NIHRDataInsights/HRCSData huggingface dataset:
Title: The MENAC Trial: A randomised, open-label trial of a Multimodal Intervention (Multimodal = Exercise, Nutrition and Anti-inflammatory Medication) versus standard care in cancer patients with Cachexia
Funder: Marie Curie

Abstract: The MENAC trial is the first phase III clinical trial of a multimodal cachexia intervention in patients with advanced cancer (lung or pancreatic) undergoing palliative chemotherapy. Cancer cachexia is characterized by weight loss, muscle wasting, anorexia and fatigue. It is prevalent in pancreatic and lung cancer where mean survival is less than one year. There is no standard of care for cachexia. Through our increased understanding of cachexia pathophysiology (muscle wasting, reduced physical activity, negative energy/protein balance, systemic inflammation), there is now a sound argument that cachexia may be reversed through multimodal intervention (comprising oral nutritional supplements (ONS) and counselling, exercise programme omega-3 fatty-acids and ibuprofen) initiated at the start of chemotherapy may be beneficial. Our pilot study (preMENAC Study NCT01419145) has informed this proposal and shown the intervention (including basic exercise) is feasible. Building on these exciting preliminary findings, we are now undertaking a phase III trial, the MENAC trial, to fully explore if a multimodal cachexia intervention is beneficial. This international trial is being led by researchers from the University of Edinburgh and the European Palliative Care Research Centre (Norway) and is being conducted primarily in the UK, Scandinavia and Canada. Approximately 70% of trial activity will take place in the UK and this is being funded through a unique collaboration between the Rising Tide Foundation for Clinical Cancer Research (74%), Marie Curie (19%) and Pancreatic Cancer UK (7%). In particular Marie Curie and Pancreatic Cancer UK are supporting trial infrastructure and additional research nurse support. Research Question Does a multimodal intervention improve nutritional status, physical function, quality of life and oncological outcomes in patients with lung or pancreatic cancer? Methods Design: An international, open-label, randomized phase III study of a multimodal cachexia intervention versus standard cancer care. Participants Patients with incurable lung or pancreatic cancer starting anti-cancer therapy. Intervention Multimodal intervention (Oral nutritional supplements, ibuprofen and a tailored exercise programme). Comparator Standard cancer care - offered the intervention after 6 weeks (endpoint) to limit contamination. Outcomes Assessed 6 weeks from baseline. Primary outcome: the effect of the intervention on weight. Secondary outcomes: physical function, muscle mass and quality of life (EORTC QLQ-C30). Patients will have follow up at 12 weeks. An evaluation process will be incorporated.


Research activity codes: 7.2 END OF LIFE CARE;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Investigating the role of parenteral nutrition in managing inoperable bowel obstruction in women with ovarian cancer
Funder: Marie Curie

Abstract: Background Bowel obstruction occurs frequently in advanced ovarian cancer affecting between 20-50% patients and has a substantial impact on quality of life. Individuals with bowel obstruction may be unable to maintain adequate oral nutrition and hydration, and intravenous feeding referred to as parenteral nutrition (PN) may be used. Patients will be started on PN as an inpatient, but then may go home on the treatment. Currently, there is uncertainty as to the role of PN in women with ovarian cancer in palliation care. This research will address the decision making process around home PN, and the views and experiences of women and their carers of PN. Aims • Explore current practice in the provision of PN in women with advanced ovarian cancer receiving palliative or end of life care. • Investigate the barriers and facilitators within the multidisciplinary team that influence decision making to instigate PN • Determine the views and experiences of women and their families. Methods Ten advanced ovarian cancer patients who are who are receiving PN for bowel obstruction will be interviewed at 3 time points about their experiences of the treatment; once whilst they are an inpatient and twice at home. Women will be asked to nominate an informal carer (family member or friend) who will be interviewed at similar intervals about their experience of their relative receiving PN. The health care professionals involved with the decision making for or patient’s treatment with PN will also be interviewed. Although, 3 interviews will be carried out with health care professionals for each patient this is likely to be with 3 different individuals. Results Thematic analysis of the data will be undertaken utilising NVivo 10. Implications It is envisaged that data from the study will be used inform the decision making process of doctors and patients with ovarian cancer considering PN.


Research activity codes: 7.2 END OF LIFE CARE
Health categories: CANCER AND NEOPLASMS
Title: A randomised, observer-blind, non-inferiority trial to evaluate alternative human papillomavirus vaccination schedules in young females in West Africa
Funder: Medical Research Council

Abstract: The trial will investigate the potential future utility of alternative HPV vaccination schedules in West Africa. The schedules aim to reduce the financial and logistical burden of HPV vaccine rollout and to provide new opportunities to optimise coverage. The following questions will be addressed: 1. Does the administration of 1 or 2 doses of a quadrivalent HPV vaccine (qHPV) result in lower type-specific seroconversion rates in 9 to 12 year old females in West Africa compared to a 3 dose schedule? 2. Does the administration of 2 doses of qHPV result in lower type-specific seroconversion rates in 4 to 8 year old females in West Africa compared to 3 doses in 9 to 12 year old females? 3. What are the long term health and economic implication of a reduced dose schedule and/or a younger age of routine vaccination in a low income West African setting? A randomised, observer-blind, non-inferiority trial will be undertaken. 9 to 12 year old females will be randomised to receive 1, 2 or 3 doses of a qHPV over up to six months. An additional group of 4 to 8 eight year old females will be recruited and will receive two doses of qHPV. The following outcome measures will be examined: Primary: - HPV types 16 and 18 neutralising antibody seroconversion rates at 7 months Secondary: - HPV types 16 and 18 neutralising antibody seropositivity rates at 12, 24 and 48 months - HPV types 16 and 18 neutralizing antibody GMT at 7, 12, 24 and 48 months - HPV types 16 and 18 antibody avidity at 7, 12, and 48 months Exploratory: HPV specific B-cell and T-cell responses will also be examined in a sub-set of subjects A sample size of 256 participants per group is based on a reference 3 dose seroconversion rate of 99% and a noninferiority margin of 5%. The figure provides over 90% power to determine the non-inferiority of the primary outcome measure using a 1-sided alpha of 1.25% allowing for multiplicity two HPV types and an attrition rate of up to 10%.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Definition of the differential proliferative tissue damaging and transcriptional responses in endogenously TCR- triggered lymphocytes versus foreign antigen stimulated lymphocytes induced by checkpoint blockade
Funder: Medical Research Council

Abstract: Inhibitors of immune checkpoints (ICP) have revolutionised cancer treatment, leading to durable treatment responses in a proportion of patients suffering from previously incurable cancers. The efficacy of this class of drugs is dependent on their ability to trigger the patient’s cytolytic CD8+ T cells targeting tumour cells. However, the broad immune stimulatory capacity of ICP-blockade is associated with a high rate of immune related (irAE). The unpredictability of both efficacy and AEs in response to these agents is a growing concern. There are limited data relating to this heterogeneity of response and the development of irAE following administration of these agents. I will use the following approaches to define the mechanisms leading to the development of irAE. 1.Assessment of rare-patients with monogenic immune dysregulation leading to similar phenotypes as irAE to define candidate genes and pathways. 2.A unique and novel murine system that clonally tracks, self-antigen responsive cells that could cause irAE, in which we can disrupt prioritised pathways identified from our above screening. The pathogenesis of irAEs and the determinant of efficacious treatment response may be biologically linked, as the development of irAEs is predictive of efficacy1, 2. A starting point in this fellowship has been our identification that haploinsufficiency of the NFKB13 locus leads to the expansion of the same B lymphocyte population that predicts responsiveness to ICP blockade4.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: EURAMOS-1: A trial of the European and American
Funder: Medical Research Council

Abstract: A randomised trial of the European and American Osteosarcoma Study Group to optimise treatment strategies for patients with resectable osteosarcoma based on histological response to pre-operative chemotherapy. Osteosarcoma is the most common bone cancer in children, adolescents, and youn adults, but is still a rare disease with an annual incidence of 2-3 million/year. The most common primary sites are the distal femur and proximal tibia, and 15-20% of patients have clinically detectable metastases at the time of diagnosis. The outcome for patients with osteosarcoma was poor before the use of effective chemotherapy, with 2-year overall survival in the region of 15-20%. The administration of multi-agent chemotherapy has dramatically improved the outcome. Most current series report 3-year disease-free survival rates of 60-70% following the administration of pre-operative multi-agent chemotherapy followed by surgical resection and continuation of chemotherapy post-operatively. These positive results, however, apply only to young patients with localised extremity tumours, while other patients - which make up at least one third of all affected individuals - have traditionally been excluded from prospective randomised trials. Judging from case series and cumulative analyses, their outcome is still considerably worse, with survival rates in the order of no more than 20-30% for patients with primary metastatic osteosarcomas or osteosarcomas of the axial skeleton.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: A randomised phase II study in metastatic melanoma to evaluate the efficacy of adoptive cellular therapy with tumour infiltrating lymphocytes (TILs).
Funder: Medical Research Council

Abstract: Research design: A propose a randomised phase II trial with two parallel arms to evaluate the efficacy of standard TIL therapy with HD-IL2 or with LD-IL2. Study population: Patients must have confirmed malignant melanoma which is refractory to standard therapy. They must have a metastatic lesion which can be excised to produce an adequate specimen to culture the TIL. Planned interventions: Both arms of the trial will include TIL with standard pre-conditioning. The control arm will include standard HD-IL2 at a dose of 600,000U/Kg. The patients randomised to the LD-IL2 arm will receive 100,000U/Kg. Proposed outcome measures: The primary objective is to establish feasibility and tolerability of TIL therapy and the RECIST response rate to TIL therapy with both standard HD-IL2 and LD-IL2 and to confirm that the response rate is likely to be greater than 20%. Secondary objectives: To include the evaluation of the duration of remission in both arms, the overall survival in both arms and the examination of toxicity and cost in relation to benefit. We will also explore potential tumour related or immunological biomarkers of response to facilitate better patient selection in the future. Assessment and Follow up: During admission the patients will be carefully and intensively monitored. After discharge the patients will be assessed clinically at least 2-weekly for until 6 weeks, then monthly for six months and then three monthly. They will have disease assessment by CT scans at 6 weeks, 3 months and then 3 monthly. They will be followed for toxicity until progression and for survival thereafter. Proposed sample size and Statistical analysis: The study design is for two parallel Simon 2-stage studies, one for LD-IL2 and one for HD-IL2. Patients will be randomised to either arm - each arm will have 24 patients in the first stage and if there are at least 6 responses then 21 further patients will be recruited to that arm (there will be a minimum of 2x24=48 patients and a maximum of 2x45=90 patients). The study design regards a response rate of < 20% to be not worthy of further consideration. After the second stage if there are more than 13 responses out of the 45 cases in an arm, that arm will be considered worthy of further consideration. If both arms meet this criterion then their respective response rate estimates will be weighed against toxicity to decide on the ‘best candidate’ for further study. Project timetables including recruitment rate: We anticipate the study can commence July 2013. All the processes are in place but full approval by MHRA/Ethics and institutions will be required. The recruitment rate will rapidly increase to 2-3 per month and we anticipate recruitment to be 12, 24, 24, 24, 6 in successive years. This will leave time for completion of all clinical and laboratory analyses within 60 months.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: A Phase II randomised clinical trial of conditioning cyclophosphamide and chemoembolisation with or without vaccination with dendritic cells pulsed with HepG2 lysate ex vivo in patients with Hepatocellular Carcinoma: IMMUNOTACE.
Funder: Medical Research Council

Abstract: RESEARCH DESIGN randomised Phase II trial of cyclophosphamide & chemoembolisation with or without vaccination with dendritic cells pulsed with HepG2 lysate in hepatocellular carcinoma. INCLUSION 1) HCC with at least 1 lesion measurable by CT/MRI 2) Suitable for TACE but not surgical resection or transplantation 3) Age >18yrs 4) Life expectancy >3 months; ECOG status<1 5) Adequate haematological, liver & renal function 6) Informed consent. EXCLUSION 1) Extra-hepatic disease 2) Prior ablative, systemic or radiation therapy 3) Investigational therapy or surgery within 4 wks 4) Child Pugh score >7 5) Hepatic encephalopathy or refractory ascites 6) Hepatic artery or main portal vein occlusion 7) Hypersensitivity to contrast agents 8) Active infection within 2 wks 9) Pregnant or lactating 10) Second cancer except non-melanotic skin or cervical carcinoma in situ 11) Severe systemic disease 12) History of HIV INTERVENTIONS Group 1: TACE + low-dose cyclophosphamide to deplete regulatory T cells Group 2: TACE + low-dose cyclophosphamide + infusion of tumor lysate pulsed DCs PRIMARY OUTCOME MEASURES Progression free survival (PFS) SECONDARY OUTCOME MEASURES 1) Radiological response 2) Rate of change in tumour marker 3) Toxicity 4) Immune response rate 5) Survival ASSESSMENT Group 1 Visit 1 Screening Visit 2 Treatment initiation+ clinical assessment, bloods & immune response Visit 3 End of treatment clinical assessment, bloods & immune response Group 2 Visit 1 Screening; Visit 1b Dendritic cell collection via leukopheresis; Visit 2 Treatment initiation, clinical assessment, bloods & immune assessment; Visit 3: End of treatment clinical assessment, bloods & immune assessment. Immune Response Assessment Weekly for first month; monthly thereafter. Tumour assessment Day 62+/-3 after randomisation & 3 monthly for 1 year PARTICIPANT FOLLOW UP. End of treatment follow up at 3 monthly intervals with clinical assessment & bloods + immune response assessment; tumour assessment SAMPLE SIZE & STATISTICS. The trial design is based on a randomized phase II trial using a Jung design (alpha=0.2, beta=0.2, relevant increase in PFS=20%) requiring 70 patients in total. PROJECT TIMETABLES INCLUDING RECRUITMENT RATE Jan 2011 Notification of funding, MHRA & Ethics submission; May 2011 Open to recruitment; June 2011 1st pt, 1st visit; June 2014 Last pt, 1st visit; June 2015 last pt, last visit; Sept 2015 Final analysis. We see>200 new HCC pts/year and an audit of our TACE activity since 2005 confirms 70 procedures/yr. We estimate recruitment of >25 patients/year allowing us to comfortably recruit the required 70 patients.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Defining defective DNA repair in Fanconi Anaemia
Funder: Medical Research Council

Abstract: In Fanconi anaemia (FA) defective DNA repair results in spontaneous as well as crosslink induced chromosome breakage. The clinical consequences of this are bone marrow failure as well as a greatly enhanced risk of developing haematological as well as epithelial cancers. However, the mechanism of the DNA repair involving FA proteins has been elusive. This proposal outlines genetic and biochemical approaches to define the DNA repair pathway in which the FA proteins participate.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Cell Proliferation
Funder: Medical Research Council

Abstract: The ultimate goal of our group is to identify novel genes involved in cancer and analyze how they are related with the genetic networks regulating cell proliferation. Normal cells have a limited ability to proliferate. When primary cells reach this limit or upon the expression of some oncogenes, they cannot growth anymore, suffering an irreversible growth arrest termed senescence.||Specifically our laboratory works in understanding senescence as it is a tumour suppressor mechanism that hinders tumour progression but also since we can use it as a model system, as often the genes identified in this way have a role in cancer or other human diseases. We use normal cells (different human and mouse cells of epithelial and fibroblast origin) and perform genetic screenings to identify genes regulating their lifespan. We use cDNA, shRNA and microRNA retroviral or lentiviral libraries in our screenings. As we already mentioned, we are interesting in identifying new genes or genetic elements regulating senescence and possibly impacting in cancer. Current experiments have identified novel candidates which a role in senescence, and we are performing genetic and molecular biology-based experiments to understand how they relate to the core pathways controlling senescence and oncogenesis.||In the past, using genetic screenings, we identified the role of glycolytic enzymes in senescence and cancer and how the Polycomb group (PcG) gene CBX7 modulates cellular lifespan by repressing the transcription of the Ink4a/Arf locus and therefore interfering with the Rb and p53 pathways. An area of continuous interest in our laboratory is to further understand the mechanism of action of CBX7 and which is its function under physiological and pathological conditions. We are pursuing that goals through the characterization of CBX7-interacting proteins that we have identified in yeast-2-hybrid screenings and by tandem affinity purification (TAP) followed by Mass Spectroscopy (MS). We are characterizing three interesting candidates flagged through those approaches. ||On the other hand, we have developed appropriate models through our collaboration with Scott Lowe (CSHL, NY, USA) to understand the role of CBX7 in cancer and in normal and pathological circumstances.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The role of p53/p73 family members in the cytotoxic response.
Funder: Medical Research Council

Abstract: The scope of the Apoptosis & Cancer Laboratory is to understand the fundamental mechanisms of cell death (apoptosis) and tissue response to injury caused by drugs, chemicals and endogenous molecules, like free radicals. In particular, we study the physiological functions of the p53 family proteins (namely p53, p63 and p73) and their involvement in tumorigenesis and neurodegeneration triggered by toxic insults. We make use of multiple scientific approaches ranging from systems biology (proteomic and genomic screenings) to the generation and characterization of genetically modified mouse models. We are also interested to the development of chemical compounds that can regulate expression and function of these transcription factors, and that could therefore have potential therapeutic applications. Objectives Alterations of proteins that control cell proliferation, cell survival and cell death are the main causes of diseases such as cancer and neurodegenerative disorders and dictate the efficacy of drug treatment. The protein members of the p53 family, composed of TP63, TP73 and TP53 itself, are transcription factors that, by binding to the DNA, modulate the expression of multiple genes that play pivotal functions in the regulation of proliferation, differentiation, cell death, stem cell renewal and cell fate commitment. While p53 has been extensively studied over the last 32 years, p73 biology is still lagging behind despite lying at the crossroads between differentiation, cell cycle control and cell death. We aim to understand the mechanisms of p73 regulation during toxic insults and to define how it influences the outcome and severity of cellular and organism response to toxic insults. To this end, we are investigating several aspect of the p53-family biology, including: 1- p73 function in DNA damage response and cancer therapy, 2- Characterization of in vivo DNA damage models & large-scale transcriptional analysis, 3- p73, metabolism and ageing, 4- Neuronal implications of p73 deficiency, 5-Bioinformatic Evaluation of predictive value of p53 family in cancer progression and chemosensitivity in collaboration with Alexej Antonov (MRC Toxicology Unit), 6- MicroRNA and the p53 family in cancer progression in collaboration with Martin Bushell (MRC Toxicology Unit), 7- The deregulation of translation, in collaboration with Anne E. Willis (MRC Toxicology Unit), 8- Function and Pharmacological inhibition of the p73 E3 ubiquitin ligase ITCH.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS