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Periodic Report Summary 3 - EEC (EURO EWING Consortium – International Clinical Trials to Improve Survival from Ewing Sarcoma)

Project Context and Objectives:
The goal of the EURO EWING Consortium (EEC) is to improve survival from Ewing sarcoma (ES). ES are fatal, rare bone cancers particularly affecting young people. About 60% of patients achieve long-term survival with current treatment but there has been little improvement in this proportion for 25 years. Of the 600 new cases of ES occurring in the EU each year, less than half will receive treatment ‘appropriate’ to deliver the best outcome.
The EEC is a coalition of the most active clinicians and scientists working on ES in Europe. Improved survival will be achieved through an integrated programme of investigator-driven, inclusive clinical trials that are rigorously designed, conducted, analysed and reported, and underpinned by complementary embedded translational research. These include i) a first line randomised study which defines standards of care to prevent development of metastases and serves as a backbone for implementation of new agents, and ii) a randomised study of current second line chemotherapy which will serve as a platform for testing of new agents. Translational research will be performed investigating tumour biology and underlying causes of differential response and toxicity. The project will be supported by new initiatives for the involvement of patients in research.
A strategically-directed clinical trials programme is necessary given that ES is a primary malignancy of bone particularly affecting children and young people, with 85% of cases occurring before 30yrs but which is very uncommon. The age-standardised incidence from national population-based registries is approximately 2.5 per million, indicating about 600 new cases in the European Union annually, of whom no more than 30% are estimated to be included in previous clinical trials at diagnosis. Survival from population data is around 55% though survival of selected groups reported in clinical trials may considerably exceed this. For those with advanced metastatic disease, long-term survival is achieved in only a very small proportion.
There are numerous uncertainties surrounding the optimum clinical management of ES. Whether regimens are equal with regard to survival and morbidity is unclear due to the absence of comparative clinical trials. Studies evaluating new therapeutics have been few and none have yet been carried forward as components of standard adjuvant regimens. If ES recurs after adjuvant treatment, survival rates with further treatment are less than 20%. Again, few trials have been undertaken in this subgroup to inform about better approaches to management.
There is a strong record of conducting ES trials in Europe by individual groups. However, these have been limited to studies of adjuvant treatment, and accrual to randomised questions is low so the overall impact on practice is insufficient to expect major advances in survival in acceptable timescales. The EEC represents a culmination of effort by several study groups who now embark on wider and more ambitious collaboration designed to deliver more rapid patient-centred outcomes from this often fatal disease.
The objectives are to:
1. Undertake an investigator-initiated first line randomised trial in patients of all ages with ES which defines standards of care for adjuvant chemotherapy to prevent development of metastases and increase survival
2. Undertake an investigator-initiated randomised trial of current second line chemotherapy in patients of all ages with ES which establishes a standard and will serve as a platform for testing of new agents
3. Undertake comprehensive translational and other companion studies which investigate underlying causes of differential response and toxicity, as well as circulating biomarkers in conjunction with systemic treatments
4. Disseminate all emerging findings in conjunction with EEC partners and external agencies and to use these for development of further strategies to improve knowledge and outcomes from ES
5. Introduce public and patient involvement into the work of EEC
Project Results:
The aim of WP1 is to carry out a first line randomised study in ES patients. The Euro Ewing 2012 trial is now open to recruitment through all four National Coordinating Centres (UoB, GEIS, EORTC and CLB). The trial is open in the UK, France, Spain, Belgium, Czech Republic, Netherlands and Hungary as well as Republic of Ireland and 106 sites are open, exceeding the originally planned 104 sites. 448 patients have been recruited and 70% of target recruitment has been met since March 2016.
The aim of WP2 is to carry out a randomised study of current second line chemotherapy. The rEECur trial is now open to recruitment through five of the planned six National Coordinating Centres (UoB, GEIS, EORTC, IOR and SSG). The trial is open in 13 countries; Denmark, France, Hungary, Italy, Norway, Spain, UK, Belgium, Poland, Czech Republic, Netherlands, Finland as well as Australia and 232 patients have been recruited.
WP3 aims to facilitate sample collection, provide reference pathology, construct tissue microarrays and perform molecular characterization of ES tumours. The collection of biomaterials is being carried out according to SOPs for sample collection which have been reviewed and shared. Biobanking has continued successfully with high levels of consent (95%) from patients participating in the Euro Ewing 2012 trial in the UK, France and Spain and has now been extended to the rEECur trial. Central review of cases has been carried out in the UK on samples from 119 trial participants. Tissue microarrays have been constructed in the UK and Spain and samples are available to construct a French tissue microarray. Depth characterisation of tumour samples has been successful and the results published in six papers in peer reviewed journals.
The aims of WP4 are to identify biomarkers of toxicity, response and outcome and quantify the levels of circulating tumour DNA in plasma and blood at diagnosis and during treatment. Biological studies in Euro Ewing 2012 patients are now open in seven countries and open in 11 countries for rEECur. Comparison of miRNAs in blood, plasma and bone marrow has been completed as has a pilot study to identify miRNAs that predict febrile neutropenia. STAG2/TP53 mutations are being investigated for clinical relevance in circulating tumour DNA. An analytical pipeline for the evaluation of circulating miRNAs in plasma has been developed.
Exosomes have successfully been isolated from pre-filtered EDTA plasma samples collected from patients with Ewing’s sarcoma treated in Euro Ewing 2012; the identification of exosomes has been confirmed by expression of exosomal proteins (TSG101, CD63) using western blot and flow cytometry, size using the nanosite and ultra-structurally by electron microscopy. In novel experiments exosomes derived from Ewing’s sarcoma cells have been isolated from patient plasma
The aim of WP5 is to involve patient advocates in the activities of the EEC and to ensure that relevant information is communicated in a clear and efficient way. A core group of patient advocates have been regular attendees at EEC meetings and have made valuable contributions and promoted the EEC at external meetings. They have provided input into a grant application and the early stage development of a clinical trial. Patient advocate representatives have been appointed for WP2 and 5 in a successful pilot. The website has been maintained and updated.
The objective of WP6 is to ensure high standards of ethics for the project. Regulatory and ethical approval has been obtained for the Euro Ewing 2012 trial in the UK, Spain, France, Belgium, Czech Republic, Republic of Ireland, The Netherlands and Hungary. Regulatory and ethical approvals have been given for the rEECur trial in the UK, Belgium, Spain, Norway, Finland, Denmark, Italy, France, Hungary, Czech Republic, Poland, the Netherlands and Australia. Informal ethical approval has been granted for rEECur in Germany. The challenges identified in opening a multi-national trial have been recorded and will be disseminated later in the project. The External Advisory Board has met twice a year and given feedback to EEC Partners.
Potential Impact:
The scope of this programme is strategic, integrating translational, complementary biology with evaluations which determine new standards of care for first and second line therapies. Support for the programme is worthwhile as, although curable in a proportion of patients, survival from ES has not significantly improved in recent decades. Furthermore, as ES affects children and young people, preventing further deaths delivers prolonged societal advantage. An additional vital goal is to achieve improved survival with reduced treatment related morbidity, both acute but especially reducing those adverse treatment consequences which are prolonged or permanent.
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