NIHRDataInsights/HRCSData huggingface dataset:
Title: CRUK/12/045: ESPAC-5F Four arm, prospective, multicentre, randomised Phase II trial of immediate surgery compared with neoadjuvant chemotherapies and neoadjuvant chemoradiotherapy
Funder: Cancer Research UK

Abstract: Background Patients with borderline resectable pancreatic cancer (BR) have low resection rates and poor survival compared with patients who have clearly resectable (RS) tumours despite high quality surgery and adjuvant therapy. Meta-analyses have identified that these patients may benefit most from neoadjuvant therapy and should be the subject of a trial. Neoadjuvant therapy needs to be assessed in this group of patients to see if their outcomes can be improved. The success of previous (ESPAC-1, 3v2) and ongoing (ESPAC-4) ESPAC trials provide the infrastructure and collaboration needed for a neoadjuvant study in pancreatic cancer. Aims The aim of this study is to assess the feasibility and outcomes of comparing immediate surgery (Arm A) with either neoadjuvant gemcitabine plus capecitabine (GEMCAP) (Arm B), neoadjuvant oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX ) (Arm C) or neoadjuvant capecitabine based chemoradiotherapy (CRT) (Arm D) followed by surgery in patients with borderline resectable pancreatic cancer. Methods The study is a four arm, open label, randomised feasibility study. Patients with borderline resectable, histologically confirmed pancreatic cancer will be randomized between the four arms of the trial. Patients who undergo resection will receive standard adjuvant chemotherapy. Patients who do not undergo successful resection will receive further therapy as physician’s choice. All patients will be followed up for 12 months after randomization. There will be agreed standard surgical protocols and quality assurance for radiology, radiotherapy and pathology. 40 patients will be recruited to Arm A, 20 to each of Arms B, C and D. The sample size is large enough to compare the resection rate of the combined arms of Arm B, Arm C and Arm D with that for Arm A (using a 1-sided test (n1=40, n2=60, p1=0.35, p2=0.55, significance level = 0.2, power =82%). Primary outcome measures: 1. Recruitment rate 2. Resection rate (R1 + R0) Secondary outcome measures: 1. R0 resection margin rate 2. Toxicity 3. Post operative complication rate 4. Post operative mortality rate 5. Response rate 6. Disease free survival rate 7. Local disease free survival rate 8. Overall survival 9. Quality of life How the results of this research will be used The results of this trial will be used to inform a Phase III follow on trial. Overall survival data will be censored by the Data Monitoring Committee to allow inclusion of study participants in any follow-on Phase III trial, which will be powered for overall survival as the primary endpoint.


Research activity codes: 6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Support for ASH’s full programme of work to eliminate the harm caused by tobacco. This involves working collaboratively to ensure that effective tobacco control remains well funded by Government, prioritised by the public health community, promoted by the media and supported by the general public.
Funder: Cancer Research UK

Abstract: ASH is a campaigning public health charity working to eliminate the harm caused by tobacco, responsible for more than a quarter of all cancer deaths. ASH’s work helps Cancer Research UK achieve its objectives as every percentage point reduction in smoking prevalence leads to an annual reduction of around 1500 deaths from cancer in England alone. Although our main focus is England we collaborate internationally and with sister organisations in the UK’s devolved administrations to maximise our effectiveness. England accounts for 84% of the UK population and parliament in Westminster leads on non-devolved issues such as tax and smuggling. Therefore policy changes in England make a major contribution to reducing UK-wide smoking prevalence. We are a small, cost-effective and focused organisation working at the cutting edge of tobacco policy development and strategic planning. We aim to ensure that our work complements that of Cancer Research UK. By funding ASH Cancer Research UK leverages support from the Smokefree Action Coalition which is coordinated and led by ASH. ASH has three core functions – campaigning, information, and networking and coalition building: 1) To press for particular concrete policy measures that will reduce the burden of addiction, disease, health inequalities and premature death attributable to tobacco – our campaigning function. 2) To change the climate of understanding, opinion and awareness about the “tobacco epidemic” through effective use of the evidence base – our information function. 3) To engage and inform other organisations and persons in pursuing our information and campaigning work – our networking and coalition building function. We are active at local, regional, national and international level. Our major priorities over the next three years which include the 2015 general election are: 1) To support sustained and effective funding of tobacco control at national, regional and local level and a successful transition to local authority control; 2) To ensure legislation is brought before parliament to implement plain, standardised packaging of tobacco products; and 3) To support the successful revision of the EU Tobacco Products Directive. The proposed activities give a sense of priorities and direction, rather than a prescriptive work programme, as ASH as a campaigning organisation needs to have the capacity to be able to react flexibly to changing political circumstances as they arise. In this we are very different from research organisations, so that our work programme will by necessity be general rather than specific.


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CANCER AND NEOPLASMS
Title: Sample collection, sample preparation and central pathology review including slide scanning from patients with operable oesophageal cancer recruited into the UK NCRI OE05 trial
Funder: Cancer Research UK

Abstract: Background<br/>The MRC-OE02 trial demonstrated a significant survival benefit for the pre-operative<br/>chemotherapy arm (cisplatin/5FU [CF]) which is now the standard of care for patients<br/>with resectable oesophageal cancer in the UK. However, even with pre-operative<br/>chemotherapy the 5 year survival rate of patients with oesophageal cancer is still<br/>very poor at 23%. The OE05 trial was designed to investigate whether preoperative<br/>chemotherapy with 3 drugs (epirubicin, cisplatin and capecitabine (oral form of 5-<br/>FU)) improves outcome of patients with oesophageal adenocarcinoma compared<br/>to OE02-type 2 drug pre-operative chemotherapy. The OE05 trial was closed for recruitment in October 2011 and is currently the largest trial in patients with oesophageal adenocarcinoma in the World. <br/><br/>Aims<br/>We aim to (i) complete our ongoing collection of slides and paraffin blocks from the pre-treatment biopsy sample and the resection specimen; to (ii) to centrally review the pathology of at least 90% of cases and to (iii) scan slides, extract DNA and RNA and produce tissue microarrays of at least 80% of cases for future research. <br/><br/>Methods<br/>This is an ongoing study. All centres which recruited patients into the OE05 trial have been contacted to request slides and paraffin blocks. The central pathology review is currently performed on glass slides to reduce costs for scanning. The biopsy slide and selected slides from the resection are scanned and will be made available via the internet on request. DNA (from blood or alternatively normal tissue and from tumour), RNA (tumour) and triplicate tissue microarrays is prepared and stored appropriately. <br/><br/>How the results of this research will be used<br/>The central pathology review will ensure that high quality pathology data are available for the analysis of the clinical data. The tissue collection and stored derivatives together with the scanned images will be a unique resource to validate our results from the translational studies in the OE02 material, identify markers that predict response to epirubicin, establish the frequency of potential new drug targets such as HER2, FGFR2, EGFR and VEGF and perform integrative analysis of molecular and morphological phenotypes.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUK/13/004: ABC-06: A randomised phase III, multi-centre, open-label study of Active Symptom Control (ASC) alone or ASC with oxaliplatin/5-FU CT for patients with locally advanced/metastatic biliary tract cancers previously treated with cisplatin/gemcitabine CT (supported by Stand Up To Cancer)
Funder: Cancer Research UK

Abstract: Background Advanced biliary tract cancer (ABC; incorporating cholangiocarcinoma and cancers of the gallbladder and ampulla) carries a poor prognosis with a 5-year survival rate of 5-15%; a major limitation to progress is the relative infrequency of these tumours and consequence lack of adequately-powered clinical trials. Although many phase II studies had suggested that ABC may be chemotherapy-sensitive, it was not until the UK NCRN ABC-02 study was reported that cisplatin and gemcitabine chemotherapy became the recognised reference regimen for the first-line treatment of patients with ABC. There is no evidence that further chemotherapy beyond progression of first-line chemotherapy improves survival. Patients often have the inherent problems of biliary obstruction and sepsis with ABC, which limit survival. Active symptom control includes addressing these problems (e.g. by biliary stenting and antibiotics, as appropriate) and other symptoms arising from tumour progression. Aims This study will determine whether fit patients (with performance score of 0-1) with ABC benefit from chemotherapy in the second-line setting (after prior therapy with cisplatin and gemcitabine) in terms of overall survival. In addition we will determine the radiological response rate, effect on patients’ quality of life and health economics of using chemotherapy in this setting. Methods Consenting patients with histologically/cytologically-verified advanced (locally advanced or metastatic) biliary tract cancer with evidence of disease progression after prior cisplatin / gemcitabine chemotherapy will be randomised (1:1) to either Active Symptom Control (ASC; the “standard” arm) or ASC with oxaliplatin/5-FU chemotherapy (the “experimental” arm). Patients will undergo tumour evaluation by CT/MR scan every 12 weeks; patients allocated to receive chemotherapy will continue treatment (pending acceptable toxicity) up to a maximum of 12 two-weekly cycles (six months). Quality of life assessments will be performed at baseline and 12-weekly thereafter. Health economics will also be formally assessed. In addition, archival tissue and prospective blood samples will be prospectively collected for translational research. How the results of this research will be used This study will provide the largest global dataset of prospectively-evaluated chemotherapy in the second-line setting for ABC. If survival is improved with chemotherapy, it will set the standard of care after cisplatin/gemcitabine failure and provide a point of reference for further studies. If there is no improvement with the addition of chemotherapy, patients will be spared ineffective treatment and studies are likely to be developed adding investigational agents to Active Symptom Control.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/044: FAKTION A phase 1b/randomised placebo controlled phase II trial of fulvestrant +/- AZD5363 in postmenopausal women with advanced breast cancer previously treated with a third generation aromatase inhibitor
Funder: Cancer Research UK

