NIHRDataInsights/HRCSData huggingface dataset:
Title: Optimizing MATrix as remission induction treatment for newly diagnosed primary CNS Lymphoma – a randomized phase III trial (OPTIMATE trial)
Funder: Cancer Research UK

Abstract: OptiMATe is an international phase 3 trial, designed in partnership with the German Lymphoma Alliance, for patients with primary CNS lymphoma (PCNSL) who are eligible for intensive treatment including consolidation with high-dose chemotherapy and autologous stem cell transplant (HDT-ASCT). Primary CNS lymphoma is a rare and aggressive blood cancer but also a brain tumour and represents an area of unmet need. Background The current standard of care for patients with PCNSL is the MATRix immunochemotherapy regimen followed by consolidation with HDT-ASCT. MATRix followed by consolidation HDT-ASCT was adopted into standard practice following the success of this approach in the CRUK-funded IELSG32 trial. The MATRix combination, although effective, is associated with significant treatment-related morbidity and mortality as well as representing a substantial treatment burden for patients. Toxicity of remission induction therapy is a major factor in preventing patients from proceeding to HDT-ASCT consolidation. Importantly, proceeding to consolidation therapy appears to be crucial for survival; two-year overall survival rates of approximately 80% were achieved in patients undergoing HDT-ASCT per protocol in the IELSG32 study. To allow more patients to undergo HDT-ASCT, the toxicity of the induction therapy needs to be addressed. Importantly, there are no existing pathobiological or imaging biomarkers that can reliably predict outcome in PCNSL. Aims This trial is investigating whether a two-step optimisation approach to remission induction therapy with MATRix can reduce toxicity and treatment burden, enabling more patients to proceed to HDT-ASCT and improve survival outcomes. Additionally, by integrating a programme of UK-led translational research with imaging and lymphoma biology studies, we aim to identify baseline and/or dynamic biomarkers to delineate PCNSL risk groups. Methods OptiMATe is a randomised phase 3 superiority design with a primary endpoint of 2-year event-free survival. Patients will be randomised between the control arm (4 cycles of MATRix followed by HDT-ASCT) and the experimental arm. Patients in the experimental arm will receive one cycle of rituximab and high-dose methotrexate only; this less intensive initial treatment cycle aims to improve the patient's performance status and neurocognitive function and reduce early treatment-related morbidity and mortality. The second optimisation step involves abbreviation of MATRix induction to 2 cycles only. Responding patients in both arms will proceed to HDT-ASCT. How will the results be used? If the experimental arm is successful, this will be a practice-changing study and quickly effect change in routine standard care. Translational biomarker outputs will inform the next phase 3 study in PCNSL.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: A statistical dynamic system for breast cancer prognosis and patient monitoring
Funder: Cancer Research UK

Abstract: Background: The identification of biomarkers that can provide clinically relevant information about breast cancer patients’ prognosis has been a very important topic of research, and several tools have been proposed and commercialised. However, all of them present several limitations, as they are only useful for specific subtypes of patients at specific timepoints. Aims: We aim to develop a dynamic prognostic and patient monitoring tool based on a multistate survival model that will track a patient from the moment of diagnosis throughout her full clinical pathway, updating accordingly the predictions when new information becomes available. The model will integrate clinical features, molecular biomarkers and individual frailty. The system will also include a test strategy based on an affordable sequencing assay. Methods: Our goal is to develop a statistical model that can integrate information from all relevant molecular biomarkers leveraging different available datasets. We will use machine learning techniques to extract the minimal subset of features needed and calibration and transfer learning techniques to overcome the limitations of individual cohorts. We propose the use of frailty models to understand the role of individual variability around the population hazards, an important feature that has not been properly studied yet. We will use existing data to derive a distribution that reflects this variability through different sources, such as intrinsic features of the patient, intrinsic features of the tumour and frailty induced over time. A systematic study of these effects on the individual probability of relapse will produce more accurate predictions and increase our understanding of why some tumours are more aggressive or are resistant to standard therapies. We plan to extend our current multistate model with additional states and transitions to reflect two scenarios: 1) the effect of neoadjuvant therapy whereby attaining pathological complete response will modify the subsequent probabilities of relapse, and 2) the patient’s status after metastatic disease, allowing for a more successful monitoring of disease progression and treatment response through the incorporation of information from plasma samples (such as circulating tumour DNA). How the results of this research will be used: These relevant biomarkers will be incorporated into an affordable sequencing essay that, together with the model, will form a prognosis and monitoring system for breast cancer patients that can help making better informed decisions and guide treatment. If successful, this approach can be extended to other cancer types.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: POINTER-PC: Pelvis Or Involved Node Treatment: Eradicating Recurrence in Prostate Cancer
Funder: Yorkshire Cancer Research

