EURAMOS-1: A trial of the European and American Osteosarcoma Study Group

Lead Research Organisation: MRC Clinical Trials Unit

Abstract

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Technical Summary

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.

Publications

10 25 50
 
Guideline Title UK guidelines for the management of bone sarcomas
Description British Sarcoma Group: UK guidelines for the management of bone sarcomas (in BMC Clinical Sarcoma Research)
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
Impact Not known
URL https://clinicalsarcomaresearch.biomedcentral.com/articles/10.1186/s13569-016-0047-1
 
Description Case study in European Science Foundation EUROCORS programme "Pan-European Clinical Trials" final report
Geographic Reach Europe 
Policy Influence Type Citation in other policy documents
 
Description EURAMOS-1
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description NICE review of ridaforolimus
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact Participated in discussions at NICE review
 
Guideline Title NCCN Clinical Practice Guidelines in Oncology Bone Cancer
Description National Comprehensive Cancer Network - EURAMOS-1 Good Responders
Geographic Reach North America 
Policy Influence Type Citation in clinical guidelines
Impact Not known
URL https://emedicine.medscape.com/article/1256857-guidelines
 
Guideline Title NCCN Clinical Practice Guidelines in Oncology Bone Cancer
Description National Comprehensive Cancer Network - EURAMOS-1 Poor Responders
Geographic Reach North America 
Policy Influence Type Citation in clinical guidelines
URL https://emedicine.medscape.com/article/1256857-guidelines
 
Description Participation in discussions -- EFGCP Multidisciplinary Workshop: A Single CTA in Multinational Clinical Trials - Dream or Option?
Geographic Reach Europe 
Policy Influence Type Participation in a national consultation
Impact Led to further ongoing discussions
 
Title EURAMOS-1 Common Data Set (collated) 
Description Collated data from our participating groups in EURAMOS-1 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact None yet; pending maturity 
 
Title EURAMOS-1 clinical trial database (EOI data) 
Description Database prospectively collecting information on patients who have joined this international clinical trial 
Type Of Material Biological samples 
Provided To Others? No  
Impact ASCO presentation 2013 Papers 2014 to 2015 -- see publications 
 
Description EURAMOS 
Organisation Cooperative Osteosarcoma Study Group
Country European Union (EU) 
Sector Academic/University 
PI Contribution Design, central coordination and analysis of trial data. Discussion, prioritisation and design of further clinical trials from this. New participants to the group are currently joining.
Collaborator Contribution Design and conduct of clinical trials This organisation involves a number of countries. Many of these countries provide money to a central pot. This pot provides money to support the running of the trial, including to MRC CTU. Design and conduct of clinical trials. This trial is a collaboration with the National Cancer Research Network (a component of NIHR and funded by the English Dept of Health) and the corresponding networks in the other UK nations. It specifically includes all the staff at each of the clinical sites that have participated in this clinical trial. Each site identified patients potentially suitable for the trial, sought informed consent, treated and followed-up patients within the trial and provided data through completion and return of case record forms. EURAMOS-1 is run in collaboration with the NCRI bone cancer Clinical Studies Group which, as a group, encourages national participation in trials. Each of the collaborating groups named above includes representatives from a number of countries. In each country, a university is acting as the delegate for many of the MRC's responsibilities as Sponsor. These are not named in detail here but are listed in the EURAMOS-1 European Framework agreement which they have co-signed. Continued provision of free drug (Peg-intron)interferon by Merck for clinical trial use and distribution to trial sites, following their take-over of Schering Plough.
Impact No primary publications yet. Methods and collaboration paper now presented and added as a publication (PMID: 20213400). Invitations to present on high-profile collaboration at international conferences and to EU-level discussions of lessons learned in being the first academic trial to run internationally after the implementation of the EU Clinical Trials Directive (EC\2001\20). 1st results from the good responders randomisation were presented at American Society of Clinical Oncology Annual Meeting 2013 in the oral sarcoma session (and was the only oral presentation on bone sarcoma at the meeting).
 
Description EURAMOS 
Organisation European and American Osteosarcoma Study Group (EURAMOS)
Department European Osteosarcoma Group (EOI)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Design, central coordination and analysis of trial data. Discussion, prioritisation and design of further clinical trials from this. New participants to the group are currently joining.
Collaborator Contribution Design and conduct of clinical trials This organisation involves a number of countries. Many of these countries provide money to a central pot. This pot provides money to support the running of the trial, including to MRC CTU. Design and conduct of clinical trials. This trial is a collaboration with the National Cancer Research Network (a component of NIHR and funded by the English Dept of Health) and the corresponding networks in the other UK nations. It specifically includes all the staff at each of the clinical sites that have participated in this clinical trial. Each site identified patients potentially suitable for the trial, sought informed consent, treated and followed-up patients within the trial and provided data through completion and return of case record forms. EURAMOS-1 is run in collaboration with the NCRI bone cancer Clinical Studies Group which, as a group, encourages national participation in trials. Each of the collaborating groups named above includes representatives from a number of countries. In each country, a university is acting as the delegate for many of the MRC's responsibilities as Sponsor. These are not named in detail here but are listed in the EURAMOS-1 European Framework agreement which they have co-signed. Continued provision of free drug (Peg-intron)interferon by Merck for clinical trial use and distribution to trial sites, following their take-over of Schering Plough.
Impact No primary publications yet. Methods and collaboration paper now presented and added as a publication (PMID: 20213400). Invitations to present on high-profile collaboration at international conferences and to EU-level discussions of lessons learned in being the first academic trial to run internationally after the implementation of the EU Clinical Trials Directive (EC\2001\20). 1st results from the good responders randomisation were presented at American Society of Clinical Oncology Annual Meeting 2013 in the oral sarcoma session (and was the only oral presentation on bone sarcoma at the meeting).
 
Description EURAMOS 
Organisation Merck
Department Schering Plough
Country United States 
Sector Private 
PI Contribution Design, central coordination and analysis of trial data. Discussion, prioritisation and design of further clinical trials from this. New participants to the group are currently joining.
Collaborator Contribution Design and conduct of clinical trials This organisation involves a number of countries. Many of these countries provide money to a central pot. This pot provides money to support the running of the trial, including to MRC CTU. Design and conduct of clinical trials. This trial is a collaboration with the National Cancer Research Network (a component of NIHR and funded by the English Dept of Health) and the corresponding networks in the other UK nations. It specifically includes all the staff at each of the clinical sites that have participated in this clinical trial. Each site identified patients potentially suitable for the trial, sought informed consent, treated and followed-up patients within the trial and provided data through completion and return of case record forms. EURAMOS-1 is run in collaboration with the NCRI bone cancer Clinical Studies Group which, as a group, encourages national participation in trials. Each of the collaborating groups named above includes representatives from a number of countries. In each country, a university is acting as the delegate for many of the MRC's responsibilities as Sponsor. These are not named in detail here but are listed in the EURAMOS-1 European Framework agreement which they have co-signed. Continued provision of free drug (Peg-intron)interferon by Merck for clinical trial use and distribution to trial sites, following their take-over of Schering Plough.
Impact No primary publications yet. Methods and collaboration paper now presented and added as a publication (PMID: 20213400). Invitations to present on high-profile collaboration at international conferences and to EU-level discussions of lessons learned in being the first academic trial to run internationally after the implementation of the EU Clinical Trials Directive (EC\2001\20). 1st results from the good responders randomisation were presented at American Society of Clinical Oncology Annual Meeting 2013 in the oral sarcoma session (and was the only oral presentation on bone sarcoma at the meeting).
 
Description EURAMOS 
Organisation Merck
Country Germany 
Sector Private 
PI Contribution Design, central coordination and analysis of trial data. Discussion, prioritisation and design of further clinical trials from this. New participants to the group are currently joining.
Collaborator Contribution Design and conduct of clinical trials This organisation involves a number of countries. Many of these countries provide money to a central pot. This pot provides money to support the running of the trial, including to MRC CTU. Design and conduct of clinical trials. This trial is a collaboration with the National Cancer Research Network (a component of NIHR and funded by the English Dept of Health) and the corresponding networks in the other UK nations. It specifically includes all the staff at each of the clinical sites that have participated in this clinical trial. Each site identified patients potentially suitable for the trial, sought informed consent, treated and followed-up patients within the trial and provided data through completion and return of case record forms. EURAMOS-1 is run in collaboration with the NCRI bone cancer Clinical Studies Group which, as a group, encourages national participation in trials. Each of the collaborating groups named above includes representatives from a number of countries. In each country, a university is acting as the delegate for many of the MRC's responsibilities as Sponsor. These are not named in detail here but are listed in the EURAMOS-1 European Framework agreement which they have co-signed. Continued provision of free drug (Peg-intron)interferon by Merck for clinical trial use and distribution to trial sites, following their take-over of Schering Plough.
Impact No primary publications yet. Methods and collaboration paper now presented and added as a publication (PMID: 20213400). Invitations to present on high-profile collaboration at international conferences and to EU-level discussions of lessons learned in being the first academic trial to run internationally after the implementation of the EU Clinical Trials Directive (EC\2001\20). 1st results from the good responders randomisation were presented at American Society of Clinical Oncology Annual Meeting 2013 in the oral sarcoma session (and was the only oral presentation on bone sarcoma at the meeting).
 
Description EURAMOS 
Organisation National Cancer Institute (NCI)
Department Children's Oncology Group (COG)
Country United States 
Sector Academic/University 
PI Contribution Design, central coordination and analysis of trial data. Discussion, prioritisation and design of further clinical trials from this. New participants to the group are currently joining.
Collaborator Contribution Design and conduct of clinical trials This organisation involves a number of countries. Many of these countries provide money to a central pot. This pot provides money to support the running of the trial, including to MRC CTU. Design and conduct of clinical trials. This trial is a collaboration with the National Cancer Research Network (a component of NIHR and funded by the English Dept of Health) and the corresponding networks in the other UK nations. It specifically includes all the staff at each of the clinical sites that have participated in this clinical trial. Each site identified patients potentially suitable for the trial, sought informed consent, treated and followed-up patients within the trial and provided data through completion and return of case record forms. EURAMOS-1 is run in collaboration with the NCRI bone cancer Clinical Studies Group which, as a group, encourages national participation in trials. Each of the collaborating groups named above includes representatives from a number of countries. In each country, a university is acting as the delegate for many of the MRC's responsibilities as Sponsor. These are not named in detail here but are listed in the EURAMOS-1 European Framework agreement which they have co-signed. Continued provision of free drug (Peg-intron)interferon by Merck for clinical trial use and distribution to trial sites, following their take-over of Schering Plough.
Impact No primary publications yet. Methods and collaboration paper now presented and added as a publication (PMID: 20213400). Invitations to present on high-profile collaboration at international conferences and to EU-level discussions of lessons learned in being the first academic trial to run internationally after the implementation of the EU Clinical Trials Directive (EC\2001\20). 1st results from the good responders randomisation were presented at American Society of Clinical Oncology Annual Meeting 2013 in the oral sarcoma session (and was the only oral presentation on bone sarcoma at the meeting).
 
Description EURAMOS 
Organisation National Cancer Research Institute (NCRI)
Department NCRI Bone Cancer CSG
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Design, central coordination and analysis of trial data. Discussion, prioritisation and design of further clinical trials from this. New participants to the group are currently joining.
Collaborator Contribution Design and conduct of clinical trials This organisation involves a number of countries. Many of these countries provide money to a central pot. This pot provides money to support the running of the trial, including to MRC CTU. Design and conduct of clinical trials. This trial is a collaboration with the National Cancer Research Network (a component of NIHR and funded by the English Dept of Health) and the corresponding networks in the other UK nations. It specifically includes all the staff at each of the clinical sites that have participated in this clinical trial. Each site identified patients potentially suitable for the trial, sought informed consent, treated and followed-up patients within the trial and provided data through completion and return of case record forms. EURAMOS-1 is run in collaboration with the NCRI bone cancer Clinical Studies Group which, as a group, encourages national participation in trials. Each of the collaborating groups named above includes representatives from a number of countries. In each country, a university is acting as the delegate for many of the MRC's responsibilities as Sponsor. These are not named in detail here but are listed in the EURAMOS-1 European Framework agreement which they have co-signed. Continued provision of free drug (Peg-intron)interferon by Merck for clinical trial use and distribution to trial sites, following their take-over of Schering Plough.
Impact No primary publications yet. Methods and collaboration paper now presented and added as a publication (PMID: 20213400). Invitations to present on high-profile collaboration at international conferences and to EU-level discussions of lessons learned in being the first academic trial to run internationally after the implementation of the EU Clinical Trials Directive (EC\2001\20). 1st results from the good responders randomisation were presented at American Society of Clinical Oncology Annual Meeting 2013 in the oral sarcoma session (and was the only oral presentation on bone sarcoma at the meeting).
 
Description EURAMOS 
Organisation National Cancer Research Institute (NCRI)
Department National Cancer Research Network (NCRN)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Design, central coordination and analysis of trial data. Discussion, prioritisation and design of further clinical trials from this. New participants to the group are currently joining.
Collaborator Contribution Design and conduct of clinical trials This organisation involves a number of countries. Many of these countries provide money to a central pot. This pot provides money to support the running of the trial, including to MRC CTU. Design and conduct of clinical trials. This trial is a collaboration with the National Cancer Research Network (a component of NIHR and funded by the English Dept of Health) and the corresponding networks in the other UK nations. It specifically includes all the staff at each of the clinical sites that have participated in this clinical trial. Each site identified patients potentially suitable for the trial, sought informed consent, treated and followed-up patients within the trial and provided data through completion and return of case record forms. EURAMOS-1 is run in collaboration with the NCRI bone cancer Clinical Studies Group which, as a group, encourages national participation in trials. Each of the collaborating groups named above includes representatives from a number of countries. In each country, a university is acting as the delegate for many of the MRC's responsibilities as Sponsor. These are not named in detail here but are listed in the EURAMOS-1 European Framework agreement which they have co-signed. Continued provision of free drug (Peg-intron)interferon by Merck for clinical trial use and distribution to trial sites, following their take-over of Schering Plough.
Impact No primary publications yet. Methods and collaboration paper now presented and added as a publication (PMID: 20213400). Invitations to present on high-profile collaboration at international conferences and to EU-level discussions of lessons learned in being the first academic trial to run internationally after the implementation of the EU Clinical Trials Directive (EC\2001\20). 1st results from the good responders randomisation were presented at American Society of Clinical Oncology Annual Meeting 2013 in the oral sarcoma session (and was the only oral presentation on bone sarcoma at the meeting).
 
Description EURAMOS 
Organisation Scandinavian Sarcoma Group (SSG)
Country Sweden 
Sector Charity/Non Profit 
PI Contribution Design, central coordination and analysis of trial data. Discussion, prioritisation and design of further clinical trials from this. New participants to the group are currently joining.
Collaborator Contribution Design and conduct of clinical trials This organisation involves a number of countries. Many of these countries provide money to a central pot. This pot provides money to support the running of the trial, including to MRC CTU. Design and conduct of clinical trials. This trial is a collaboration with the National Cancer Research Network (a component of NIHR and funded by the English Dept of Health) and the corresponding networks in the other UK nations. It specifically includes all the staff at each of the clinical sites that have participated in this clinical trial. Each site identified patients potentially suitable for the trial, sought informed consent, treated and followed-up patients within the trial and provided data through completion and return of case record forms. EURAMOS-1 is run in collaboration with the NCRI bone cancer Clinical Studies Group which, as a group, encourages national participation in trials. Each of the collaborating groups named above includes representatives from a number of countries. In each country, a university is acting as the delegate for many of the MRC's responsibilities as Sponsor. These are not named in detail here but are listed in the EURAMOS-1 European Framework agreement which they have co-signed. Continued provision of free drug (Peg-intron)interferon by Merck for clinical trial use and distribution to trial sites, following their take-over of Schering Plough.
Impact No primary publications yet. Methods and collaboration paper now presented and added as a publication (PMID: 20213400). Invitations to present on high-profile collaboration at international conferences and to EU-level discussions of lessons learned in being the first academic trial to run internationally after the implementation of the EU Clinical Trials Directive (EC\2001\20). 1st results from the good responders randomisation were presented at American Society of Clinical Oncology Annual Meeting 2013 in the oral sarcoma session (and was the only oral presentation on bone sarcoma at the meeting).
 
Title EURAMOS-1 
Description EURAMOS-1 is an international phase 3 trial randomised controlled trial investigating treatment optimisation on the basis of histological response in the adjuvant treatment of osteosarcoma. Primary objectives: 1. To examine, in a randomised controlled trial, whether the addition of ifosfamide and etoposide (IE) to post-operative chemotherapy with cisplatin, doxorubicin and methotrexate improves event-free survival for patients with resectable osteosarcoma and a poor histological response to 10 weeks of pre-operative chemotherapy. 2. To examine, in a randomised controlled trial, whether the addition of interferon-alpha ifn) as maintenance therapy after post-operative chemotherapy with cisplatin, doxorubicin and methotrexate improves event-free survival for patients with resectable osteosarcoma and a good histological response to 10 weeks of pre-operative chemotherapy. Secondary objectives: 3. To investigate whether the addition of IE to post-operative therapy for poor responders, and the addition of ifn as maintenance therapy for good responders, leads to an improvement in overall survival, short-term toxicity, long-term toxicity and quality of life. 4. To investigate whether the addition of IE to post-operative therapy for poor responders, and the addition of ifn as maintenance therapy for good responders, leads to an improvement in event-free and overall survival in patients with localized osteosarcoma at entry. 5. To investigate whether biological or clinical correlates to histological response and outcome can be identified. 6. To establish whether this international cooperation in clinical trials for osteosarcoma is feasible. The trial is currently in follow-up. Results of the primary analysis (for event-free survival) of the good responders randomisation have been presented but active follow-up continues for the poor responders primary outcome measure and all secondary outcome measures. The current principle source of funding for this trial is an MRC Trial Grant. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2006
Development Status Under active development/distribution
Clinical Trial? Yes
Impact 1. Informed EU level policy guidance on research in rare diseases under the EU Clinical Trials Directive. Chief Investigator invited to contribute to European Science Foundation Forward Look on "Investigator Driven Clinical Trials", 2009. 2. Lead to establishment of an expanded collaboration of international research groups (EURAMOS Strategy Group) for the design and implementation of future clinical trials. 
URL http://www.euramos.org
 
Description EURAMOS good responders lay summary 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Lay summary of trial results (First results of the EURAMOS-1: Information for trial participants and families) was prepared and made available via the trial website and sent to investigators to give to participants.

Unknown
Year(s) Of Engagement Activity 2013
URL http://www.euramos.org
 
Description EURAMOS-1 infographic 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact We produced an infographic to summarise some of the key EURAMOS-1 results. This was distributed via social media, and to study participants.
Year(s) Of Engagement Activity 2016
URL http://www.ctu.mrc.ac.uk/news/2016/euramos_results_26082016
 
Description Presentation of the EURAMOS-1 Poor Responders randomisation first results 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact First results of this important comparison were presented at international conferences. More presentations will follow in China, UK and Germany, at least, given by the lead investigators. A paper is in development.

MAP chemotherapy will the international standard of care.
Year(s) Of Engagement Activity 2014
URL https://www.ctos.org/PDFs/CTOS%202014%20AM%20FP%20complete%20rfs%20electronic.pdf