Abstract: Background Endocrine therapy resistant ER+ breast cancer is the commonest cause of breast cancer death. Overcoming endocrine resistance will improve on current therapies in the metastatic setting and enhance survival in early breast cancer. Multiple potential mechanisms of endocrine resistance have been defined pre-clinically and the ER usually persists in resistance acting as a focus for crosstalk with multiple intracellular signalling networks such as the mTOR/PI3K/Akt pathway. This pathway is activated in approximately 50% of early ER+ BC due to mutations in PIK3CA, copy number alterations in AKT or loss of PTEN protein expression. Furthermore the adaptive up-regulation of the pathway has been demonstrated in models of aromatase inhibitor resistance. The clinical importance of this pathway in endocrine resistance has recently been demonstrated with the mTOR inhibitor everolimus in combination with exemestane, resulting in significant improvement in progression free survival over exemestane alone in a randomised phase III study, albeit with additional toxicity. However, ligand independent activation of the ER is not surmounted by agents such as exemestane in contrast to fulvestrant which induces ER degradation. Aims 1. To study the activity and safety of the pan-Akt inhibitor AZD5363 in combination with the SERD fulvestrant in a randomised phase II study vs fulvestrant alone in patients with endocrine resistant advanced breast cancer. 2. To study the activity of AZD5363 related to the activation status of the tumour PI3K/PTEN pathway. Methods 1. A safety run in phase will evaluate pharmacokinetic interactions between AZD5363 and fulvestrant. 2. Once the safety of fulvestrant+AZD5363 is established a randomised phase II study of the combination vs fulvestrant alone will be conducted using PFS as the primary endpoint and clinical benefit, overall survival and toxicity as secondary endpoints. Patients will be stratified for PIK3CA mutation status on cfDNA and PI3K/Akt pathway status will be further examined by mutation testing and PTEN expression analysis by IHC on primary tumour blocks. Primary blocks and DNA samples will be stored for subsequent biomarker analysis (separate application). How the results of this research will be used? If combination therapy meets the predefined endpoints for superiority, a randomised phase III trial vs the combination of exemestane and everolimus will be proposed. Patient selection for such a study of combination endocrine and mTOR/PI3K/Akt inhibitor therapies may be informed by results from the PI3K/PTEN analysis.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Exploitation of cell cycle proteins as diagnostic biomarkers and therapeutic targets in cystic tumours of the pancreas.
Funder: Cancer Research UK

Abstract: Background: Pancreatic cystic tumours are an emerging diagnostic challenge for the clinician. Between 2% and 13% of patients that undergo an MRI for non-pancreatic reasons are found to have an incidental pancreatic cyst. In a post-mortem series 25% of patients had a pancreatic cyst of which 32% were potentially premalignant, 3% were malignant. Currently, pre-malignant cysts (Intraductal papillary mucinous neoplasms (IPMN) or mucinous cystadenomas (MCA)) are either observed or removed surgically according to international guidance. Observation requires cross sectional imaging 3-12 monthly and is associated with a growing cost to the NHS. Pancreatic surgery mortality (0.5-4%) and morbidity (19-50%) are not insignificant and due to the difficulties in pre-operative diagnosis, it is probable that more patients are currently operated on than is absolutely necessary. The majority of normal human cells including pancreatic cells exist in non-proliferating states. In contrast, cancer cells exhibit characteristic uncontrolled growth. The initiation of DNA replication is a crucial point in the cell cycle. Chemotherapy has not been shown to improve survival in this unique cancer so surgical resection is the only current therapy. New diagnostic tools and novel treatments are urgently required. The second part of this study will evaluate whether a new molecular pathway can be targeted using a new generation of drugs to treat pancreatic cancer arising from a cystic lesion. Study aims: 1.) Accurately characterise the histological, molecular and prognostic profiles of pancreatic cystic tumours. 2.) Evaluate the potential of cell cycle proteins as diagnostic and prognostic biomarkers to guide therapy in pancreatic cysts. 3.) Carry out a target validation study of loss of Cdc7 function in vitro, using siRNA and small molecule Cdc7 kinase inhibitors. Methodology: The project involves a strong collaboration between the UCL Institute for Liver and Digestive Health, UCL Department of Pathology and Harvard University. Cystic tumour samples will be stained for cell cycle markers (Mcm2, geminin, Cdc7 and phosphohistone H3) and protein expression analysis performed. Results will be correlated with histological and prognostic information to develop a treatment algorithm. Cdc7 will then be evaluated as a therapeutic target and CDC7-SMI/siRNA used to inhibit growth in invasive IPMN cell lines. How will the research be used: To differentiate between pancreatic cystic tumours, enabling appropriate treatment and follow-up. In malignant cystic tumours this study will evaluate a novel treatment adjunct, which will ultimately require validation through future studies within in-vivo models.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Genomic Analysis of BRCA1 Variant Tumours
Funder: Cancer Research UK