Abstract: Over 4,500 Yorkshire men are diagnosed with prostate cancer each year. Even after curative treatment, prostate cancer can come back in the glands (known as nodes) in the pelvis. When this happens, men can then be treated with highly targeted x-rays called Stereotactic Ablative Radiotherapy (SABR for short), which treats only the affected glands in 3 to 5 treatment visits. However further cancer can develop in other pelvic glands, and therefore, widening the area treated may be better at stopping the cancer from returning. Treating this larger area is called Extended Nodal Irradiation (ENI for short). ENI is usually given in 20 visits but could also be given in 5, which would be more convenient, but we need to be sure that that the side effects are similar. People in this study will receive SABR as normal or ENI in 5 or 20 treatment visits, decided randomly: neither the doctor nor patients choose their treatment; instead, the computer decides, meaning the study is more likely to find the true result. This study will find out if: ENI is better at stopping the cancer spreading than SABR The side effects with 5 ENI treatments are similar to 20 ENI treatments.

Lay abstract: Over 4,500 Yorkshire men are diagnosed with prostate cancer each year. Even after curative treatment, prostate cancer can come back in the glands (known as nodes) in the pelvis. When this happens, men can then be treated with highly targeted x-rays called Stereotactic Ablative Radiotherapy (SABR for short), which treats only the affected glands in 3 to 5 treatment visits. However further cancer can develop in other pelvic glands, and therefore, widening the area treated may be better at stopping the cancer from returning. Treating this larger area is called Extended Nodal Irradiation (ENI for short). ENI is usually given in 20 visits but could also be given in 5, which would be more convenient, but we need to be sure that that the side effects are similar. People in this study will receive SABR as normal or ENI in 5 or 20 treatment visits, decided randomly: neither the doctor nor patients choose their treatment; instead, the computer decides, meaning the study is more likely to find the true result. This study will find out if: ENI is better at stopping the cancer spreading than SABR The side effects with 5 ENI treatments are similar to 20 ENI treatments.

Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/036: SIOP Intracranial Ependymoma II; An international clinical trial for the diagnosis and treatment of children, adolescents and young adults with intracranial Ependymoma
Funder: Cancer Research UK

Abstract: Background: The clinical management of ependymoma in Childhood to young adults is complex and the clinic-pathological correlates of outcome remain poorly understood. Overall the prognosis remains poor and at relapse is dismal. Close to half of the patients may ultimately die from the disease and those that survive face serious long-term sequalae. Despite this there is currently no clinical trial open in Europe for Children and young people with Intracranial ependymoma. The outcome for ependymoma is likely to be enhanced by simply improving the accuracy of diagnosis and harmonising the standard of care following initial surgery' as well as investigating enhanced adjuvant strategies Aims: To test the hypothesis that there will be an improvement in EFS and OS in patients who receive 6 cycles of chemotherapy following complete surgical resection and radiotherapy when compared to those that undergo complete surgical resection and radiotherapy alone To evaluate the efficacy of the front line window chemotherapy in patients with residue after surgery in a randomised Phase II study To determine the Toxicity, feasibility and outcomes of a 8 Gy boost in patients with residue after surgery who received 59.4 Gy To evaluate the efficacy of adding Valproic acid as a Histone deacetylase inhibitor to primary chemotherapy strategy for children ineligible to receive radiotherapy through age, tumour location or parental / Clinician choice through a randomised Phase II study To test the hypothesis that Conformal Radiotherapy does not adversely affect Neuro-Cognitive outcomes in Children with ependymoma To test the hypothesis that key molecular events in paediatric ependymoma pathogenesis are predictive of clinical behaviour Methods: 500 patients under 21 years of age throughout Europe will be recruited to 3 main study arms depending on age tumour, location and extent of surgical resection. Central review will verify allocation to study arm. Prospective biological studies agreed by European ependymoma biology consortium Biomarkers of Ependymomas in Children and Adolescents (BIOMECA) will investigate the molecular pathology of ependymoma, define Clinico-pathological markers for future patient treatment stratification, identify molecular markers that are valid surrogates of response to treatments, provide experimental evidence to guide future therapy and characterise of novel disease features. The Neuropsychological and Quality of life of survivors will be rigorously assessed How the results of this research will be used. To determine the new standards of management and treatment for ependymoma


Research activity codes: 6.1 PHARMACEUTICALS;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: IMAXT : imaging and molecular annotation of xenografts and tumors
Funder: Cancer Research UK

Abstract: We propose to develop an entirely new way for scientists and physicians to understand cancer and predict its clinical behaviour. Our integrated approach will produce faithful three-dimensional representations of tumours and their host environments, wherein each cell is identified and molecularly annotated. These models will be presented in an interactive, virtual reality (VR) framework. Investigators will literally be able to walk inside a tumour, visualize the arrangement of tumour cells in relation to each environmental cell type, and perform interactive comparative molecular analyses in real time. We call this project IMAXT, Imaging and Molecular Annotation of Xenografts and Tumours. This approach harnesses our innate pattern recognition capabilities while maintaining the statistical rigour of molecular measurements. We wish not only to provide research tools that allow us to better understand how cancer develops and responds to therapy but also to transform the way that patients are diagnosed and treatments planned. Though this approach will be applicable to nearly all tumour types, we will begin in breast cancer, where both inter- and intra-individual heterogeneity are apparent and inform treatment decisions and prognosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Modelling the prevention of childhood acute lymphoblastic leukaemia
Funder: Cancer Research UK

Abstract: Childhood acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer in the UK and in most developed societies and now benefits from a high cure rate, albeit with toxic chemotherapy with some long term health consequences. Its causation has long been contentious. Accumulated evidence indicates that, as long suspected, common infections play a role, but in a manner that is paradoxical. A major risk factor (in a complex or multifactorial causation) appears to be a deficit of microbial infections and immune network priming during the first year of life. In this context, subsequent, or ‘delayed’ common infections are dysregulated and can trigger the emergence of an overt ALL clone from within a previously covert pre-leukaemic cell population generated pre-natally. The relevant immune priming microbes in infants are likely to be beneficial bacteria that form part of the so-called human microbiome. This suggests that ALL might be preventable by reconstitution of a more diverse microbiome in infancy. We now have an animal model of infection-driven ALL in which this prospect can be evaluated. In this model, mice expressing the common ALL-initiating fusion gene ETV6-RUNX1 develop ALL if switched from a specific pathogen-free environment to conventional housing with endemic pathogens. This broadly parallels what we believe occurs when infants who, having acquired a ETV6-RUNX1 fusion gene in utero, transit from a relatively isolated home environment into schools with multiple social contacts and opportunities for infectious exposures. The long term goal is to prevent or reduce the incidence of ALL, by microbiome reconstitution in infancy.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS
Title: KHP ECMC
Funder: Cancer Research UK

Abstract: We intend to focus our ECMC functions on the design and delivery of highly novel new systemic therapies, including and especially first-in-class agents, and on new surgical devices and imaging for surgery. It is our aspiration that a significant subset of these novel interventions to be tested in the clinical setting will arise from preclinical discovery and development work in the King’s Health Partners laboratories. Several of the currently planned trials, and some already recruiting in our ECMC, conform to this description, and provide confidence that we can deliver on this ambitious aspiration. The clinical exploitation of new therapies originating in-house, particularly molecular and cellular immunotherapies delivered as academic studies, will be matched by trials arising from industry collaboration, whether with colleagues in the pharmaceutical industry, in smaller biotechnology counterparts, or medical device companies. We will apply funding to key members of staff to facilitate planned recruitment to, and GMP production for, phase I trials of i) Molecular immunotherapies, ii) Cell immunotherapies, and iii) Small molecules. We will also support application of iv) Pharmacodynamic biomarkers and imaging in early phase trials, and v) Novel devices and imaging in surgery.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: Leicester ECMC
Funder: Cancer Research UK

Abstract: Delivering cancer Research that transforms lives The Leicester ECMC will deliver innovative cancer research of the highest calibre by building on the close working relationship and strengths within the University of Leicester and University Hospitals of Leicester NHS Trust and developing our key strategic partnerships. Specifically, multidisciplinary research groups comprising clinical and basic scientists will work together for the benefit of patients to: 1. Increase the number of agents investigated in early phase trials for treatment and prevention; particularly in the fields of haematological malignancies, lung, mesothelioma and colorectal cancers. This will include novel compounds discovered through the Leicester Structural and Chemical and Biology Institute, Pharmaceutical Industry contacts, repurposed drugs and links with other ECMCs. We will increase the number of clinical studies developed and led by Leicester academics and research focussed NHS clinicians. 2. Optimise treatment opportunities for patients by genotyping patients attending the Hope Clinical Trials Facility to personalise drug selection, • utilising cfDNA genomic profiling to monitor for disease recurrence, • using reverse translation approaches to understand patterns of resistance • developing ex vivo models to aid drug discovery for the benefit of patients. 3. Increase links with industry and other ECMCs through joint early phase studies, which recognise the individual strengths of ECMC collaborators, and share our biomarker techniques through our new Molecular Diagnostic Laboratory Infrastructure.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Liverpool ECMC
Funder: Cancer Research UK

