NIHRDataInsights/HRCSData huggingface dataset:
Title: CRUK/08/015: TOTEM: A Phase I/II trial of the mTOR inhibitor temsirolimus (CCI-779; Torisel) plus Cisplatin and Gemcitabine as first line therapy for advanced bladder cancer (and other urothelial cell carcinomas)
Funder: Cancer Research UK

Abstract: (1) Advanced bladder cancer affects ~2,500 UK patients a year and, for fit patients with good renal function, optimum chemotherapy combines Cisplatin and Gemcitabine, with a response rate of approximately 50%. (2) Even with chemotherapy, the prognosis for advanced bladder cancer is poor, with 8 month median progression-free survival (PFS) and 15 - 18 month median survival. Despite a recent increase in our understanding of the molecular basis of bladder cancer, there has been a paucity of clinical studies using molecularly-targeted compounds in advanced bladder cancer. Temsirolimus, an mTOR inhibitor, has recently been demonstrated to improve survival in advanced renal cancer, and molecular studies suggest that temsirolimus may have activity against bladder cancer too. (3) This trial will assess the addition of temsirolimus to the standard cisplatin/gemcitabine chemotherapy in the treatment of advanced bladder cancer. Its aim is to assess safety of this novel combination, determine an appropriate temsirolimus dose, and assess its activity and feasibility of use. (4) The trial is an open-label, single arm phase Ib/II design. Once the Maximum Tolerated Dose (MTD)has been established in the Phase Ib portion, the phase II will assess the efficacy, in advanced bladder cancer patients only. The trial will determine a Recommended Dose for Sustained Tolerability (RDST) – a dose at which at least half of patients should be able to tolerate at least 3 cycles of the combination therapy, rather than the usual determination of a Recommended Dose, on the basis of toxicity data in the first cycle only. The rationale for this is that other Phase I studies with molecularly–targeted agents often show that patients withdraw (or are withdrawn) from treatment as the result of multiple low-grade toxicities over multiple cycles, rather than from a Dose-Limiting Toxicity in the first cycle.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/09/006: UKALL14: An international randomised trial for adults with newly diagnosed acute lymphoblastic leukaemia.
Funder: Cancer Research UK

Abstract: Acute Lymphoblastic Leukaemia (ALL) in adults has a poor prognosis. We will carry out a randomised controlled trial to test whether standard therapy induction chemotherapy plus a new drug or drugs is better than standard chemotherapy alone . After remission, we plan to test some novel ways of carrying out bone marrow transplant in patients who are at highest risk of relapsing from their disease with the hope of translating remissions into cure. Background ALL has a poor prognosis in adults. We have previously shown that (i) our induction regimen results a high rate of complete remission but that many patients still relapse (ii) certain factors at diagnosis confer a particularly high risk of relapse (iii) the presence of minimal residual disease after induction therapy is a poor prognostic factor (iv) sibling allogeneic bone marrow transplant (BMT) conditioned with myeloablative therapy gives the highest expectation of cure to those under 40 (v) in patients over 40, the reduction in relapse risk resulting from myeloablative BMT is outweighed by the treatment related mortality, resulting in no overall survival benefit. Revelance 100% of this project is related to cancer Specific aims Aim 1a. (precursor-B ALL) Does the addition of monoclonal antibody (or antibodies) to standard induction chemotherapy result in improved EFS in patients with precursor B-cell ALL? Aim 1b (T ALL) Does the addition of nelarabine improve outcome for patients with T cell ALL? Aim 2. To determine the tolerability of pegylated asparaginase in induction and to compare anti-asparaginase antibody levels between patients in the 4 randomisation groups from aim 1. Aim 3. To determine whether risk-adapted introduction of unrelated donor HSCT (myeloablative conditioning in patients <40 years old and non-myeloablative conditioning in patients >40 years old) result in greater EFS for patients at highest risk of relapse. Aim 4 To compare 2 schedules of administration (standard vs, 'collapsed') of keratinocyte growth factor (palifermin) for efficacy in preventing the severe mucosal toxicity of etoposide/TBI HSCT conditioning regimen. Outline plan of research We plan to recruit appropriate numbers of patients in 2 countries (UK and USA) and treat them according to a protocol in order to investigate the hypotheses on which our aims are based.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: RATHL: A randomised trial to assess Response Adapted Therapy using FDG-PET imaging in patients with advanced Hodgkin Lymphoma.
Funder: Cancer Research UK

Abstract: Treatment of Hodgkin lymphoma is successful for most patients, but at present all are treated according to clinical features at presentation, causing over-treatment for some and inadequate therapy for others. The aim here is to test whether PET scanning to assess the initial response to chemotherapy can be used to guide subsequent treatment. Last updated 14/08/2007 Advanced Hodgkin lymphoma can be cured in many cases, but with standard ABVD chemotherapy the treatment still fails in around one quarter, and in those cured, late toxicity remains a significant problem. Cure rates might be increased using more intensive initial treatment, but the resulting toxicity will be unacceptably high if even those with a good chance of cure are subjected to it. Baseline clinico-pathologic characteristics have proven poor discriminators in this respect, but there is increasing evidence that FDG-PET functional imaging can give highly accurate prognostic information if performed early during the course of treatment. The specific aim of this research is to prospectively evaluate the use of FDG-PET to permit early assessment of tumour response. This will allow selective escalation of therapy for those with a poor prognosis, and test de-escalation of treatment to minimise long-term toxicity for those with a good initial response. All patients will receive 2 courses of ABVD chemotherapy and then undergo a FDG-PET scan. Patients who become PET negative will be randomised between ABVD and AVD, the omission of bleomycin aiming to reduce lung toxicity whilst achieving an equivalent outcome. Those who remain PET positive will undergo treatment escalation with the BEACOPP-14 regimen, attempting to improve remission rates thereby. Last updated 14/08/2007


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: CRUK/08/008: mEOC: A multicentre randomised trial comparing oxaliplatin + capecitabine versus carboplatin + paclitaxel in patients with previously untreated mucinous cancer of the ovary.
Funder: Cancer Research UK

Abstract: To determine whether a combination of oxaliplatin and capecitabine is superior to conventional treatment with carboplatin and paclitaxel in the treatment of advanced mucinous carcinoma of the ovary.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Head and neck squamous cell carcinoma Tissue Collection for the PET NECK trial (PET NECK COLLECT)
Funder: Cancer Research UK

Abstract: PET-NECK is one of the largest head and neck cancer (HNC) trials worldwide. It compares PET-CT guided surveillance policy with current management of planned neck dissection for nodal metastasis in 560 patients with advanced HNC receiving chemoradiotherapy. Aims and Relevance to Cancer PET-NECK provides an unprecedented opportunity to prospectively collect and 'bank' high quality tissue and blood samples from large cohort of well documented patients with a rare cancer. This would enable much needed research projects, which to date, have not been possible due to the lack of significant numbers of high quality samples. We have already been approached for a project studying markers for early detection of recurrent disease. Outline plan Using standardised protocols, 20ml-blood samples collected at pre-treatment, 3 months and 1 year after treatment. Also tissue micro-arrays and 10-micron scrolls are constructed from blocks of diagnostic biopsies and neck dissections. Quality of blood samples assessed by DNA extraction, and of TMAs by immunohistochemistry. Samples bio-banked in Clinical Sciences Research Institute, which holds Human Tissue Authority license. MREC approval for trial and tissue collection already secured. Sixteen HNC centres in UK are currently in set-up.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: T-VIN: Collection and storage of tissue and blood samples from patients with vulval intrapithelial neoplasia receiving topical treatment, for future translational research
Funder: Cancer Research UK

Abstract: T-VIN: Collection and storage of tissue and blood samples from patients with vulval intrapithelial neoplasia receiving topical treatment, for future translational research


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUK/09/030: HOT-II: Randomised double-blind controlled phase III trial of hyperbaric oxygen therapy in patients suffering long-term adverse effects of radiotherapy for pelvic cancer
Funder: Cancer Research UK

Abstract: 1. Background Retrospective studies and the first analysis of one prospective randomised trial suggest that hyperbaric (high pressure) oxygen therapy relieves symptoms and signs of radiation-induced bowel injury in the majority of affected individuals. 2. Relevance to cancer Curative radiotherapy is prescribed to an increasing number (12,000 per year) of UK patients with pelvic malignancies, and more individuals are living with a significant legacy of treatment related morbidity. The UK prevalence of radiation-induced bowel morbidity causing significant impairment of physical functioning is unknown, but the US estimate is 1 million individuals. 3. Specific aims of the research i) To test the clinical benefits of high pressure oxygen therapy in restoring bowel function to patients suffering chronic radiation-induced gastrointestinal complications. ii) To investigate cell and molecular mechanisms underlying therapeutic response. 4. Plan of research The plan is to conduct a randomised double-blind controlled phase III trial involving 75 volunteers suffering bowel complications of prior pelvic radiotherapy. The primary endpoint is the Modified Inflammatory Bowel Disease Questionnaire. Secondary endpoints include physician assessment of adverse effects using LENT SOMA scales and the Defaecation Problems Subscale of EORTC QLQ-CR38. The protocol incorporates analysis of the costs of hyperbaric oxygen to patients. Translational endpoints include i) the induction of peripheral blood stem cells and ii) stimulation of neoangiogenesis and resolution of fibrosis in rectal mucosa.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: The study of key genetic and biological variables associated with clonal progression and systemic manifestations of relapsed Multiple Myeloma (MM)
Funder: Cancer Research UK

Abstract: Myeloma X Relapse (Intensive) is a clinical intervention study to establish the role of a second autologous transplant (ASCT) at relapse in multiple myeloma. The evolution of the malignant plasma cell and effects on the host in the setting of relapse are poorly understood and our detailed diagnostic and ongoing analysis of changes in the nature of the disease and its effect on the local and systemic microenvironment (allied to further independently funded projects) will significantly improve our understanding of these disease processes.We propose that for every trial entrant samples will undergo detailed diagnostic analysis and central review including 6 colour flow cytometry and MRD assessment with results reported in real time. This diagnostic analysis is provided for in CRUK main grant. The aim of this application is to enable detailed molecular processing and storage of samples for sequential FISH on CD138- selected tumour cells at key time points, p53 assessment and assessment of other prognostic markers especially cmyc rearrangements as they develop during treatment and as the disease evolves. In addition, to allow the additional studies eluded to above, blood and bone marrow will be used to prepare and store genomic DNA, mRNA with plasma, serum and urine being stored in addition. For the planned Haematopoietic stem cell translational studies, CD138 negative BM cells, trephine biopsy tissue blocks and 'pig tail' aliquots of collected stem cells will be stored for analysis under experimental investigations. The storage of these samples will provide resources for future disease evolution analysis and enable other key areas of investigation. Full details of the proposed investigations are under development, but the current proposed areas of investigation are: Genetic evolution: the determination of acquired tumour molecular abnormalities and how this relates to disease response and duration of response. Tumour effect on local microenvironment: the determination what effect the relapsed clonal disease will have on the biology of bone turnover and immune dysfunction. Tumour effect on systemic manifestations: the determination of the effect of genetic polymorphisms in the pro-inflammatory/innate immune system response in the tumour-bearing host in terms of systemic symptoms such as fatigue and pain perception and the effects on treatment outcomes and quality of life. These allied studies are NOT part of this application, rather this application seeks to establish tissue storage of trial entrants to permit these further studies and genetic analysis of the relapsed cancerous cells in MM.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUK/08/040: MARALL - Phase 2 study combining humanised anti-CD20 (Veltuzumab), anti-CD22 (Epratuzumab) or both monoclonal antibodies with intensive chemotherapy in adults with recurrent acute lymphoblastic leukaemia (ALL)
Funder: Cancer Research UK

Abstract: This is a Phase I/II study to determine the safety and tolerability of the combination of veltuzumab and epratzumab with intensive chemotherapy in patients with relapsed B-cell ALL. A maximum of 55 patients will be treated with a combination of UKALL XII induction chemotherapy and the monoclonal antibodies veltuzumab and epratuzumab. Veltuzumab and epratuzumab are humanised monoclonal antibodies that target CD20 and CD22 surface proteins, respectively. Both of these proteins are expressed on ALL tumour B cells. One group of patients will receive modified UKALL XII + veltuzumab; a second, modified UKALL XII + epratuzumab and if limited toxicity is found in these first 2 groups, a third group will receive, modified UKALL XII + both veltuzumab and epratuzumab. Patients will be assessed for safety, tolerability and disease response. Safety and tolerability will be measured by the number of Dose Limiting Toxicities (DLTs) in each group. Disease response will be measured by the microscopic appearance of patient bone marrow samples at day 29, and by molecular tests for tumour cells in bone marrow. http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=7566


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Senior Cancer Research Fellowship: Cortical control of spindle morphogenesis and chromosome segregation
Funder: Cancer Research UK

Abstract: The goal of this research is to study how the dramatic changes in cell shape accompanying animal cell division are accomplished and regulated, and to determine whether defects in the mechanical properties of the dividing cells can contribute to mis-segregation of chromosomes and to therefore to the development of cancer. Dynamic changes in cell shape and actin organisation during passage through mitosis are a poorly understood but universal feature of animal cell divisions. In exploring the molecular mechanisms involved in the dynamic remodelling of the cortical actin cytoskeleton during mitosis, we have identified a critical, previously unappreciated role for the actin-based mitotic cortex in centrosome separation, metaphase spindle organisation and orderly chromosome separation. Because genome instability and aneuploidy play an important role in tumour evolution, these findings make cortical remodelling and crosstalk between the actinbased cortex and the microtubule-based spindle important subjects for basic cancer research. Moreover, since many of the drugs currently used as cancer therapies act by perturbing the mitotic spindle to kill cancer cells, it is hoped that this work will lead to the development of actin-based anti-cancer agents that act in a similar fashion to selectively kill dividing tumour cells. The central aims of this proposed project are therefore to identify how the cortex is remodelled upon entry into mitosis, to elucidate the mechanisms used to coordinate these changes in cortical architecture with establishment of the mitotic spindle, and to study how defects in cortical organisation affect the checkpoint regulating the transition from metaphase to anaphase, genomic instability and cancer cell death. For this analysis, we will use RNAi screens to identify the central molecular players. These proteins will then be characterised in detail, biochemically, in cell culture systems and in the context of symmetric and asymmetric divisions in an epithelium within the living fly. Building on these findings, we will then test how different wellcharacterised human cancer cell lines respond to induced cortical defects, focusing on the effects of these treatments on spindle morphogenesis, genomic instability and apoptosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Career Development Fellowship: Molecular study of TAO1 kinase to understand the mechanisms that ensure accurate segregation of human chromosomes
Funder: Cancer Research UK

Abstract: When a mother cell divides into two, its chromosomes have to be segregated into two equal sets. Inaccurate segregation will give rise to irregular chromosome numbers, a hallmark of tumours. My goal is to identify key proteins that ensure accurate segregation, and thereby infer how they may go awry during tumourigenesis. ONCOLOGICAL SIGNIFICANCE: Aneuploidy or irregular chromosome numbers is often found in tumours. While aneuploidy can arise from inaccurate segregation of chromosomes, the precise molecular lesions that trigger aneuploidy remain unknown. By identifying molecular mechanisms that prevent aneuploidy in normal cells, I aim to gain insight into molecular lesions that promote aneuploidy in tumours. BACKGROUND: Microtubules (MT) attach to chromosomes, and mediate the forces that segregate the chromosomes into two equal sets. Correct chromosomemicrotubule attachment is therefore crucial for accurate segregation. I am interested in identifying molecular principles that govern chromosome-microtubule attachment. Multi-protein structures called ækinetochoresÆ that assemble on the chromosome serve as platforms for microtubule attachment. Kinetochores also monitor chromosome-microtubule attachment status. When attachment is erroneous, the kinetochores recruit checkpoint proteins that delay separation of chromosomes and thus prevent mis-segregation. To understand how erroneous attachments are detected, it is essential to understand the biochemical regulatory links among kinetochore proteins, in terms of protein-protein interactions and kinase-substrate relationships. This knowledge is also critical to address more complex questions on how correct mechanical pull is biochemically regulated in time and space. RESEARCH PLANS: We recently identified TAO1 kinase as a key player that is essential to prevent mis-segregation. Cells lacking TAO1 mis-segregate chromosomes because of their failure to establish correct chromosome-microtubule attachments. But the underlying molecular mechanisms are unknown. I aim to first identify TAO1-interactors and biochemical changes that TAO1 undergoes in response to defective attachments. I will then perturb these changes using mutant protein expression, and analyse its effect in detecting attachment errors and preventing mis-segregation. I expect the findings to reveal TAO1-mediated pathways that prevent aneuploidy, and might have important consequences in exploiting kinetochore regulation as a target for new anti-cancer drugs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Career Development Fellowship: National colorectal cancer intelligence (funded by the Bobby Moore Fund for Cancer Research UK)
Funder: Cancer Research UK

Abstract: To link routinely available health service databases together to generate a rich data source and use it survey and monitor national trends and patterns in colorectal cancer care and outcome Last updated 15/10/2007 Background to the proposal Colorectal cancer affects 34,500 and kills 16,000 people a year in the UK. All patients should receive the best possible treatment but evidence suggests that there are significant variations in management and outcome. Equalising services and ensuring a high quality of care for all is a top priority. Quantifying inequalities in colorectal cancer care and survival is difficult. Numerous disparate data sources contain valuable information about different aspects of patient management but none contain all the information required to monitor care nationally. Recently, however, we have pooled extracts from each English cancer registry of all patients diagnosed with colorectal cancer and linked these data to an extract of Hospital Episodes Statistics (HES). Thus we have generated a dataset that allows each patientÆs treatment pathway to be mapped from diagnosis to cure or death. This allows us to monitor the hospital careers and outcomes of colorectal cancer patients at a population level and scrutinize the clinical performance of the NHS. Relevance to cancer For the first time this project would generate the high quality data required by the NHS to reliably monitor the quality of its colorectal cancer services, optimise care and, ultimately, improve UK cancer survival. The methods and techniques developed will be directly applicable to other cancer sites and, potentially, other disease sites. Specific aims of the research À To develop and exploit the national colorectal cancer dataset and, via the amalgamation of further available routine datasets, create an impressive and powerful longitudinal epidemiological resource. À Interrogate this resource to monitor and predict cancer trends, identify the impacts of interventions and identify and address inequalities in care and outcome. Outline plan of research 1. Continue the development of the national colorectal cancer dataset to enhance the extent and timeliness of its content 2. Lead the way in the development and application of appropriate statistical methodologies to analyse these complex data 3. Exploit the dataset to reliably monitor clinical performance/outcomes of NHS colorectal cancer services Last updated 15/10/2007


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: CANCER AND NEOPLASMS