequent amendment. Clinical Data analysis The main analysis, including clinical data values, will be descriptive and will be focused to inform future prospective studies. For continuous variables, the mean and standard deviation will be presented, together with the mean between-group difference, and 95% confidence interval. For binary outcomes, the percentage and frequency of patients in the outcome category of interest will be presented. When necessary intracluster correlation coefficients will be reported, together with 95% confidence interval. Where appropriate p-values will be presented. Baseline characteristics, collected at the time of commencing the study will provide an overview of the study population, both at the RDC and site level. It is expected that patients may differ based on which RDC they are recruited at and described with summary statistics including the index of multiple deprivation score for the RDC postcode, percentage of patients with comorbidities, and the cancer type. At the individual patient level, variables can include gender, age at baseline data collection, individual Index of Multiple Deprivation (IMD) values, baseline measures of all physiological measurements, comorbidity. Baseline characteristics will be summarised as the mean, standard deviation and range for continuous, approximately symmetric variables; medians, interquartile range and range for continuous, skewed variables; frequencies/percentages of patients/RDC in each category for categorical variables. Laboratory Data Analysis Analysis of laboratory data will lie in the first instance with the clinical and scientific lead for each work package with further details provided in the laboratory manual and local laboratory protocols. The assays will give a read out for each patient that will be assessed using receiver operating characteristic curve analysis against each endpoint. Firstly, this will be performed using a single biological parameter for cancer versus non-cancer, or most likely cancer subtype, and then in combination with other laboratory and clinical endpoints as a multiparametric signature for the same endpoints as outlined in the protocol.

Clinical and Immunogenetic Characterization of Giant Cell Arteritis (GCA) and Polymyalgia Rheumatica (PMR)

Giant cell arteritis (GCA), also known as temporal arteritis, is the most common form of primary systemic vasculitis, with up to 75,000 cases a year identified in the EU and US. It occurs almost exclusively in people over the age of 50 years and is considered to be a medical emergency. If not treated with high-dose glucocorticoids immediately, the thickening of the inflamed blood vessel wall can cause irreversible visual loss or stroke. GCA can lead to significant morbidity across a variety of systems, due to both the disease, and complications of treatment. Diagnosis may be confirmed with a temporal artery biopsy, imaging (e.g. USS/CT/MRA/PET-CR) or based on clinical signs (e.g. erythrocyte sedimentation rate) and symptoms (e.g. a new headache, jaw claudication, visual disturbances, temporal artery abnormality such as tenderness or decreased pulsation) . Polymyalgia rheumatica (PMR) is characterised by inflammatory limb-girdle pain with early morning stiffness, and a systemic inflammatory response demonstrated by elevated inflammatory markers. The UK GCA Consortium is a multi-centre observational study, the main arms of which recruit prospective (participants with suspected GCA) and retrospective cohorts (participants with confirmed GCA diagnosis). Analysis of data collected on these cohorts will help achieve the primary aim of finding genetic determinants of GCA and PMR susceptibility, in order to yield novel insights into disease pathogenesis. Secondary aims, and their associated analyses, are as follows: - Phenotype: characterising GCA and PMR subtypes, based on clinical features; imaging; cells; subcellular fractions and molecules in the circulation and/or arterial tissue; genetic/epigenetic/transcriptomic/proteomic or metabolomics factors, including next generation sequencing (whole exome sequencing) of selected cases. - Life impact: determining what aspects of the disease and treatments affect patients' quality of life, as assessed by patient-reported outcomes. - Long-term outcomes: characterising prognosis of GCA and PMR - both effects of the disease and its treatment - by longitudinal follow-up through electronic linkage to health records. - Exploratory analyses: exploring the potential role of environmental factors and co-morbidities on phenotype and outcomes. - Diagnosis, prognosis: improving diagnosis of GCA and PMR, and identifying factors that predict diagnosis, such as diagnostic clinical features, and prognostic and diagnostic biomarkers. - Disease activity: monitoring participants who commence a synthetic or biological disease-modifying anti-rheumatic drug (s/bDMARD). Finding a biomarker for GCA and PMR disease activity, which might be clinically useful in helping to optimise steroid and s/bDMARD treatments for individual patients.

Axillary Management in Breast Cancer Patients with Needle Biopsy Proven Nodal Metastases After Neoadjuvant Chemotherapy

Background: The presence of cancer in the axillary lymph nodes on needle biopsy in patients with early stage breast cancer before neoadjuvant chemotherapy (NACT) has been the determinant of the need for axillary treatment (in the form of axillary lymph node dissection (ALND) or axillary radiotherapy (ART)) after completion of NACT. Treatment to the axilla damages lymphatic drainage from the arm and patients can subsequently develop lymphoedema, restricted shoulder movement, pain, numbness, and other sensory problems. As more effective chemotherapy is now available that results in complete eradication of cancer in the axilla in around 40 to 70% of patients, extensive axillary treatment might no longer be necessary in patients with no evidence of residual nodal disease. Aim: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy, who after NACT have no residual cancer in the lymph nodes on sentinel node biopsy, is non-inferior to axillary treatment in terms of disease free survival (DFS) and results in reduced risk of lymphoedema at 5 years. Methods: Study design: A pragmatic, phase 3, open, randomised, multicentre trial and embedded economic evaluation in which participants will be randomised in a 1:1 ratio. Study population: T1-3N1M0 breast cancer patients aged 18 years or older, with needle biopsy proven nodal metastases, who after NACT have no residual cancer in the lymph nodes on dual tracer sentinel node biopsy and removal of at least 3 lymph nodes (sentinel nodes and marked involved node). Intervention: All participants will receive human epidermal growth factor receptor 2 (HER2)-targeted treatment, endocrine therapy and radiotherapy to breast or chest wall, if indicated according to local guidelines. Patients in the intervention group will not receive further axillary treatment (ALND or ART), whereas those receiving standard care will receive axillary treatment (ALND or ART) as per local guidelines. Follow-up is annually for at least 5 years. Outcomes: The co-primary outcomes are disease free survival(DFS) and self-reported lymphoedema defined as 'yes' to the two questions participants will be asked - 'arm heaviness during the past year' and 'arm swelling now' from the Lymphoedema and Breast Cancer Questionnaire at 5 years. Secondary outcomes: arm function assessed by the QuickDASH (disabilities of the arm, shoulder and hand) questionnaire; health related quality of life assessed using euroqol EQ-5D-5L; axillary recurrence free interval (ARFI); local recurrence; regional (nodal) recurrence; distant metastasis; overall survival; contralateral breast cancer; non-breast malignancy; costs; quality adjusted life years (QALYs) and cost-effectiveness. Sample size: A sample size of 1900 patients would have the ability to demonstrate a 3.5% non-inferiority margin with a 5% 1-sided significance level and 85% power, allowing for 7% non-collection of primary outcome data assuming a 90% 5-year disease free survival rate in the control arm. It would also be able to detect at least a 5% difference in proportion of patients with lymphoedema with 90% power, a 5% 2-sided significance level and allowing for 25% non-collection of primary outcome data over 5 years. Analysis plan: All analyses will be carried out on an intention-to-treat basis to preserve randomisation, avoid bias from exclusions and preserve statistical power. Time to event outcomes, including disease free survival and axillary recurrence free interval, will be assessed using Kaplan-Meier curves and compared using Cox proportional hazards models. The proportion of patients experiencing lymphoedema at 5 years will be compared across trial arms using a chi-squared test and a logistic regression model used to adjust for stratification variables. Arm morbidity and health related quality of life will be scored using the appropriate manuals and assessed using a longitudinal mixed model regression analysis if model assumptions valid or a standardised area-under-the-curve analysis. For economic evaluation, incremental cost per QALY gained at 5 years will be estimated. Timelines for delivery: Total project duration is 120 months based on 6 months for set up; 60 months recruitment period (including an 18 months internal pilot phase); and 54 months for follow up, analysis, writing up and dissemination.

PreOperative Endocrine Therapy for Individualised Care With Abemaciclib

In women with hormone sensitive early breast cancer, taking a hormone therapy (also known as endocrine therapy) for at least five years after surgery is very effective at reducing the risk of the cancer returning. However, for some women their cancer may eventually become resistant to these drugs. POETIC-A Registration part will identify those who have a higher risk of developing resistance to standard endocrine therapy (ET). At least 8000 women diagnosed with early stage breast cancer will enter the Registration stage from 80 centres. Study doctors will use aromatase inhibitors (AIs), a type of ET, to treat the cancer for between 2 weeks and 6 months before surgery. A sample will be taken from the cancer during surgery and the study laboratory will measure a biological marker called Ki67. If the level of Ki67 does not drop after 2 weeks of AI treatment, the patient is likely to be less sensitive to endocrine therapy, and the study doctor will explore additional treatments after surgery in the POETIC-A Treatment part. Everyone who agrees to join the Treatment stage (2032 patients) will be randomly put into one of the 2 treatment groups; Group1: ET only; or Group2: ET plus a new drug called abemaciclib. The first aim of the Treatment stage is to confirm whether abemaciclib given in combination with ET is more effective than giving ET alone in preventing the cancer coming back. The study laboratory will perform a second test on the cancer sample, called an AIR-CIS test. This test aims to find out if particular groups of patients based on their tumour biology are more suitable for treatment with abemaciclib. Patients in Group 2 will receive ET plus abemaciclib for 2 years. Patients in both groups will have regular study visits during this period.

Improving Radical Treatment Through MRI Evaluation of Pelvic Sigmoid Cancers

A randomised phase II multicentre trial, IMPRESS will determine whether the use of MRI imaging in staging sigmoid cancers results in a change to the treatment plan by identifying more high risk tumours compared to those patients who were staged using CT imaging. The proposed intervention will be additional radiological and pathological assessment and the reporting of supplementary diagnostic information which would not otherwise have been available. This may affect treatment according to local MDT protocols and also affect the provision of prognostic information to patients in subsequent discussions.

The Role of Ixazomib in Autologous Stem Cell Transplant in Relapsed Myeloma - Myeloma XII (ACCoRd)

Myeloma XIV: Frailty-adjusted Therapy in Transplant Non-Eligible Patients With Newly Diagnosed Multiple Myeloma

A Study to Assess Disease Activity and Safety of Lutikizumab in Adult and Adolescent Participants With Moderate to Severe Hidradenitis Suppurativa

A Study to Evaluate the Efficacy and Safety Study of Povorcitinib in Participants With Prurigo Nodularis (STOP-PN2)

Study to Evaluate the Efficacy and Safety of Ruxolitinib Cream in Participants With Hidradenitis Suppurativa (TRuE-HS1)