Abstract: The primary strategic areas of the proposed Liverpool ECMC are pancreatic cancer and haemato-oncology, with expertise in cancer biology and pharmacology to develop novel biomarkers of efficacy, resistance and drug safety. Other areas of focus supported by local expertise are breast cancer brain metastases, hepatobiliary cancers, urological oncology, and uveal melanoma. These cancers are important in terms of unmet patient needs and Liverpool has particular expertise and resources to contribute to the ECMC Network in these areas.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: Reducing Inequalities in Cancer Outcomes in Yorkshire: Realising our potential for innovation in Diagnosis, Patient Management, Survivorship and Palliative Care Research
Funder: Yorkshire Cancer Research

Abstract: The death rate is higher in Yorkshire than the rest of England resulting in about 200 extra deaths each year of which more than half are in Hull. There are other significant cancer outcome inequalities between different groups; for example poorer people and older people are more likely to die sooner. We will conduct research to understand these differences and develop and test ways to reduce the inequalities and improve access to care and best treatments. We need to attract the best researchers to Yorkshire to do this work and attract more national research funding.

Lay abstract: The death rate is higher in Yorkshire than the rest of England resulting in about 200 extra deaths each year of which more than half are in Hull. There are other significant cancer outcome inequalities between different groups; for example poorer people and older people are more likely to die sooner. We will conduct research to understand these differences and develop and test ways to reduce the inequalities and improve access to care and best treatments. We need to attract the best researchers to Yorkshire to do this work and attract more national research funding.

Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CANCER AND NEOPLASMS
Title: Fibroblast Activation Protein Expressing Cancer Associated Fibroblasts From Lung Cancer As Imaging Biomarkers For Immunotherapy Stratification
Funder: Cancer Research UK

Abstract: Background Lung Cancer remains a cancer of unmet need and is the leading cause of cancer related death. Cancer immunotherapy treatments have gained clinical approvals in non-small cell lung cancer (NSCLC) as they have shown efficacy in refractory disease. However, response is only seen in a small proportion of patients with failure in the majority, raising critical questions: ‘Is there immune recognition evasion in NSCLC?’ and ‘Could in vivo imaging biomarkers be used to predict response in adaptive treatment regimens?’ My fellowship application focuses on a subtype of cancer associated fibroblasts which express fibroblast activation protein (FAP+CAFs). Pre-clinical studies have suggested targeting FAP (+/- companion therapeutics) can result in accelerated immunotherapy-mediated tumour death in non-pulmonary solid organ malignancies, with the CXCL12/CXCR4 chemokine axis playing a crucial role. My hypotheses are: • In human NSCLC, FAP+CAFs mediate immune recognition evasion through the CXCL12/CXCR4 axis. • Novel translational imaging compounds can identify FAP+CAF presence and activity in humans. Aims and Methods Aim 1: Isolation, identification and phenotyping of FAP+CAFs from human NSCLC. Primary culture of NSCLC will assess the FAP+CAF (against paired normal fibroblasts) for markers of fibroblast activation, regenerative capacity and differential proteomic/cytokine expression (focusing on the CXCL12/CXCR4 pathway). Aim 2: Delineation of the contribution of FAP+CAFs in the tumour microenvironment to immune recognition evasion. A) To delineate the ex vivo spatiotemporal location of T-cells in NSCLC following pharmacotherapy in a precision cut lung slice model. B) To develop a murine model to assess companion pharmacotherapy with immunotherapy and incorporate in vivo dual photon imaging. T-cell recruitment will be assessed following FAP inhibition and CXCL12/CXCR4 blockade in A) and B) and synergistically with immunotherapy treatment in B). Aim 3: To develop two novel clinical-grade FAP imaging agents for future translational studies. A) A PET tracer to image FAP+CAF distribution in humans. B) A peptide based optical imaging probe to determine FAP+CAF activity in humans utilising fiber based optical endomicroscopy during bronchoscopy. Clinical grade development of radiolabelled mAb for FAP (A) and FAP optical probe (B) will be undertaken to allow for measuring FAP presence, distribution and activity in vivo. How the results of this research will be used. The proposal will allow critical insights into the role of FAP+CAFs in immune mediated evasion in NSCLC and develop translational imaging tools to study these in vivo. Ultimately, these translational approaches aim to stratify patients for adaptive immunotherapy regimes.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS