euro ewing 2012

International Randomised Controlled Trial for the
Treatment of Newly Diagnosed Ewing's Sarcoma Family
of Tumours
Euro Ewing 2012
Version 5.0
2nd June 2017
Coordinating Sponsor: University of Birmingham
Sponsor protocol number: RG_11-152
CAS code: SA3008
EudraCT number: 2012-002107-17
ISRCTN reference number: ISRCTN 92192408
This project has received funding from the European Union’s Seventh Framework Programme for
research, technological development and demonstration under grant agreement no °602856.

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TABLE OF CONTENTS
Table of contents ................................................................................................................................... 2
Introductory Pages ................................................................................................................................ 6
SIGNATURE PAGE ................................................................................................................................ 9
Amendments ........................................................................................................................................ 10
Trial Synopsis ...................................................................................................................................... 12
Trial Schema ........................................................................................................................................ 15
Abbreviations ....................................................................................................................................... 16
1. Background and Rationale ............................................................................................................ 18
1.1 Background............................................................................................................................ 18
1.1.1 Characterisation of ESFT .................................................................................................. 18
1.1.2 Treatment results in localised disease .............................................................................. 18
1.1.3 Treatment results in patients with primary pulmonary metastases and regional lymph
nodes ........................................................................................................................................... 18
1.1.4 Treatment results in patients with disseminated disease ................................................. 19
1.1.5 The value of bisphosphonates in the treatment of ESFT .................................................. 19
1.2 Trial Rationale........................................................................................................................ 20
1.2.1 Rationale for an international study ................................................................................... 20
1.2.2 Rationale for a VIDE and VAC/VAI versus VDC/IE/VC randomisation ............................. 21
1.2.3 Rationale for zoledronic acid randomisation ..................................................................... 22
2. Objectives and Outcome Measures ............................................................................................. 22
2.1 Objectives .............................................................................................................................. 22
2.2 Outcome Measures ............................................................................................................... 23
2.2.1 Primary outcome measure ................................................................................................ 23
2.2.2 Secondary outcome measures .......................................................................................... 23
3. Trial Design ..................................................................................................................................... 23
4. Eligibility .......................................................................................................................................... 23
4.1 Randomisation R1 ................................................................................................................. 23
4.2 Randomisation R2 ................................................................................................................. 24
5. Screening and Consent ................................................................................................................. 24
5.1 Screening ............................................................................................................................... 24
5.2 Informed Consent .................................................................................................................. 24
6. Randomisation................................................................................................................................ 25
6.1 Randomisation R1 ................................................................................................................. 25
6.2 Randomisation R2 ................................................................................................................. 27
6.3 Procedure for online randomisation ...................................................................................... 29
6.4 Emergency randomisation ..................................................................................................... 30
7. Treatment details ............................................................................................................................ 30
7.1 Investigational Medicinal Products (IMPs) ............................................................................ 30
7.2 Arm A treatment schedule ..................................................................................................... 31
7.2.1 Arm A: Overview ................................................................................................................ 31
7.2.2 Arm A: VIDE chemotherapy .............................................................................................. 32
7.2.3 Arm A: VAI chemotherapy ................................................................................................. 33
7.2.4 Arm A: VAC chemotherapy ............................................................................................... 34
7.2.6 Arm A: BuMel ..................................................................................................................... 35
7.2.7 Arm A: Zoledronic acid treatment ...................................................................................... 37
7.3 Arm B treatment schedule ..................................................................................................... 38

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7.3.1 Arm B: Overview ................................................................................................................ 38
7.3.2 Arm B: VDC/IE chemotherapy ........................................................................................... 39
7.3.3 Arm B: IE/VC chemotherapy ............................................................................................. 40
7.3.4 Arm A: BuMel ..................................................................................................................... 41
7.3.5 Arm B: Zoledronic acid treatment ...................................................................................... 41
7.4 Dose Modifications ................................................................................................................ 41
7.4.1 VIDE/VAI/VAC chemotherapy (Arm A) .............................................................................. 41
7.4.2 VDC/IE/VC chemotherapy (Arm B) ................................................................................... 44
7.4.3 Zoledronic acid (Arms A and B) ......................................................................................... 46
7.5 Treatment Compliance .......................................................................................................... 46
7.6 IMP Handling ......................................................................................................................... 46
7.7 Supportive Treatment ............................................................................................................ 46
7.7.1 Venous Access .................................................................................................................. 46
7.7.2 Antiemetics ........................................................................................................................ 46
7.7.3 Neutropenia ....................................................................................................................... 47
7.7.4 Blood products ................................................................................................................... 47
7.7.5 Pneumocystis carinii infection prophylaxis ........................................................................ 47
7.7.6 Hydration ........................................................................................................................... 47
7.8 Concomitant Medication ........................................................................................................ 47
7.9 Patient Follow Up .................................................................................................................. 47
7.10 Patient Withdrawal ................................................................................................................. 48
7.10.1 Withdrawal from Euro Ewing 2012 trial treatment ............................................................. 48
7.10.2 Withdrawal of consent to data collection ........................................................................... 48
7.10.3 Loss to follow-up ................................................................................................................ 48
8. Patient Monitoring and Assessment ............................................................................................ 48
8.1 Overview – Schedule of assessments .................................................................................. 49
8.2 Assessments at diagnosis ..................................................................................................... 50
8.2.1 Basic patient information ................................................................................................... 50
8.2.2 Blood chemistry ................................................................................................................. 50
8.2.3 Haematology ...................................................................................................................... 50
8.2.4 Radiological assessments ................................................................................................. 50
8.2.5 Other assessments ............................................................................................................ 50
8.2.6 Estimation of tumour involvement ..................................................................................... 50
Primary tumour volume ......................................................................................................................... 50
8.2.7 Diagnosis of ESFT ............................................................................................................. 51
8.2.8 Definition of pulmonary/pleural metastatic disease ........................................................... 51
8.2.9 Regional lymph node involvement..................................................................................... 52
8.3 Assessments during treatment .............................................................................................. 52
8.3.1 Prior to each cycle of chemotherapy ................................................................................. 52
8.3.2 Cardiac assessments ........................................................................................................ 52
8.3.3 Radiological assessments ................................................................................................. 52
8.3.4 Bone Marrow assessments ............................................................................................... 53
8.4 Assessments at the end of treatment .................................................................................... 53
9. Biological Studies .......................................................................................................................... 54
10. Adverse Event Reporting .............................................................................................................. 56
10.1 Reporting Requirements ........................................................................................................ 56
10.1.1 Adverse Events and Adverse Reactions ........................................................................... 56
10.1.2 Serious Adverse Events .................................................................................................... 56

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10.1.3 Reporting period ................................................................................................................ 57
10.1.4 Post study SARs and SUSARs: ........................................................................................ 57
10.2 Reporting Procedure ............................................................................................................. 57
10.2.1 Site ..................................................................................................................................... 57
10.2.2 UK Coordinating Centre .................................................................................................... 58
10.2.3 Reporting to the Competent Authority and Research Ethics Committee .......................... 58
10.2.4 Investigators ...................................................................................................................... 59
10.2.5 Data Monitoring Committee ............................................................................................... 59
11. Data Handling and Record Keeping ............................................................................................. 60
11.1 Data Collection ...................................................................................................................... 60
11.2 Archiving ................................................................................................................................ 60
12. Quality Management ...................................................................................................................... 60
12.1 Site Set-up and Initiation ....................................................................................................... 60
12.2 On-site Monitoring ................................................................................................................. 61
12.3 Central Monitoring ................................................................................................................. 61
12.4 Audit and Inspection .............................................................................................................. 61
12.5 Notification of Serious Breaches ........................................................................................... 61
13. End of Trial Definition .................................................................................................................... 62
14. Statistical Considerations ............................................................................................................. 62
14.1 Definition of Outcome Measures ........................................................................................... 62
14.1.1 Primary outcome measure ................................................................................................ 62
14.1.2 Secondary outcome measures .......................................................................................... 62
14.2 Induction/consolidation chemotherapy randomisation: general principles ............................ 63
14.3 Sample Size Calculations ...................................................................................................... 64
14.3.1 Induction/consolidation randomisation (R1) ...................................................................... 64
14.3.2 Zoledronic acid randomisation (R2)................................................................................... 65
14.4 Analysis of Outcome Measures ............................................................................................. 66
14.5 Planned Subgroup Analyses ................................................................................................. 68
14.6 Planned Interim Analysis ....................................................................................................... 68
14.7 Planned Main Analyses ......................................................................................................... 68
15. Trial Organisational Structure ....................................................................................................... 68
15.1 Coordinating-sponsor ............................................................................................................ 69
15.2 National Coordinating Centres .............................................................................................. 69
15.3 Trial Management Group ....................................................................................................... 69
15.4 Trial Steering Committee ....................................................................................................... 69
15.5 Data Monitoring Committee ................................................................................................... 69
15.6 Finance .................................................................................................................................. 70
16. Ethical Considerations .................................................................................................................. 70
17. Confidentiality and Data Protection ............................................................................................. 71
18. Insurance and Indemnity ............................................................................................................... 71
19. Publication Policy .......................................................................................................................... 71
20. Reference List ................................................................................................................................. 73
Appendix 1 – United Kingdom Specific Quality and Trial management Plan ............................... 76
Records of Screening/enrolment ....................................................................................................... 76
Informed Consent Form Review ........................................................................................................ 76
Site Set-up and Initiation .................................................................................................................... 76
Pharmacy ........................................................................................................................................... 76
On-site Monitoring .............................................................................................................................. 76

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Serious Breach Notification ................................................................................................................ 77
Archiving ............................................................................................................................................ 77
Appendix 2 – Definition of Adverse Events ...................................................................................... 78
Appendix 3 – Common Terminology Criteria for Adverse Events ................................................. 80