Abstract: Whilst we know that certain genetic changes in the gene BRCA1 confer a high likelihood of breast and ovarian cancer development some changes, although found in patients with a family history of disease, are of uncertain relevance. Researchers have tentatively classified these into one of five subclasses based on a number of criteria, but these measures are not good enough to be reported to the patients themselves and are not taken as a measure likely to inform patient management or treatment options. This project aims to examine features of tumour DNA found in patients with known pathogenic changes BRCA1 to aid in the classification of some of unclassified changes. Firstly we will examine loss of heterozygosity in 100 tumours from pathogenic and UV carriers of various sub-types and compare the rates of LOH to that already seen in recognised pathogenic and polymorphic carriers. Unlike the majority of pathogenic BRCA1 genetic changes, most unclassified variants are missense changes, occurring in the context of an expressed protein. Our second experiment will address whether tumours with a pathogenic missense change have the same genomic scars that are apparent in tumours in which BRCA1 is lost.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Computational Biology Group
Funder: Cancer Research UK

Abstract: This research focuses on the genomic analysis of regulatory systems We study how the biology of an organism is shaped by regulation of gene expression. We investigate this at various levels of complexity, from single-celled bacteria and yeast to complex mammals. Expression of a gene - i.e. production of a protein - is a complex exercise requiring large, gluttonous protein machines which expend the cell's energy reserves. Hence, the organism needs to be judicious in choosing which proteins to produce when and where. Furthermore, the expression of all genes at all times would be detrimental to the organism. Expression must be rigourously regulated so that the right genes are ‘switched on or off’ in response to changes in the internal and external environments of the cell. ****The question of 'when to produce' is the only issue in bacteria, which consist of a single cell. The bacterial cell comes under a variety of stresses to which it must rapidly adapt in order to survive. The control of not only ‘when’ but also ‘where’ is crucial in mammals. All tissue types in the human body carry the same set of genes; yet, they are different from one another. This is because different subsets of genes are expressed in different tissues. ****While decisions relating to 'when' and 'where' are taken at different stages during the protein production process, we study the regulatory mechanism operating at the first stage known as transcription, in which DNA is converted to messenger RNA. Regulation at this level is achieved by a class of proteins called transcription factors, whose activity may be regulated by the environment, either directly or via complex signalling cascades. Transcription factors represent the major focus of our research. We investigate how they regulate gene transcription, the mechanisms by which they themselves are regulated, and the interactions of these factors with other cellular processes, such as metabolism.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: CANCER AND NEOPLASMS
Title: Leeds Cancer Research UK Centre Core Award (Bridge Funding)
Funder: Cancer Research UK

Abstract: The Leeds Cancer Research UK Centre brings together internationally-respected scientists with doctors and nurses at one of the largest hospital complexes in the UK. Jointly they are carrying out world-leading research to benefit people with cancer. The Centre is a partnership between Cancer Research UK, Leeds Teaching Hospitals NHS Trust and the University of Leeds, one of the UK's leading research universities. Researchers at the Centre are focusing on bowel, bladder and kidney cancers, as well as melanoma skin cancer. They are also specialising in children's cancers, lung cancer, and leukaemia and lymphoma. Leeds boasts world-class experts in a number of key areas. A particular strength is research into the gene faults that cause cancer, and how patterns of gene activity are controlled in cancer cells. Another area is biomarkers - investigating the molecular 'hallmarks' of cancer cells, to help doctors detect the disease earlier and track how well treatment is working. Researchers at the Centre are also working on exciting new targeted treatments for cancer - discovering and developing novel drugs and testing them in early stage clinical trials. And they have great experience in running large-scale clinical trials and studies, investigating the effectiveness of new treatments or the causes of cancer. There is a strong tradition of research training in Leeds, and the Centre will provide a further boost. This will help to train the next generation of cancer researchers, ensuring that we continue to make progress in beating cancer for decades to come.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS