International Open-label Phase I Dose Escalation Study of Dinutuximab Beta in Combination With Vincristine/Doxorubicin/Cyclophosphamide and Ifosfamide/Etoposide in Pediatric, Adolescent, and Adult Patients With GD2-positive Ewing Sarcoma
Phase: PHASE1
Conditions: High-risk GD2-Positive Ewing Sarcoma
Sponsor: Prof. Dr. Dirk Reinhardt

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INTERNATIONAL OPEN-LABEL PHASE I DOSE ESCALATION STUDY OF 
DINUTUXIMAB BETA IN COMBINATION WITH 
VINCRISTINE/DOXORUBICIN/CYCLOPHOSPHAMIDE AND 
IFOSFAMIDE/ETOPOSIDE IN PEDIATRIC, ADOLESCENT, AND ADULT 
PATIENTS WITH GD2-POSITIVE EWING SARCOMA 
 
PROTOCOL TITLE: 
International open-label phase I dose escalation 
study of dinutuximab beta in combination with 
vincristine/doxorubicin/cyclophosphamide and 
ifosfamide/etoposide in pediatric, adolescent, 
and adult patients with GD2-positive Ewing 
sarcoma 
PROTOCOL CODE:  
CESS-GD2 
EUCT NUMBER: 
2024-515245-42-00 
VERSION NUMBER:  
1.2 
DATE OF ORIGINAL FINAL VERSION:  
07. FEB. 2025   
SPONSOR NAME/ADDRESS:  
Gesellschaft für Pädiatrische Onkologie und 
Hämatologie / German Society of Pediatric 
Oncology and Hematology   
GPOH gGmbH  
  
Sponsor´s Office:  
Holsterhauser Platz 2  
GERMANY – 45147 Essen  
 
CONFIDENTIAL 
  
The information contained in this document is regarded as confidential and, except to the extent 
necessary to obtain informed consent, may not be disclosed to another party unless such disclosure is 
required by law or regulations. Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them.  
GPOH protocols and their content are for research purposes only and should not be copied, 
redistributed, or used for any other purpose. The procedures in this protocol are intended only for use 
at approved sites under the direction of GPOH. Use of this information for regulatory purposes is 
permitted only after approval by the GPOH. 
 
 

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Table of Contents 
 
 
Table of Contents .................................................................................................................................... 2 
Protocol information ................................................................................................................................. 6 
Compliance Statement ............................................................................................................................ 7 
Abbrevations ............................................................................................................................................ 8 
1. 
Protocol Summary ......................................................................................................................... 10 
1.1. 
Synopsis ............................................................................................................................... 10 
1.2. 
Trial Scheme ........................................................................................................................ 14 
1.3. 
Schedule of Activities ........................................................................................................... 15 
2. 
Introduction .................................................................................................................................... 17 
2.1. 
Study Rationale .................................................................................................................... 17 
2.1.1. 
Rationale for the Inclusion of Minors ............................................................................... 17 
2.2. 
Background .......................................................................................................................... 17 
2.3. 
Risk/Benefit Assessment ..................................................................................................... 18 
2.3.1. 
Known Potential Risks ..................................................................................................... 18 
2.3.2. 
Potential Benefits ............................................................................................................. 18 
2.3.3. 
Assessment of Potential Risks and Benefits ................................................................... 19 
2.3.4. 
Description and Threshold of Burden .............................................................................. 20 
3. 
OBJECTIVES AND ENDPOINTS .................................................................................................. 20 
3.1. 
Primary Objective ................................................................................................................. 20 
3.2. 
Secondary Objectives .......................................................................................................... 20 
3.3. 
Exploratory Objectives ......................................................................................................... 20 
3.4. 
Primary Endpoint .................................................................................................................. 21 
3.5. 
Secondary Endpoints ........................................................................................................... 21 
3.6. 
Exploratory Endpoints .......................................................................................................... 21 
4. 
STUDY DESIGN ............................................................................................................................ 21 
4.1. 
Overall Design ...................................................................................................................... 21 
4.2. 
Scientific Rationale for Study Design ................................................................................... 21 
4.3. 
Justification for Dosing ......................................................................................................... 22 
4.4. 
Start and End of Trial Definition ........................................................................................... 23 
5. 
STUDY POPULATION .................................................................................................................. 23 
5.1. 
Inclusion Criteria .................................................................................................................. 24 
5.2. 
Exclusion Criteria ................................................................................................................. 25 
5.3. 
Screen Failures .................................................................................................................... 25 
5.4. 
Definition of women of childbearing potential and of fertile men ......................................... 25 
6. 
INVESTIGATIONAL MEDICINAL PRODUCTS ............................................................................ 26 

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6.1. 
Declaration of Investigational Medical Products and Auxiliary Medicinal Product ............... 26 
6.2. 
Study Intervention Description ............................................................................................. 26 
6.2.1. 
Dosing and Administration ............................................................................................... 26 
6.3. 
Preparation/Handling/Storage/Accountability ...................................................................... 27 
6.3.1. 
Acquisition and Accountability ......................................................................................... 27 
6.3.2. 
Formulation, Appearance, Packaging, and Labelling ...................................................... 27 
6.3.3. 
Product Storage and Stability .......................................................................................... 28 
6.3.4. 
Preparation and precautions for disposal and other handling instructions ...................... 28 
7. 
PRE-SCREENING FOR GD2 ........................................................................................................ 29 
7.1 Central GD2 determination .......................................................................................................... 30 
8. 
SCREENING AND INFORMED CONSENT .................................................................................. 30 
8.1. 
Informed Consent ................................................................................................................. 30 
8.2. 
Patient numbering ................................................................................................................ 31 
8.3. 
Treatment assignment ......................................................................................................... 31 
8.4. 
Information to be collected on screening failures................................................................. 31 
9. 
STUDY PROCEDURES AND ASSESSMENTS ........................................................................... 32 
9.1. 
Prior Medication/Procedures ................................................................................................ 32 
9.2. 
Demographics and Medical history ...................................................................................... 32 
9.3. 
Vital signs ............................................................................................................................. 32 
9.4. 
Body Surface Area ............................................................................................................... 32 
9.5. 
Physical examination ........................................................................................................... 32 
9.6. 
Performance status .............................................................................................................. 32 
9.7. 
Laboratory evaluations ......................................................................................................... 32 
9.8. 
Pharmacokinetic (PK) and Complement-Dependent Cytotoxicity (CDC) Sampling ............ 33 
9.9. 
Pregnancy Testing ............................................................................................................... 34 
9.10. 
Imaging ................................................................................................................................. 34 
10. 
TREATMENT ............................................................................................................................ 34 
10.1. 
Study Treatment ................................................................................................................... 34 
10.1.1. 
Dosing Regimen .............................................................................................................. 36 
10.1.2. 
Treatment Duration of Dinutuximab Beta ........................................................................ 36 
10.2. 
Dose Escalation Guidelines ................................................................................................. 36 
10.2.1. 
Starting Dose Rationale ................................................................................................... 36 
10.2.2. 
Provisional Dose Levels .................................................................................................. 36 
10.2.3. 
Guidelines for dose escalation and determination of Maximum Tolerated Dose (MTD) . 37 
10.2.4. 
Definitions of dose limiting toxicities (DLTs) .................................................................... 38 
10.3. 
Dose Modifications ............................................................................................................... 39 
10.3.1. 
Hematological Toxicity ..................................................................................................... 39 
10.3.2. 
Mucositis / Gastrointestinal Toxicity CTCAE Grade ≥ 3 .................................................. 40 
10.3.3. 
Nephrotoxicity / Renal Function Monitoring ..................................................................... 40 

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10.3.4. 
Cardiac Toxicity ............................................................................................................... 42 
10.3.5. 
Neurotoxicity CTCAE Grade ≥ 3 ...................................................................................... 42 
10.4. 
Follow up for toxicities .......................................................................................................... 42 
11. 
CONCOMITANT THERAPY ............................................................................................................. 43 
11.1. 
Required Concomitant Therapy as part of supportive care ................................................. 43 
11.2. 
Permitted concomitant Therapy ........................................................................................... 44 
11.3. 
Prohibited concomitant therapy............................................................................................ 44 
11.4. 
Contraceptive Requirements ................................................................................................ 44 
12. 
OTHER SUPPORTIVE CARE .......................................................................................................... 45 
13. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL ....... 45 
13.1. 
Patient replacement ............................................................................................................. 46 
13.2. 
Withdrawal of consent to data collection .............................................................................. 46 
13.3. 
Lost to follow-up ................................................................................................................... 46 
14. 
SAFETY MONITORING AND REPORTING ......................................................................................... 46 
14.1. 
Definition and Reporting of Adverse Events (AE) ................................................................ 46 
14.1.1. 
Handling of Laboratory test abnormalities ....................................................................... 47 
14.2. 
Definition and Reporting of Serious Adverse Events (SAE) ................................................ 47 
14.2.1. 
Timing of SAE Reporting ................................................................................................. 48 
14.2.2. 
Serious Adverse Event Reporting .................................................................................... 49 
14.3. 
Serious Breach Reporting .................................................................................................... 50 
14.4. 
Reporting of Pregnancy ....................................................................................................... 50 
15. 
STATISTICAL CONSIDERATIONS ......................................................................................... 50 
15.1. 
Statistical Hypotheses .......................................................................................................... 50 
15.2. 
Sample Size Determination .................................................................................................. 50 
15.3. 
Populations for Analyses ...................................................................................................... 51 
15.3.1. 
Full Analysis Set (FAS) .................................................................................................... 51 
15.3.2. 
Safety Set (SAF) .............................................................................................................. 51 
15.3.3. 
Per-protocol set ................................................................................................................ 51 
15.3.4. 
Dose-Determining Analysis Set (DDS) ............................................................................ 52 
15.4. 
General Approach ................................................................................................................ 52 
15.5. 
Statistical Analyses .............................................................................................................. 52 
15.5.1. 
Study Treatment .............................................................................................................. 52 
15.5.2. 
Protocol Compliance ........................................................................................................ 52 
15.6. 
Analysis of the Primary Endpoint(s) ..................................................................................... 52 
15.6.1. 
Handling of Missing Values, Censoring, and Discontinuations ....................................... 53 
15.7. 
Analysis of the Secondary Endpoint(s) ................................................................................ 53 
15.7.1. 
Early Efficacy signals ....................................................................................................... 53 
15.8. 
Safety Analyses ................................................................................................................... 53 
15.8.1. 
Analysis of Adverse Events (AEs) ................................................................................... 53 

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15.8.2. 
Analysis of Laboratory Abnormalities .............................................................................. 54 
15.8.3. 
Analysis of Tolerability ..................................................................................................... 54 
15.9. 
Planned Interim Analyses .................................................................................................... 54 
16. 
DATA HANDLING AND RECORD KEEPING ........................................................................... 54 
16.1. 
Data Management ................................................................................................................ 54 
16.2. 
Record Retention ................................................................................................................. 55 
16.3. 
Archiving ............................................................................................................................... 55 
16.4. 
End of Trial Definition ........................................................................................................... 55 
17. 
OPERATIONAL CONSIDERATIONS ....................................................................................... 56 
17.1. 
Regulatory, Ethical, and Study Oversight Considerations ................................................... 56 
17.1.1. 
Statement on the future use of biological samples .......................................................... 56 
17.2. 
Study Discontinuation and Closure ...................................................................................... 57 
17.2.1. 
Temporary Halt ................................................................................................................ 57 
17.3. 
Confidentiality and Privacy ................................................................................................... 58 
17.4. 
Key Roles and Study Governance ....................................................................................... 58 
17.4.1. 
Sponsor ............................................................................................................................ 58 
17.4.2. 
Data Safety Monitoring Committee (DSMC) .................................................................... 58 
17.4.3. 
Quality Management ........................................................................................................ 59 
17.4.4. 
Clinical Monitoring............................................................................................................ 59 
17.4.5. 
Quality Assurance and Quality Control ............................................................................ 59 
17.5. 
Publication and Data Sharing Policy .................................................................................... 59 
I. 
APPENDIX 1 LANSKY AND ECOG SCALE ........................................................................................... 61 
II. 
APPENDIX 2 PROTOCOL CONTENT ACCORDING TO ANNEX 1 (EU) NO 536/2014 ................................. 62 
III. 
APPENDIX 3 - DESCRIPTION OF MEASURES IN CASE OF DATA SECURITY BREACH ............................. 67 
References ............................................................................................................................................ 69 
 

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Protocol information 
The trial is being conducted under the umbrella of the German Society of Pediatric Oncology and 
Hematology (GPOH gGmbH) acting as sponsor of the clinical trial according to the protocol, the local 
and European law (CTR 536/2014), and to the principles of good clinical practice.  
  
Protocol title  
International open-label phase I dose escalation study of 
dinutuximab beta in combination with 
vincristine/doxorubicin/cyclophosphamide and 
ifosfamide/etoposide in pediatric, adolescent, and adult 
patients with GD2-positive Ewing sarcoma  
Short title 
International Phase I Trial of dinutuximab beta with VDC/IE in 
GD2-Positive Ewing Sarcoma 
Protocol code 
CESS-GD2 
Protocol version and date  
1.2 dated by 07. FEB. 2025   
EUCT number: 
2024-515245-42-00 
Sponsor  
Gesellschaft für Pädiatrische Onkologie und Hämatologie / 
German Society of Pediatric Oncology and Hematology   
GPOH gGmbH  
  
 
Sponsor´s Office:  
Holsterhauser Platz 2  
GERMANY – 45147 Essen  
 
Managing Director  
  
Prof. Dr. Dirk Reinhardt, MD  
dirk.reinhardt@gpoh-trials.org  
  
By my signature, I indicate I have reviewed this protocol and find its content to be acceptable.  
  
 
 
Essen, 07.02.2025 
 
 
Place, Date 
 
 
Signature 
Prof. Dr. Dirk Reinhardt 
Sponsor Representative  
 

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Compliance Statement 
• 
I have read the current protocol version and agree to abide by all provisions set forth therein.  
• 
I agree to conduct and personally supervise the conduct of this study at my site in accordance 
with the design and specific provisions of this protocol and informed consent. I agree to ensure 
its conduct is in compliance with the Ethics Committee (EC) procedures, instructions from 
GPOHs representatives, the Declaration of Helsinki, ICH Good Clinical Practices Guidelines 
and national regulations governing the conduct of clinical studies.  
• 
I agree to maintain adequate and accurate records and to make those records available for 
audit and inspection in accordance with relevant regulatory requirements.  
  
Investigator´s Name:  
…………………………………………………………………………………  
  
Site:  
…………………………………………………………………………………  
  
Address:  
…………………………………………………………………………………  
  
…………………………………………………………………………………  
  
…………………………………………………………………………………  
  
  
  
 
Place, Date  
  
Signature  

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Abbrevations 
Ab 
Antibody 
ADCC 
Antibody dependent cell-mediated cytotoxicityl 
AE  
Adverse event 
ANC  
Absolute neutrophil count 
AR  
Adverse reaction 
ASR 
Annual safety report 
BSA  
Body surface area 
β-HCG 
Beta human chorionic gonadotropin 
Ccrea 
Creatinin clearance 
CDC 
Complement dependent cytoxicity 
CESS  
Cooperative Ewing Sarcoma study 
CHO 
Chinese hamster ovary 
CHMP 
Committee For Medicinal Products For Human use 
CNS 
Central nervous system 
COG  
Children`s Oncology group 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract Research organization 
CTR 
Clinical trials regulation 
CT  
Computed tomography 
CTIS 
Clinical trial information system 
CTCAE  
Common terminology criteria of adverse events 
CTV  
Clinical target volume 
D  
Doxorubicin 
DDS 
Dose determing analysis set 
DLT 
Dose limited toxicity 
DOC  
Death of complications 
DOR 
Duration of response 
DSMC  
Data and safety monitoring committee 
EC  
Ethics committee 
ECOG 
Eastern Cooperative Oncology group 
eCRF  
Electronic case report form 
EDC  
Electronic data capture system 
EFS  
Event-free survival 
EoT  
End of treatment 
EWS 
Early warning score 
FAS 
Full analysis set 
FCBP  
Females with childbearing potential 
FDA 
Food and Drug administration 
FDG-PET  
Fluorodeoxyglucose-positron emission tomography 
FPFV 
First patient first visit 
FISH  
Fluorescence in situ hybridisation 
GCP  
Good clinical practice 
G-CSF  
Granulocyte-colony stimulating factor  
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GD2 
Disialogangliosid 2 
GFR 
Glomerular filtration rate 
GLP 
Good laboratory practice 
GMP 
Good manufacturing practices 
GPOH  
German Paediatric Oncology group 
HCO3 
Bicarbonate 
HIV 
Human immunodeficiency virus 
HBV 
Hepatitis B virus 
HBC 
Hepatitits C virus 
HR  
Metastatic high-risk 

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I  
Ifosfamide 
ICH  
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
ICF 
Informed consent form 
ICMJE 
International Committee of Medical Journal Editors 
IE  
Ifosfamide, etoposide 
IMP  
Investigational medical product 
ISF 
Investigator site file 
ITT 
Intention to treat 
IV  
Intravenous 
LPFV 
Last patient first visit 
LPLV 
Last patient last visit 
LVEF  
Left ventricular ejection fraction 
MRI  
Magnetic resonance imaging 
MTD 
Maximun tolerated dose 
NCI 
National cancer institute 
NGS 
Next generation sequencing 
NCT 
Neutron capture therapy 
ORR  
Overall response rate 
OS  
Overall survival 
PAS  
Periodic-acid-schiff 
PD 
Progressive disease 
PDGFR  
Platelet-derived growth factor receptor 
PET-MRI  
Positron emission tomography–magnetic resonance imaging 
PIS 
Patient information sheet 
PK 
Pharmakokinetic 
PR 
Partial response 
QC 
Quality control 
QT 
Measurement shown on ECG 
RDE 
Recommended dose of expansion 
RECIST  
Response evaluation criteria in solid tumours 
RP2D 
Reccommended phase 2 dose 
RR 
Respiration rate 
RT-PCR  
Reverse transcriptase polymerase chain reaction 
SAE  
Serious adverse event 
SAP  
Statistical analysis plan 
SAR  
Serious adverse reaction 
SD 
Stable disease 
SF  
Shortening fraction 
SmPC  
Summary of product characteristics 
SoA 
Schedule of activities 
SOP 
Standard operationg procedures 
SR  
Localised standard-risk 
SUSAR  
Suspected unexpected serious adverse reaction 
TBD 
To be determined 
TP 
Total protein 
TmP 
Tubular maximum reabsorption of phosphate 
TV  
Tumour volume 
ULN  
Upper limit of normal  
V  
Vincristine 
VAI  
Vincristine, actinomycin D, ifosfamide 
VDC  
Vincristine, doxorubicin, cyclophosphamide 
WBC  
White blood cell 
WMA 
World medical association 
WOCBP 
Women of child bearing potential 
 

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1. Protocol Summary  
1.1. 
Synopsis 
Protocol title: 
International open-label phase I dose escalation study of 
dinutuximab beta in combination with 
vincristine/doxorubicin/cyclophosphamide and 
ifosfamide/etoposide in pediatric, adolescent, and adult patients 
with GD2-positive Ewing sarcoma  
 
Short title: 
International Phase I Trial of dinutuximab beta with VDC/IE in 
GD2-Positive Ewing Sarcoma 
 
Protocol Code: 
CESS-GD2 
 
EU-CT Number: 
2024-515245-42-00  
 
Clinical Phase: 
Phase I  
Study Type: 
Interventional 
Sponsor: 
GPOH gGmbH  
 
International Coordinating 
Investigator: 
Prof. Dr. med. Uta Dirksen, MD  
University Hospital Essen, Pediatrics III 
Cooperative Ewing Sarcoma Study (CESS) Group 
West German Cancer Centre 
German Cancer Consortium 
Hufelandstraße 55 
45147 Essen, Germany 
uta.dirksen@uk-essen.de 
 
Key words: 
Biomarker-driven trial, GD2 expression, targeted therapy, high-
risk Ewing Sarcoma trial 
 
Rationale: 
Immunotherapeutic approaches have emerged as an effective 
therapeutic approach in cancer. We will investigate the cell-
surface ganglioside GD2 as a target since it is expressed on the 
cell surface of Ewing Sarcoma cells and clinical trials support the 
safety and efficacy of anti-GD2 antibodies in pediatric solid 
cancers. 
Dinutuximab beta is a chimeric antibody that targets the 
disialoganglioside GD2. GD2 is expressed on a number of solid 
malignancies and was clinically investigated in pediatric patients 
with neuroblastoma. Expression in normal tissues is restricted to 
cerebellar neurons, skin melanocytes and peripheral pain fibers. 
Due to this expression pattern, anti-GD2 antibodies have been 
studied as targeted immunotherapy for neuroblastoma. With the 
results of these clinical trials, combination therapies with 
dinutuximab beta became a standard component of high-risk 
neuroblastoma therapy. GD2 expression is found in several EWS 
samples with variable expression-levels, and it is expected that 
anti-GD2 treatment is best suited as biomarker-driven approach.  
The administration of vincristine, doxorubicin, cyclophosphamide, 
ifosfamide and etoposide (VDC/IE) has been shown to be an 
effective systemic therapy and is therefore currently part of the 
standard treatment in Ewing Sarcoma. The international newest 
standard induction chemotherapy in the standard- and high-risk 
group consists of alternating VDC/IE. High-risk patients with a 

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GD2 positive tumor could benefit from an addition of dinutuximab 
beta to the standard chemotherapy with VDC/IE.  
The rationale for this trial is to investigate the feasibility, toxicity, 
and biological activity of dinutuximab beta in combination with 
standard chemotherapy in EWS. 
 
Objective(s): 
Primary objective  
 
Dose finding to determine the recommended phase II dose 
(RPD2) of dinutuximab beta in combination with vincristine, 
doxorubicin & cyclophosphamide and ifosfamide & etoposide. 
 
Secondary and exploratory objectives  
 
To assess safety, pharmacokinetic and antitumor activity of 
dinutuximab beta in combination with standard induction 
chemotherapy  
 
 
Endpoints: 
For details, please refer to 
Section 3 
Primary Endpoints 
 
Recommended dose of dinutuximab beta in combination with 
standard chemotherapy agents based on number of patients 
withs DLTs.  
 
Secondary Endpoints  
Progression Free Survival (PFS) 
Event Free survival (EFS) 
Duration of Response (DOR) 
 
Exploratory Endpoints  
• 
Biobanking of liquid biopsies, stool, and tumor material 
for ancillary studies 
Investigational medicinal products 
(IMP): 
 
For details,  
please refer to Section 0 
Dinutuximab beta, vincristine, cyclophosphamide, ifosfamide, 
etoposide, doxorubicin 
 
Dinutuximab beta dosing: 
 
For details, please refer to Section 
10.1.1 
Dose-Escalation  
 
Recommended dose:  
10mg/m2/d 10-day continuous infusion 
The starting dose  
Level 1: 50% of the recommended dose; 5mg/m2/d 10-day 
continuous infusion 
Level 2:  75% of the recommended dose; 7.5mg/m2/d 10-day 
continuous infusion 
Level 3:  100% of the recommended dose; 10mg/m2/d 10-day 
continuous infusion 
 
Inclusion-/Exclusion-Criteria 
Inclusion criteria: 
 
For details,  
please refer to Section 
5.1 
1. Histologically confirmed, newly diagnosed Ewing Sarcoma 
(m/f/d) or so-called Ewing-like sarcoma (i.e. translocation-
positive small blue round cell sarcoma other than 
Rhabdomyosarcoma) of bone and / or soft tissue with 
evidence of EWS translocation by fluorescence in situ 
hybridization (FISH), real-time polymerase chain reaction 
(RT-PCR), or next-generation sequencing (NGS) assay 
2. High risk stratification (metastatic disease) 

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3. Centrally confirmed GD2-positive tumor (biopsy of original 
and/or residual tumor or liquid biopsy in peripheral blood)  
4. Availability of fresh frozen tumor tissue for central GD2-
detection 
5. Age ≥12 months 
6. Start of first line treatment according to standard induction 
treatment (Cycle 1-4: VDC – IE – VDC – IE) 
7. Wash-out phase with a minimum of 14 days after the last the 
dose of the last chemotherapy 
8. Lansky (<16 years) Performance Score ≥70% or ECOG (≥16 
years) ≤ 2 
9. Adequate bone marrow function as evidenced by meeting all 
the following requirements: 
a. White blood cell count > 2000/µl 
b. ANC ≥1000 cells/μL (G-CSF allowed) 
c. Platelet count 75,000 cells/μL without the use of 
platelet transfusion within the last 2 days 
d. Hemoglobin ≥9 g/dL without the use of red 
blood cell transfusion within the last 2 days 
10. Adequate hepatic function as evidenced by meeting all the 
following requirements:  
a. Serum total bilirubin ≤1.5 x upper limit of normal 
(ULN)  
b. Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 5 x ULN 
11. Adequate cardiac function: confirmed by echocardiography 
with a left ventricular ejection fraction (LVEF) of ≥ 50% 
12. Adequate renal function: creatinine clearance or glomerular 
filtration rate (GFR) > 60 mL/min/1.73 m2 
13. No known active HIV, HBV, or HCV infection  
14. No severe neurological impairment, particularly no motor or 
sensory deficits, except for neurological deficits caused by 
Ewing sarcoma 
15. Female patients of childbearing potential must present with a 
negative serum pregnancy test and agree to employ 
adequate birth control measures for the duration of the study 
and until 3 months after the end of treatment. Female 
patients who are lactating must agree to stop breast-feeding 
from the start of study treatment until 1 month after the end 
of treatment. 
16. Patient or their legal representative is willing and able to 
comply with the requirements of the study protocol 
Exclusion criteria: 
 
For details,  
please refer to Section 5.2 
1. Relapsed or refractory Disease state 
2. Patients with hypersensitivity against at least 1 component of 
the investigational medicinal product  
3. Significant illnesses and/or any of the following:  
● 
significant psychiatric disabilities or uncontrolled seizure 
disorders  
● 
active uncontrolled peptic ulcer disease  
● 
clinically significant neurologic deficit or objective 
peripheral neuropathy  
● 
clinically significant, symptomatic fluid in a third space  
4. Active and uncontrolled CNS metastases (indicated by 
clinical symptoms, cerebral edema, corticosteroid and/or 
anticonvulsant requirement, or progressive disease); for 
controlled CNS metastases, patient should have been off 
corticosteroids for at least 28 days without overt evidence of 
significant neurological deficits prior to enrollment 

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5. Significant cardiac conduction abnormalities, including 
known familial prolonged QT syndrome, or screening QTc 
>480 msec 
6. Active, uncontrolled infection or an unexplained fever 
>38.5°C which in the Investigator’s opinion might 
compromise the patient’s participation in the study or affect 
the study outcome  
7. Chronic Grade ≥2 diarrhea 
8. Diagnosis of any malignancy other than the disease under 
study 
9. Any other medical or social condition deemed by the 
Investigator to be likely to interfere with a patient’s ability to 
cooperate and participate in the study or interfere with the 
interpretation of the results. 
 
Statistical analysis: 
 
For details,  
please refer to Section 15 
Design: 3+3 design with three pre-defined dose levels (Level 1: 
50%, Level 2: 75%, Level 3: 100%). 
 
At each level at least 3 at max. 6 patients will be included 
depending on the occurrence of DLTs. At Level 1 a toxicity-
adjusted dose escalation is implemented based on the observed 
Common Toxicity Criteria (CTCAE Version 5) grades: 
 
• 
CTC grade I=100% dose escalation (=Level 3) 
• 
CTC grade II= 50% dose escalation (=Level 2) 
 
Sample size: 
Total N= 3 (min) - 18 (max) 
Definitions: 
The evaluation of the tumor will be performed centrally 
according to the revised RECIST guideline (version 1.1). 
 
Complete response (CR): Disappearance of all target lesions. 
Any pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm 
 
Partial response (PR): At least a 30% decrease in the sum of 
diameters of target lesions, taking as reference the baseline sum 
diameters. 
 
Stable disease (SD): Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for PD, taking as reference 
the smallest sum diameters while on study. 
 
Progressive disease (PD): At least a 20% increase in the sum 
of diameters of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. 
(Note: the appearance of one or more new lesions is also 
considered progression). 
 
 
 
 

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1.2. 
Trial Scheme 
 
 
 

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1.3. 
Schedule of Activities 
 
 
Screening/ 
Pre-Phase  
1. Cycle 
VDC+ 
Dinu  
2. Cycle 
IE+Dinu 
3. Cycle 
VDC+Dinu 
4. Cycle 
IE+Dinu  
5. Cycle 
VDC+Dinu 
End of 
Treatment 
(day 15+-
7) 
Follow up 
(for 11 
months 
after EoT) 
End of trial 
visit (at 12 
months 
after EoT)  
 Timepoint 
Day -14 to 
0 
Day 1 to 
21±7  
Day 22 to 
42±7 
Day 43 to 
63±7 
Day 64 to 
85±7 
Day 86 to 
106±7 
Day 107±7 
every 4 
weeks  
 
ICF  
x 
 
 
 
 
 
 
 
 
Demographic and medical 
history   
x 
 
 
 
 
 
 
 
 
Medications and Procedures   x 
 
 
 
 
 
 
 
 
Evaluation of Inclusion/ 
Exclusion criteria  
x 
 
 
 
 
 
 
 
 
Disease state1 
 
 
 
 
 
 
 
x 
 
Vital signs, RR2  
x 
x 
x 
x 
x 
x 
x 
 
x 
Height, weight, BSA3  
x 
x 
x 
x 
x 
x 
x 
 
x 
Serum Pregnancy Test4  
x 
x 
x 
x 
x 
x 
 
 
 
CT/MRI5 
x 
 
 
 
 
 
x 
 
 
[18]FDG-PET-CT/MRI6 
x 
 
 
 
 
 
x 
 
 
Physical Examination 
x 
x 
x 
x 
x 
x 
x 
 
x 
Sexual development status7 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
 
 
 
Echocardiography 
x 
 
 
x 
 
x 
 
 
 
ECG8 
x 
x 
x 
x 
x 
x 
x 
 
 
Performance status9  
x 
x 
x 
x 
x 
x 
x 
 
 
Local laboratory 
assessment10 
x 
x 
x 
x 
x 
x 
x 
 
 
Shipment Fresh Frozen 
Tumor sample 
x 
 
 
 
 
 
 
 
 
Peripheral Blood samples for 
GD2 reference  
x 
x 
x 
x 
x 
x 
x 
 
x 
AE/SAE documentation 
After 
signing ICF 
x 
x 
x 
x 
x 
x 
 
x 
Concomitant Medication 
x 
x 
x 
x 
x 
x 
x 
 
x 

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1 Patient status: dead or alive, and recording of events (progression; relapse; secondary malignancy; death, independent cause), if any. 
2 Vital signs including sitting blood pressure, heart rate, respiration rate (RR), and temperature should be made after the subject has been sitting or lying, supine or semi 
recumbent, for at least 5 minutes. 
3 Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be measured. Height, weight and BSA may be 
performed within 5 days prior to the start of a cycle and ±1 day for other visits.  
4 A ß-HCG pregnancy test is required in females of childbearing potential regularly at screening until end of treatment. 
5 CT or MRI of tumor and metastases should be performed according to local practice during day -28 and start of treatment. Choice of imaging method should be same as at 
initial diagnosis. 
6 PET-CT/MRI of tumor and metastasis is highly recommended and may be performed according to local physicians’ decision during day -28 and start of treatment. In case at 
initial diagnosis PET imaging was required, restaging is highly recommended. 
7 Applies to children and adolescent subjects. Patients who are staged during screening who may achieve menarche during participation of the trial, need to be evaluated 
regularly. 
8 ECG should be performed before each cycle and whenever clinically indicated.  
9 Lansky (<16 years) Performance Score or ECOG (≥16 years). 
10  Includes initial testing of viral serology and regular serum chemistry, hematology. 
 

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2. Introduction 
2.1. 
Study Rationale  
This study aims to investigate the cell-surface ganglioside GD2 as a target since it is expressed on the 
cell surface of Ewing Sarcoma cells and clinical trials support the safety and efficacy of anti-GD2 
antibodies in pediatric solid cancers. Furthermore, this phase I study aims to assess the recommended 
phase 2 dose of dinutuximab beta.  
Spasov et al. showed results, that GD2 as well-characterized tumor-associated antigen is expressed in 
40% to 90% of Ewing sarcoma cells, making it a suitable target for therapeutic intervention. The group 
presents three cases of newly diagnosed, metastatic, GD2-positive Ewing sarcoma or Ewing-like 
sarcoma that were treated with the anti-GD2 antibody dinutuximab beta alongside standard 
chemotherapy. The treatment was well-tolerated, and all patients achieved complete remission without 
signs of relapse. These findings suggest that first-line anti-GD2 immunotherapy in patients with 
metastatic, GD2-positive Ewing sarcoma or Ewing-like sarcoma could be a promising treatment option 
that merits further clinical investigation. These findings form the basis to run this clinical trial. 
2.1.1. 
Rationale for the Inclusion of Minors 
Ewing Sarcoma is the second most common malignant bone tumor in children, adolescents and young 
adults with an age peak between 10-20 years of age.  
Dinutuximab beta has been a part of treatment in childhood cancer for many years, especially in the 
treatment of neuroblastoma (literature). It has been shown to cause few side effects in children and 
young adults (Literature). Side effects include neuropathic pain, peripheral neuropathy, hypersensitivity 
reactions, capillary leak syndrome, photophobia, and hypotension and have demonstrated reversibility 
with continuous use of the antibody (Barone et al., 2021). 
2.2. 
Background 
 
Ewing sarcoma (ICD-10 C40-C41) is a highly malignant tumor of bone or soft tissues that occurs in 
children, adolescents and young adults. Current international therapeutic approaches consist of 
multiagent chemotherapy with anthracyclines, alkylating agents and topoisomerase inhibitors, major 
surgery, and radiotherapy (Grünewald et al., 2018). These therapies cure only a proportion of Ewing 
sarcoma patients and are associated with high acute and late toxicities (Grünewald et al., 2018; Ranft 
et al., 2017). 
Approximately 40% of all patients suffer from recurrent disease and relapsed or refractory disease is 
literally incurable. Survival rates of less than 13% in this cohort imply an urgent need for innovative 
treatment strategies. The survival rate of primary disseminated Ewing sarcoma is less than 30% and did 
not improve in the past decades even with implementation of high dose chemotherapy (Rasper et al., 
2014; Stahl et al., 2011). 
Consequently, new treatments are required for this population of young cancer patients.  
Immunotherapeutic approaches have emerged as an effective therapeutic approach in cancer and also 
in the treatment of sarcoma. This trial will investigate the cell-surface ganglioside GD2 as a target since 
it is expressed on the cell surface of Ewing sarcoma cells and clinical trials support the safety and 
efficacy of anti-GD2 antibodies in pediatric solid cancers. 
Dinutuximab beta is a chimeric antibody that targets the disialoganglioside GD. GD2 is expressed on 
several solid malignancies and was clinically investigated in pediatric patients with neuroblastoma. 
Expression in normal tissues is restricted to cerebellar neurons, skin melanocytes and peripheral pain 
fibers (Hung & Yu; Marx et al., 2020). Due to this expression pattern, anti-GD2 antibodies have been 

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studied as targeted immunotherapy for neuroblastoma (Ladenstein et al., 2018). With the results of 
these clinical trials, combination therapies with dinutuximab beta became a standard component of high-
risk neuroblastoma therapy. A trial conducted by the Children's Oncology Group (COG) investigated 
dinutuximab beta in combination with granulocyte macrophage stimulating factor in osteosarcoma 
patients, the trial was negative as less patients (11/39) than expected (>16/39) remained disease free. 
The efficacy in combination with chemotherapy was not assessed in this group of patients (Hingorani et 
al., 2022). In contrast to Osteosarcoma, Ewing sarcoma cells express neuronal features similar to 
neuroblastoma and for some soft tissue Ewing sarcomas the term peripheral neuroectodermal tumor 
had been used for years (Grünewald et al., 2018). 
GD2 expression is found in several Ewing sarcoma samples with variable expression-levels, and it is 
expected that anti-GD2 treatment is suited as a biomarker-driven approach. In the literature, case 
reports of patients with primary disseminated or relapsed GD2-expressing Ewing sarcomas indicate 
effectiveness of a treatment with dinutuximab beta. One paper describes three patients with primary 
high risk metastatic Ewing sarcoma with a high expression of GD2. Dinutuximab beta was given in all 
three patients together with VAI as a consolidation chemotherapy. Results show a positive effect, where 
complete response was achieved within 5-10 months and the response is ongoing over the course of at 
least 20 months (Spasov et al., 2022). Another manuscript showed a long-lasting response in highly 
pre-treated patients with relapsed Ewing sarcoma (Wingerter et al., 2021). 
The administration of vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) 
has been shown to be an effective systemic therapy and is therefore currently part of the standard 
treatment in Ewing Sarcoma (Brennan et al., 2022; Reed et al., 2023; Womer et al., 2012). Alternating 
VDC/IE is the new standard induction therapy in the standard- and high-risk group (Brennan et al., 
2022). However, in metastatic patients the outcome remains poor (DuBois et al., 2023) and the addition 
of ifosfamide and etoposide to a standard regimen does not affect their outcome (Grier et al., 2003). 
Patients with early relapse or progressive disease and a GD2 positive tumor could benefit from an 
addition of dinutuximab beta to the standard induction chemotherapy.  
The rationale for this trial is to investigate the feasibility, toxicity, and biological activity of dinutuximab 
beta in combination with standard chemotherapy in EWS.  
2.3. 
Risk/Benefit Assessment  
2.3.1. 
Known Potential Risks  
Extrapolation from pediatric clinical safety data with dinutuximab beta reversible side effects, such as 
neuropathic pain, peripheral neuropathy, hypersensitivity reactions, capillary leak syndrome, 
photophobia, and hypotension. All of them have demonstrated reversibility with continuous use of the 
antibody (Mastrangelo et al., 2021). These events are readily monitored and manageable.  
More information about the known and expected benefits, risks, serious adverse events (SAE) and 
reasonably anticipated AE of dinutuximab beta are outlined in detail in the SmPC. 
Common risks of the standard induction chemotherapy are well known and to be expected.   
2.3.2. 
Potential Benefits 
 
The outcome in primary metastasis remains poor without any improvement for decades. Clinical trials 
that tested new agents in unselected groups of patients did not improve outcome (DuBois et al., 2023). 
In the past decades biomarker-driven therapies proved to be game changers in many cancers.  
There is an urgent need for effective combinations in primary metastatic Ewing sarcoma, as the outcome 
has not improved since decades. The addition of dinutuximab beta will build on a standard induction 
chemotherapy that has been used in several clinical trials on both sites of the Atlantic using a drug 
combination that is used since 1995 (Granowetter et al., 2009) and has been used in all US American 

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Ewing Sarcoma trials since and also on the European Continent and is the international standard for the 
treatment of Ewing Sarcoma (Grünewald et al., 2018). 
The drug dinutuximab beta is an anti-GD2 monoclonal antibody, produced in Chinese hamster ovary 
(CHO) cells (ch14.18/CHO). This antibody has a better glycosylation-pattern to avoid the clearance by 
xeno antibodies and is more tolerated than the murine anti-GD2 antibody (Ladenstein et al., 2013). The 
effect relies on immune effector functions like complement-dependent cytotoxicity and antibody 
dependent cell-mediated cytotoxicity (ADCC). Furthermore, binding of dinutuximab beta GD2 
expressing to tumor cells interferes with proliferation and invasiveness of the tumor, and induces 
apoptosis, which was shown also in adult type GD2-expressing malignoma (Aixinjueluo et al., 2005). 
The anti-GD2 therapy improved neuroblastoma treatment outcomes. Consequently, the drug 
development included small children below the age of six with the youngest child included at age 1.5      
years (Cheung et al., 1987). Since 2015, GD2-antibody therapy (dinutuximab) has had an FDA-approval 
for the initial treatment of neuroblastoma, following intensive multimodal therapy. Approval was granted 
based on the results from the prospective, randomized NCT00026312 trial that randomized isoretinoic 
acid versus dinutuximab beta and GM-CSF, interleukin-2 (IL-2), and cis-retinoic acid (isotretinoin) in 
pediatric children with high-risk neuroblastoma with at least a partial response to initial multimodality 
therapy (Yu et al., 2010). 
In Europe, dinutuximab beta is approved for children aged > 12 months and in this age group for first-
line treatment and at relapse. The randomized clinical trials that led to the approval showed no difference 
in outcome after randomization for dinutuximab beta plus subcutaneous IL2 and dinutuximab beta alone 
but more toxicity in the group who received IL2. The trial included patients, aged 1-20 years (Ladenstein 
et al., 2018). A study in patients with relapsed or refractory disease combined dinutuximab with GM-
CSF, and irinotecan, and temozolomide which was effective also in patients who had received 
dinutuximab beta mono before with an acceptable toxicity and an overall response rate of 41.5% (Mody 
et al., 2017).  
As described in Section 2.2 case reports of combination of dinutuximab beta and classical Ewing 
sarcoma chemotherapy have shown a very promising response in primary metastatic very high-risk 
Ewing sarcoma patients and at relapse. The immunochemotherapy approach was well tolerated in all 
patients (Spasov et al., 2022; Wingerter et al., 2021). 
The history of dinutuximab beta shows that it is safe, with manageable side effects in very young 
children, adolescents and young adults with GD2 positive tumors. 
2.3.3. 
Assessment of Potential Risks and Benefits 
Given the observed safety profile of dinutuximab beta in children and young adults and the known risk 
profiles of the induction chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide and 
etoposide, the risk for combination in the proposed study is expected to be manageable. Careful 
measures are taken to ensure participant safety; the potential risks are justified by the potential benefits 
for individuals with very high-risk metastatic Ewing sarcoma. The first 5-10 days of the first two cycles 
of dinutuximab beta following the standard chemotherapy should be applied in an inpatient setting. 
Special caution concerning neurotoxicity should be paid to the first cycle of dinutuximab beta following 
etoposide and ifosfamide, as both ifosfamide and dinutuximab beta can lead to neurotoxicity (see 
SmPC). In case of good tolerability of the first two cycles of dinutuximab beta treatment, an outpatient 
administration may be taken into consideration. Regular appointments for check-up during the cycles of 
dinutuximab beta administration should be made to detect any side effects at an early stage.  

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Based on the known toxicities of the standard chemotherapy and dinutuximab beta, the following are 
considered the most common and significant risks (Barone et al., 2021): 
• 
pain 
• 
fever 
• 
hypersensitivity reactions/allergy 
• 
capillary leak syndrome 
• 
diarrhea  
• 
elevated liver enzymes 
• 
neurotoxicity 
2.3.4. 
Description and Threshold of Burden 
 
Patients treated with dinutuximab beta will, besides the known risk for side effects due to the standard 
chemotherapy, experience an increased risk of toxicity due to the addition of dinutuximab beta. Known 
toxicities are described in section 2.3.3. Special attention should be paid to the first dinutuximab beta 
cycle following chemotherapy with ifosfamide as both, ifosfamide and dinutuximab beta, increase the 
risk for neurotoxicity.  
The first two cycles of dinutuximab beta following standard induction chemotherapy will be administered 
in an inpatient setting for at least the first 5 days of each cycle to monitor patients closely. Monitoring 
during the inpatient treatment should include regular assessment of vital parameters and neurological 
status. The administration of gabapentin and morphine during the dinutuximab beta treatment decrease 
the risk of side effects. However, administration of these medications also requires monitoring provided 
by an inpatient stay.  
Patients will stay in the hospital for at least 5 days for the first two cycles of dinutuximab beta treatment, 
depending on the tolerability and toxicity. The following cycles can be administered in an outpatient 
setting depending on the side effects experienced during the first two cycles of dinutuximab beta 
treatment in combination with standard induction chemotherapy.  
3. OBJECTIVES AND ENDPOINTS 
3.1. 
Primary Objective 
Dose finding to determine the recommended phase II dose (RPD2) of dinutuximab beta in combination 
with vincristine, doxorubicin & cyclophosphamide and ifosfamide & etoposide. 
3.2. 
Secondary Objectives 
The secondary objectives are to assess the safety, pharmacokinetics, and antitumor activity of 
dinutuximab beta when administered in combination with standard induction chemotherapy. 
3.3. 
Exploratory Objectives 
To collect and biobank liquid biopsies, stool samples, and tumor material for future ancillary studies 
aimed at exploring potential biomarkers and understanding the biological mechanisms associated with 
treatment response and resistance. 

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3.4. 
Primary Endpoint 
Recommended dose of dinutuximab beta in combination with standard chemotherapy agents based 
on number of patients with dose limiting toxicities (DLTs).  
3.5. 
Secondary Endpoints 
The secondary endpoints of this study are designed to evaluate the clinical efficacy of the treatment 
regimen. These include: 
1. Progression-Free Survival (PFS): The time from the start of treatment until the first 
documented evidence of disease progression or death from any cause, whichever occurs first. 
2. Event-Free Survival (EFS): The time from the initiation of treatment to the occurrence of any 
treatment-related event, including disease progression, relapse, occurrence of a second 
malignancy, or death from any cause. 
3. Duration of Response (DOR): The time from the first documentation of a complete or partial 
response to the treatment until the first occurrence of disease progression or relapse. 
Progression of disease is defined as recurrent or progressive disease under active oncological therapy 
or at the end of treatment assessment. 
Relapse of disease is defined as recurrent disease at any site in patients with complete clinical remission 
after completion of active oncological therapy and after the end of treatment assessments. 
3.6. 
Exploratory Endpoints 
To support the exploration of biological mechanisms and potential biomarkers, the following exploratory 
endpoints will be assessed: 
1. Biobanking of Liquid Biopsies and Tumor Material: Collection and storage of liquid biopsies 
(e.g., blood samples), stool samples, and tumor tissue for ancillary studies. These samples will 
be used for future research to investigate biomarkers, treatment response, and resistance 
mechanisms, as well as other molecular and immunological correlates. 
4. STUDY DESIGN 
 
4.1. 
Overall Design  
This is a multi-center, phase 1, open-label, dose escalation study enrolling high-risk Ewing sarcoma 
patients that have been tested with GD2-positivity in a classical 3+3 design. 
4.2. 
Scientific Rationale for Study Design  
The classical 3+3 study design, commonly utilized in phase I clinical trials, offers a structured and ethical 
approach to determining the safety, tolerability, and appropriate dosage levels of new treatments such 
as the introduction of dinutuximab beta as additional to standard chemotherapy in high-risk Ewing 
sarcoma patients. This design is particularly valuable in pediatric clinical trials due to the unique 
physiological and developmental considerations in this population. This needs to be considered even if 
the trial also allows the enrolment of adolescents and (young) adults.  
The 3+3 design helps minimize the exposure of the targeted population to potentially harmful doses. 
Starting at a low dose and only escalating after safety confirmation ensures a cautious and ethical 
approach. It allows for careful monitoring of adverse events and side effects, ensuring that any potential 
harm is detected early before escalating to higher doses. 
The structured escalation process (3 patients per dose level, with additional cohorts if dose-limiting 
toxicities occur) allows for a stepwise increase in dose, providing clear data on the maximum tolerated 

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dose (MTD) and the recommended dose for subsequent studies. Continuous assessment of safety at 
each dose level ensures that CESS-GD2 can be halted or adjusted if severe adverse reactions are 
observed, protecting the enrolled patients from undue harm. 
Additionally, the 3+3 design is straightforward, making it easier to implement and understand for clinical 
teams. This simplicity enhances compliance and accurate data collection. Given the limited number of 
newly diagnosed high-risk Ewing sarcoma patients (~40 patients/year) generally eligible, the 3+3 design 
optimizes the use of available participants by requiring fewer patients compared to other dose-escalation 
designs, especially since the frequency of GD2 positivity in high-risk Ewing's sarcoma patients is not yet 
well researched and therefore a more complex sample size calculation would probably jeopardize the 
feasibility of the clinical trial in general.  
The classical 3+3 study design is well-suited for the purpose of this clinical trials due to its focus on 
safety, ethical considerations, feasibility, and regulatory acceptance. Its structured and cautious 
approach ensures that the unique needs and vulnerabilities of pediatric patients are adequately 
addressed, thereby fostering the safe and effective development of new pediatric treatment options. 
 
 
4.3. 
Justification for Dosing 
The decision to initiate treatment with 50% of the approved dosage for neuroblastoma in this dose-
escalation study is grounded in both scientific literature and safety considerations. Starting at a lower 
dosage allows for the careful monitoring of patient response and minimizes the risk of adverse effects, 
particularly in a dose-sensitive adult population. 
A risk assessment further supports this approach, indicating that starting at 50% of the approved 
neuroblastoma dose provides a safe baseline from which to escalate. The assessment outlines that a 
stepwise increase to 75% and subsequently to 100% of the approved dose allows for the identification 
of any dose-limiting toxicities (DLTs) in a controlled manner, thus optimizing patient safety. 

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The choice of 100 mg/m2 as the maximum dosage per cycle, equivalent to the dosage used in standard 
neuroblastoma treatment, is justified by its established efficacy and safety profile in this specific 
indication. The literature supports that doses up to 100 mg/m2  per cycle are well-tolerated in the majority 
of patients, with the therapeutic benefits outweighing the risks when administered within a carefully 
monitored clinical framework. 
In conclusion, the dose-escalation schema starting at 50% of the neuroblastoma-approved dosage, 
followed by intermediate escalation steps to 75% and 100%, is a scientifically sound and ethically 
responsible approach. It balances the need for efficacy with the imperative of patient safety, as 
supported by both published research and thorough risk assessments. 
4.4. 
Start and End of Trial Definition  
The start of the trial is designated as the date the first investigational site is open for recruitment, that is, 
the date the first site received the site activation letter. 
End of trial is defined as the time when the last patient completes the last follow-up visit. An interim 
clinical trial report will be written after all patients have completed the trial treatment or discontinued the 
study (independently from follow up). The final clinical trial report will be written at the end of the study 
(latest 6 months after database lock). 
A patient is considered to have completed the trial if he or she has completed all phases of the trial 
including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), Section 
1.3. 
The sponsor confirms that for this trial which includes minors, Regulation (EC) No 1901/2006 Article 41, 
Para. 2; Guideline 2009/C 28/01 EC 4.2 as well as Ethical Considerations for Clinical Trials on Medicinal 
Products Conducted with the Pediatric Population, Final 2008, 19.1, apply, with possibly shorter 
timelines to submit the clinical study report, in case that is necessary by this legal background. 
5. STUDY POPULATION 
 
CESS-GD2 will be conducted in patients, aged at least 12 months with GD2-positive high-risk Ewing 
sarcoma. The investigator or a delegated designee must ensure that only patients who meet all the 
following inclusion and none of the exclusion criteria are offered treatment in the study. 

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5.1. 
Inclusion Criteria 
 
1. Histologically confirmed, newly diagnosed Ewing Sarcoma (m/f/d) or so-called Ewing-like 
sarcoma (i.e. translocation-positive small blue round cell sarcoma other than 
Rhabdomyosarcoma) of bone and / or soft tissue with evidence of EWS translocation by 
fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (RT-PCR), or 
next-generation sequencing (NGS) assay 
2. High risk stratification (metastatic disease) 
3. Centrally confirmed GD2-positive tumor (biopsy of original and/or residual tumor or liquid 
biopsy in peripheral blood)  
4. Availability of fresh frozen tumor tissue for central GD2-detection 
5. Age ≥12 months 
6. Start of first line treatment according to standard induction treatment (Cycle 1-4: VDC – IE – 
VDC – IE) 
7. Wash-out phase with a minimum of 14 days after the last the dose of the last chemotherapy 
8. Lansky (<16 years) Performance Score ≥70% or ECOG (≥16 years) ≤ 2 
9. Adequate bone marrow function as evidenced by meeting all the following requirements: 
a. White blood cell count > 2000/µl 
b. ANC ≥1000 cells/μL (G-CSF allowed) 
c. Platelet count 75,000 cells/μL without the use of platelet transfusion within the last 2 
days 
d. Hemoglobin ≥9 g/dL without the use of red blood cell transfusion within the last 2 days 
10. Adequate hepatic function as evidenced by meeting all the following requirements:  
a. Serum total bilirubin ≤1.5 x upper limit of normal (ULN)  
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x ULN 
11. Adequate cardiac function: confirmed by echocardiography with a left ventricular ejection 
fraction (LVEF) of ≥ 50%  
12. Adequate renal function: creatinine clearance or glomerular filtration rate (GFR) > 60 
mL/min/1.73 m2 
13. No known active HIV, HBV, or HCV infection  
14. No severe neurological impairment, particularly no motor or sensory deficits, except for 
neurological deficits caused by Ewing sarcoma 
15. Female patients of childbearing potential must present with a negative serum pregnancy test 
and agree to employ adequate birth control measures for the duration of the study and until 3 
months after the end of treatment. Female patients who are lactating must agree to stop 
breast-feeding from the start of study treatment until 1 month after the end of treatment. 
16. Patient or their legal representative is willing and able to comply with the requirements of the 
study protocol. 
 

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5.2. 
Exclusion Criteria 
1. Relapsed or refractory Disease state 
2. Patients with hypersensitivity against at least 1 component of the investigational medicinal 
product  
3. Significant illnesses and/or any of the following:  
a. significant psychiatric disabilities or uncontrolled seizure disorders  
b. active uncontrolled peptic ulcer disease  
c. clinically significant neurologic deficit or objective peripheral neuropathy  
d. clinically significant, symptomatic fluid in a third space  
4. Active and uncontrolled CNS metastases (indicated by clinical symptoms, cerebral edema, 
corticosteroid and/or anticonvulsant requirement, or progressive disease); for controlled CNS 
metastases, patient should have been off corticosteroids for at least 28 days without overt 
evidence of significant neurological deficits prior to enrollment 
5. Significant cardiac conduction abnormalities, including known familial prolonged QT 
syndrome, or screening QTc >480 msec 
6. Active, uncontrolled infection or an unexplained fever >38.5°C which in the Investigator’s 
opinion might compromise the patient’s participation in the study or affect the study outcome  
7. Chronic Grade ≥2 diarrhea 
8. Diagnosis of any malignancy other than the disease under study 
9. Any other medical or social condition deemed by the Investigator to be likely to interfere with a 
patient’s ability to cooperate and participate in the study or interfere with the interpretation of 
the results. 
5.3. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical trial but are not 
subsequently assigned to the trial intervention or entered in the trial. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details and 
eligibility criteria. 
Subjects who do not meet the criteria for participation in this trial (screen failure) may be rescreened 
within 14 business days. Rescreened participants should be assigned the same participant number as 
for the initial screening. See also Section 8 for details. 
5.4. 
Definition of women of childbearing potential and of fertile 
men 
For this protocol, a woman is considered of childbearing potential (WOCBP), i.e. fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.  
To this protocol, a man is considered fertile after puberty unless permanently and documented sterile 
by bilateral orchidectomy. 
All descripted requirements in this and other related sections based on the MA/CTFG 
"Recommendations related to contraception and pregnancy testing in clinical trials", current version, and 
with CPMP/ICH/286/95 ICH M3(R2). 

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6. INVESTIGATIONAL MEDICINAL PRODUCTS 
6.1. 
Declaration of Investigational Medical Products and 
Auxiliary Medicinal Product 
 
The following drugs are regarded as Investigational Medicinal Products (IMPs) for the purposes of this 
trial:  
• 
dinutuximab beta, 
• 
vincristine, 
• 
cyclophosphamide, 
• 
ifosfamide, 
• 
etoposide, 
• 
doxorubicin. 
Regulation (EU) No 536/2014 Article 2 (5) defines an IMP as “a medicinal product which is being 
tested or used as a reference, including as a placebo, in a clinical trial”. Further information on IMPs 
can be found in “The rules governing medicinal products in the European Union” Volume 10 – 
Guidance documents applying to clinical trials, Clinical Trials Regulation (EU) No 536/2014 
Questions and Answers (currently being updated).  
The following drugs are regarded as Auxiliary Medicinal Product (AxMPs) for the purposes of this trial:  
• 
mesna, 
• 
G-CSF/filgrastim. 
Regulation (EU) No 536/2014 Article 2 (8) defines an AxMP as “a medicinal product used for the 
needs of a clinical trial as described in the protocol, but not as an investigational medicinal product”.  
6.2. 
Study Intervention Description 
 
This phase I study is an open-label non-randomized study. Patients are enrolled into dose levels in 
accordance with the planned dose escalation schedule. Aim of the study is to assess safety and 
antitumor activity of dinutuximab beta in combination with standard induction chemotherapy. Aim of the 
trial is to assess the recommended phase 2 dose. The sponsor performs the dose-level allocation after 
the patient and/or the patient's legal representative has given their written informed consent and the 
pediatric patient, if appropriate, has given assent.   
Furthermore, the patient must have completed the necessary screening assessments. The site staff will 
register the patient to the database by submission of the registration form. The sponsor will assign the 
patient to the trial, thereby the subject receives a patient identification number that will be used on all 
study-related documentation or correspondence (including fax and/or email) referencing that patient to 
the site. No patient will receive investigational product until the investigator or designee has received 
the following information in writing from the sponsor:  
• 
Confirmation of the patient’s enrollment and; 
• 
Specification of the dose level for that patient.  
6.2.1. 
Dosing and Administration 
Doses will be escalated in a 3+3 design with three pre-defined dose levels, namely Level 1: 50%, Level 
2: 75%, Level 3: 100%. At each level at least 3 at max. 6 patients will be included depending on the 
occurrence of DLT. Starting dose will be 5 mg/m²/d, which equals 50% of the final dose. Dinutuximab 
beta will be administered as an intravenous infusion once a day over a time of 24 hours, for 10 days. At 

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Level 1 a toxicity-adjusted dose escalation is implemented based on the observed Common Toxicity 
Criteria (CTCAE Version 5) grades. Specifically, if no DLTs were observed in the initial 3 patients, CTC 
grades of ≤ 1 will result in a 100% dose escalation (=Level 3), equaling 10 mg/m²/d. At least CTC grade 
=2 will result in a 50% dose escalation (=Level 2), which equals 7.5 mg/m²/d. The dinutuximab beta 
infusion starts at the end of the standard chemotherapy treatment cycle, administered sequentially after 
the completion of chemotherapy.  
6.3. 
Preparation/Handling/Storage/Accountability 
 
6.3.1. 
Acquisition and Accountability 
 
 
Dinutuximab beta 
Dinutuximab beta will be provided by the sponsor. For order and shipment details please refer to the 
investigator site file and/or Pharmacy File.  
IMP must be received by a designated person at the study site and kept in temperature-controlled 
location. The IMP must be stored according to the storage conditions described on the IMP packaging 
label and stored in a locked, safe area to prevent unauthorized access.  
The investigator or designee is responsible for taking an inventory of each shipment of IMP received 
and comparing it with the accompanying IMP accountability form. The investigator or designee will verify 
the accuracy of the information on the form, sign and date it, retain a copy in the study file, and return a 
copy to the sponsor.  
The investigational site must maintain accurate records demonstrating dates and amounts of IMP 
received, to whom it was administered (subject-by-subject accounting), and accounts of any IMP 
accidentally or deliberately destroyed or returned. Accurate recording of all IMP administration will be 
made in the appropriate Section of the subject’s CRF and source documents.  
GPOH (or designee) will review with the investigator and relevant site personnel the process for IMP 
return, disposal, and/or destruction including responsibilities for the site versus GPOH (or designee). 
Other IMPs 
All IMPs (except dinutuximab beta) are expected to be held as routine hospital stock and should 
therefore be stored and handled according to local institutional policy. Treatment should be prepared 
and administered according to the relevant Summary of Product Characteristics (SmPC) and local 
practice unless the trial protocol requires otherwise. See section 6.3.4 for more information. 
All IMPs shall be traceable. They shall be stored and destroyed as appropriate and proportionate to 
ensure the safety of the subject and the reliability and robustness of the data generated in the clinical 
trial. Compliance and drug accountability will be assessed by the investigator and/or study personnel at 
each patient visit. The information will be captured in the Drug Accountability Form. 
This shall also apply to auxiliary medicinal products. Please also see the Pharmacy File for further 
details. 
6.3.2. 
Formulation, Appearance, Packaging, and Labelling 
Dinutuximab beta is a mouse-human chimeric monoclonal IgG1 antibody produced in a mammalian cell 
line (CHO) by recombinant DNA technology. 
Dinutuximab beta will be supplied in vials, each contains 20 mg dinutuximab beta in 4.5 mL. 1 mL of 
concentrate contains 4.5 mg dinutuximab beta. Medication will be provided as multi-market pack  within 
commercial packing (with Greek, Polish, Portuguese and English as languages available on the 
packaging). They will include storage conditions for the drug but no information about the patient. 
Supportive drug information in local languages will be provided via the trial electronic system. 
The container is a clear Type I glass vial (6 mL) with a halobutyl rubber stopper and an aluminum flip-
off cap, holding a minimum extractable volume of 4.5 mL of concentrate for infusion solution. Each 
carton contains 1 vial.  

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Dinutuximab beta will be provided as concentrate for infusion solution (pharmaceutical form). It appears 
as colourless to slightly yellow liquid. 
Justification for Labelling Exemptions Based on CTR 536/2014 Annex 6, Section 8 
In accordance with the provisions of CTR 536/2014, Annex 6, Section 8, the information listed in 
Sections A, B, and C on the label of an investigational product may be omitted if alternative mechanisms 
for providing this information are in place, such as the use of a centralized electronic randomization 
system or a central information system, provided that the safety of the trial participants and the reliability 
and robustness of the data are not compromised. 
For this study, a centralized electronic system will be used for both the provision of dose per patient and 
the management of essential product information. This system ensures that all necessary data, including 
dosing and product identification, are securely tracked and available to the study team in real-time, thus 
maintaining full transparency and traceability of the investigational product. 
Furthermore, the investigational product, dinutuximab beta, will not be dispensed directly to the patient. 
Instead, it will be handled exclusively by the study team, ensuring that administration is controlled and 
monitored within the clinical site. This reduces the risk of mislabelling or mishandling and ensures that 
all product-related information is properly recorded and accessible through the central system. 
This approach ensures compliance with the regulatory requirements while safeguarding both the safety 
of the participants and the integrity of the clinical trial data. 
All other investigational medicinal products (IMPs) should be used in their authorized formulations, with 
appropriate appearance, packaging, and labelling according to the legal and regulatory standards of the 
participating countries. 
6.3.3. 
Product Storage and Stability 
 
Dinutuximab beta has a shelf life of 4 years. Please check the expiry date before use. 
The chemical and physical in-use stability for the diluted solution (solution for infusion) has been 
demonstrated for up to 48 hours at 25 °C (50 mL syringe) and for up to 7 days at 37 ºC (250 mL infusion 
bag), after cumulative storage in a refrigerator (2 °C – 8 °C) for 72 hours.  
From a microbiological point of view, the diluted solution should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and would 
not normally be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and 
validated aseptic conditions.  
Dinutuximab beta must be stored in a refrigerator (2 °C – 8 °C). The vial must be stored in its original 
outer carton to protect it from light.  
For storage conditions after dilution of the medicinal product, see instructions above. 
Dinutuximab beta must be received by designated personnel at the trial site, handled and stored safely 
and properly, and kept in a secured location to which only the investigator and designated site personnel 
have access. Upon receipt, Dinutuximab beta should be stored according to the instructions specified 
in this protocol, the pharmacy file or the shipment documentation/label.  
 
6.3.4. 
Preparation and precautions for disposal and other 
handling instructions 
 
The solution for infusion must be prepared under aseptic conditions. The solution must not be exposed 
to direct sunlight or heat.  
The patient specific daily dose of dinutuximab beta is calculated based on body surface area. 
Dinutuximab beta should be diluted aseptically to the patient specific concentration/dose with sodium 
chloride 9 mg/mL (0.9%) solution for infusion containing 1% human albumin (e.g. 5 mL of human albumin 
20% per 100 mL sodium chloride solution).  
For continuous infusions, the solution for infusion can be prepared freshly daily.  

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The daily dose depending on the respective dose level and ranges from dose level 1 to dose level 3. 
Dose level 1   
5 mg/m²/d 10-day continuous infusion once daily as an IV infusion over 24 hours. 
Infusions starts at the end of the respective standard chemotherapy i.e. VDC day 3 and IE day 5.  
Dose level 2  
7.5 mg/m²/d 10-day continuous infusion once daily as an IV infusion over 24 hours.  
Infusions starts at the end of the respective standard chemotherapy i.e. VDC day 3 and IE day 6. 
Dose level 3 
10 mg/m²/d 10-day continuous infusion once daily as an IV infusion over 24 hours.  
For continuous 24-hour infusions, the daily dose is 5-10 mg/m2 and the calculated dose should be diluted 
in 100 mL sodium chloride 9 mg/mL (0.9%) containing 1% human albumin.  
The solution for infusion should be administered via a peripheral or central intravenous line. Other 
intravenously co-administered agents should be delivered via a separate infusion line. The container 
should be inspected visually for particulates prior to administration. It is recommended that a 0.22 
micrometre in-line filter is used during infusion.  
For continuous infusions, any medical device suitable for infusion at a rate of 2 mL per hour can be 
used, e.g. syringe infusion pumps/infusers, electronic ambulatory infusion pumps. Note that elastomeric 
pumps are not considered suitable in combination with in-line filters.  
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
7. PRE-SCREENING FOR GD2  
GD2 is a disialoganglioside, a type of glycolipid, prominently expressed on the surface of 
neuroectodermal tumors, such as neuroblastoma and melanoma, as well as in certain types of 
sarcomas. Its high expression in these cancers makes it a valuable biological marker for diagnosis and 
targeted therapy (Nazha et al., 2020). 
GD2's limited expression in normal tissues, primarily restricted to peripheral nerves, minimizes the risk 
of adverse effects when targeting GD2 in cancer therapy. 
Screening for GD2 expression in Ewing sarcoma can be performed using several techniques, including 
immunohistochemistry (IHC) (Kailayangiri et al., 2012), flow cytometry (Dobrenkov & Cheung, 2014), 
and molecular imaging (Theruvath et al., 2022; Wu et al., 1986) 
Only patients with GD2-positive Ewing sarcoma are eligible for this study. A sample will be considered 
positive if GD2 is detectable within the established limit of detection. The limit of detection is determined 
by using known dilutions of GD2 in a tissue matrix, allowing differentiation between background signals 
(normal tissue, no GD2 added) and specific GD2 signals. This assessment will be performed  
by the central laboratory. 
If the GD2 tumor status is unknown when the patient is initially considered for this study, 
patients/guardians will be asked to sign the molecular pre-screening ICF, if the patient is not already 
enrolled to the clinical trial “iEuroEwing” (Full title: International Euro Ewing (iEuroEwing) trial for 
treatment optimization in patients with Ewing sarcoma; EU-CT 2022-501180-40-00). The study sites will 
pre-screen patients for GD2 by sending a tumor or peripheral blood sample to a laboratory designated 
by GPOH. The tumor sample may be a previously obtained archival sample, or a sample obtained for 
the purpose of pre-screening for this study (fresh-frozen tumor). Additionally, in case of local GD2 
determination, the corresponding report should be submitted along with the patient’s archival tumor 
sample to the central laboratory, which will perform GD2 detection as a part of the determination of 
patient’s eligibility for the trial. Provision of the tumor sample to the central laboratory for the GD2 
detection is mandatory. The GD2 analysis results will be communicated to the study center within 
approximately 2 weeks of receipt of the sample.  
 

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7.1 Central GD2 determination  
 
The assay used to detect and quantify GD2 in any frozen tissue uses liquid chromatography-coupled 
tandem mass spectrometry (LC-MS/MS). Upon receipt of frozen tumor tissue samples, these are dried 
using a SpeedVac and pulverized using a tissue homogenizer. To ensure the accuracy of GD2 positivity 
determination, a calibration and linearity assay was conducted. The levels of GD2 at known 
concentrations were evaluated in relation to an internal standard. 
The relationship between signal intensity and GD2 concentration was analyzed and demonstrated to be 
linear within the tested range of concentrations. 
• 
The GD2 assay demonstrated excellent linearity, with a coefficient of determination (R²) of 
0.9996, indicating a strong correlation between the measured responses and the GD2 
concentrations. 
• 
 The linearity was assessed using a weighted regression approach, specifically employing 
a weighting factor of 1/y². 
• 
The assay's limit of quantification (LOQ) was determined to be 2.4 pmol in 200 µL, and the 
limit of detection (LOD) was 0.8 pmol in 200 µl, confirming its sensitivity for low-
concentration measurements.  
 
These values were calculated using the three lowest concentrations of the regression line, following one 
of the standard methods for determining LOQ and LOD: LOQ = 10σ / S and LOD = 3.3σ / S, were 
σ represents the standard deviation of the response, and S is the slope of the regression line. This 
method confirms the assay's high sensitivity and reliability for low-concentration GD2 measurements. 
Because the amount of GD2 required to answer to anti-GD2 based treatments is not known, the cut-off 
for GD2 positivity was set at the LOD (0.8 pmol) and the cut-off for GD2 quantification at the LOQ (2.4 
pmol). Based on published data assessing GD2 concentration via LC-MS/MS, the GD2 levels in 
Neuroblastoma range from 40 pmol to 2000 pmol (Paret et al., 2022). In Ewing sarcoma (ES), the GD2 
concentration is heterogeneous and in most samples is expected to be at the lower end of the 
Neuroblastoma range based on methods such as immunohistochemistry (Kailayangiri et al., 2012). Due 
to the high sensitivity of our assay, also ES samples with low GD2 expression will be detected. 
 
8. SCREENING AND INFORMED CONSENT  
The investigators will recruit patients from their existing clientele or from newly referred patients. 
Additional recruitment measures are not planned and are not ethically justifiable.  
Whether a patient is offered participation in the clinical trial is a decision of the respective investigator 
and is based solely on the inclusion and exclusion criteria. If there are competing studies, each trial site 
has its own comprehensible rules as to which clinical trials are discussed with the patient. The sponsor 
will not influence the trial sites regarding expected recruitment or a decision to include a specific patient.  
8.1. 
Informed Consent  
Investigators must ensure that they adequately explain the aim, trial treatment, anticipated benefits, and 
potential risks of taking part in the trial to the patient and/or parent/legal guardian as appropriate. The 
Investigator should also explain that the patient and/or parent/legal guardian is completely free to refuse 
to take part or withdraw from the trial at any time. The patient and/or parent/legal guardian should be 
given sufficient time (e.g. 24 hours, whenever clinically possible) to read the patient information sheets 
(PIS) and to discuss the patient’s participation with others outside of the site research team if they wish 
to. The patient and/or parent/legal guardian must be given an opportunity to ask questions which should 
be answered to their satisfaction. The right of the patient and/or parent/legal guardian to refuse to 
participate in the trial without giving a reason must be respected.  

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As the trial includes children and adolescents, written consent/assent will be obtained from the patient 
wherever it is possible to do so (as appropriate according to age and national legislation). For those 
children who are not able to read, write or understand regarding assent, the clinician will explain the 
study and obtain verbal assent which will be documented in the patient’s medical records.  
Patients should be re-consented at the age of majority in accordance with national guidance/legislation. 
Minor patients who reach legal age during trial participation will only be allowed to continue participating, 
if their prior assent is superseded by a legal informed consent.  
If the patient and/or parent/legal guardian agrees to participate in the trial, they should be asked to sign 
and date the latest version of the Informed Consent Form (ICF). The Investigator must then sign and 
date the form on the same day or later, but before any study-related procedure started. A copy of the 
ICF should be given to the patient and/or parent/legal guardian, a copy should be filed in the patient’s 
medical records, and the original placed in the Investigator Site File (ISF) or country specific equivalent.  
It is strongly recommended that details of the informed consent discussions should be recorded in the 
patient’s medical records; this should include date of, and information regarding, the initial discussion, 
the date consent was given, with the name of the trial and the version number of the PIS and ICF. 
Throughout the trial, the patient and/or parent/legal guardian should have the opportunity to ask 
questions about the trial and any new information that may be relevant to the patient’s continued 
participation should be shared with them in a timely manner. On occasion, it may be necessary to 
reconsent the patient, in which case the process above should be followed and the patient’s right to 
withdraw from the trial respected.  
Investigators will be expected to maintain a screening log of all potential study participants. This log will 
contain limited information about the potential participant and will include the date and outcome of the 
screening process. 
8.2. 
Patient numbering 
Each patient is identified in the trial by a Patient Number (Patient No.), assigned when the patient is 
first pre-screened and is retained as the primary identifier for the patient throughout his/her entire 
participation in the trial. The Patient No. consists of a 4-digit Site Number (Center No.) (as assigned by 
GPOH to the study site) with a sequential 5-digit patient number suffixed to it, so that each patient is 
numbered uniquely across the entire database. 
Upon signing the informed consent form (ICF), the patient is assigned to the next sequential Patient 
No. available to the investigator. 
8.3. 
Treatment assignment  
The assignment of a patient to a particular cohort will be coordinated by the sponsor.  
8.4. 
Information to be collected on screening failures 
Patients who sign the pre-screening ICF or main ICF but do not meet the screening requirements, the 
inclusion/exclusion criteria or cannot be assigned to a treatment cohort (because the slots are already 
fully recruited) will be considered a screen failure. The reason will be entered on the Screening Log, and 
each patient’s screening information will be added to the clinical database. No other data will be entered 
into the clinical database for patients who are screening failures. 
Patients who are tested for GD2 but are negative are not documented as screening failures because 
they do not meet the biological prerequisite for study participation. Screening failure only refers to GD2-
positive patients who still do not meet the inclusion criteria or for whom an exclusion criterion is identified 
during the screening assessments. 

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9. STUDY PROCEDURES AND ASSESSMENTS  
9.1. 
Prior Medication/Procedures  
All prior medications/procedures within 14 days of ICF signing should be recorded. All treatment-related 
prior medications/procedures should be recorded regardless of time.  
9.2. 
Demographics and Medical history  
Demographics including gender and month of birth will be documented at the time of the Screening Visit. 
A complete medical history including evaluation for past (up to 5 years) or present cardiovascular, 
respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, lymphatic, haematological, 
immunologic, dermatological, psychiatric, genitourinary, obstetrical, surgical history, including those 
symptoms related to the Ewing sarcoma, or any other diseases or disorders will be performed at 
screening.  
9.3. 
Vital signs  
Vital signs (including sitting blood pressure, heart rate, respiration, and temperature) will be measured 
at each visit from the time of signing of the ICF until last follow-up visit, including any unscheduled visits. 
Recordings of systolic and diastolic blood pressures (by standard sphygmomanometer reading), heart 
rate, and temperature should be made after the subject has been sitting or lying, supine or semi 
recumbent, for at least 5 minutes. Close monitoring of the cardiac function should be implemented. ECG 
should be performed prior each cycle and whenever  clinically indicated. 
9.4. 
Body Surface Area  
Height in centimetres (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, but 
without shoes) will be measured. Body surface area (BSA) will be calculated using the patient’s weight 
and height, in accordance with local site procedure. The baseline BSA will be used to determine the 
dose at C1D1 latest. Height, weight and BSA may be performed within 5 days prior to the start of a cycle 
and ±1 day for other visits. 
9.5. 
Physical examination  
All subjects will have a complete physical examination at screening until last follow-up and at any 
unscheduled visits as clinically indicated. Subjects, who discontinue treatment should have a physical 
examination done at the 28-day Safety Follow-Up Visit. 
9.6. 
Performance status 
Performance status will be assessed using the ECOG or Lansky performance scales, depending on 
the patient’s age (Appendix I). The assessment can be performed within 5 days prior to the start of a 
cycle and with a ±1-day window for other visits. For patients turning 13 during the study, the Lansky 
scale will continue to be used throughout the study period to maintain consistency in assessment. 
9.7. 
Laboratory evaluations 
Laboratory tests will be conducted and analysed by the trial site’s local laboratory, even if the study 
medication is temporarily halted. More frequent examinations can be performed at the investigator’s 
discretion if medically necessary.  
Efforts should be made to minimize the volume of blood drawn throughout the study. Use the smallest 
tube required by the local laboratory for each test and combine blood draws for routine safety labs to 
minimize wastage and reduce the number of venepunctures. If a patient has an indwelling venous 
catheter suitable for blood draws, it should be utilized whenever possible. The maximum volume of blood 
that may be drawn within a 24-hour period is 0.8 mL/kg, and within a 4-week period is 2.4 mL/kg 
according to the “Ethical considerations for clinical trials on medicinal products conducted with the 
paediatric population.” Eur J Health Law. 2008 Jul;15 (2):223-50. The maximum blood volumes required 
by this protocol over 24-hour and 4-week periods are provided in the table below. If the volume 

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requested exceeds these limits for a particular patient, the additional blood samples should not be taken 
unless necessary for the patient’s medical care. If it is anticipated that the volume limit will be exceeded, 
prioritize haematology, chemistry, and pregnancy test samples. 
 
Assessment 
Volume per 
Assessment 
Screening 
1. 
Cycle 
2. 
Cycle 
3. 
Cycle 
4. 
Cycle 
5. 
Cycle 
EoT 
FU 
Weeks 
 
2 
2-4 
2-4 
2-4 
2-4 
2-4 
2-4 
4 
Serum 
Pregnancy 
Testing1 
2 ml 
x 
x 
x 
x 
x 
x 
 
 
Blood 
Count 
0.2 ml 
x 
x 
x 
x 
x 
x 
 
 
Serum 
Chemistry 
2.4 ml 
x 
x 
x 
x 
x 
x 
 
 
Virus 
diagnostics 
2ml 
x 
 
 
 
 
 
 
 
PK  
2 ml* 
 
x* 
x* 
x* 
x* 
x* 
 
 
CDC 
2 ml** 
 
x* 
x* 
x* 
x* 
x** 
 
 
GD2 liquid 
biopsy 
7 ml 
x 
x 
x 
x 
x 
x 
x 
x 
 
Max. 
 
21.6 ml 
 
13.6 ml 
 
19.6 
ml 
 
19.6 
ml 
 
19.6 
ml 
 
19.6 
ml 
 
21.6 
ml 
 
7 ml 
 
7ml 
1 Not applicable to infants and male participants and can be replaced by a urine pregnancy test 
* samples collected twice 
** samples collected three times 
At any point during the study, any clinically relevant abnormal laboratory parameters (such as those 
requiring dose modification, interruption of a cycle, leading to clinical signs or symptoms, or 
necessitating therapeutic intervention) must be documented in the database, regardless of whether they 
are specifically requested in the protocol. 
GPOH will receive a copy of the laboratory certification and a tabulation of normal ranges for each 
required parameter. Additionally, if a patient has laboratory tests conducted by a different external 
laboratory, GPOH must also be provided with the certification and normal range tabulation from that 
laboratory. 
9.8. 
Pharmacokinetic (PK) and Complement-Dependent 
Cytotoxicity (CDC) Sampling  
The collection of blood samples for the specified purposes is part of the exploratory endpoint. 
PK samples will be collected during all cycles at the following time points: 
• 
Prior to the antibody (Ab) infusion (pre-dose) 
• 
Day 10, immediately after the end of the infusion 
Complement-Dependent Cytotoxicity (CDC) will be collected at the following time points: 
➢ during the cycle 1-4: 
• 
Prior to the antibody infusion 
• 
Day 10 immediately after the end of the infusion 
➢ during the cycle 5: 
• 
Prior to the antibody infusion 
• 
Day 10 immediately after the end of the infusion 
• 
After the end of the antibody infusion on Day 21 
 
Details are given in the respective lab manual. 
In case that the decision is taken to discontinue the study treatment before cycle 5, within the window 
given in table above Section 9.7, for CDC please take an additional sample after the end of the antibody 
infusion on Day 21 of this respective last cycle.  

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9.9. 
Pregnancy Testing 
A ß-HCG pregnancy test will be obtained in females of childbearing potential (FCBP) (see Inclusion 
Criteria for definition) regularly at screening until end of treatment in serum.  
If a subject achieves menarche during the study period, the subject must start having pregnancy testing 
performed as per protocol. The subject may not receive the protocol treatment until the investigator has 
verified that the result of the pregnancy test is negative. Any pregnancies that occur in women, who 
have received study treatment must be reported.  
In addition, FCBP and male subjects that have reached puberty and are less than 18 years of age must 
agree to undergo physician-approved reproductive education and discuss the side effects of the 
chemotherapy on reproduction with parent/parents and/or guardians/guardians at screening according 
to local practice. 
9.10. 
Imaging 
During the screening phase (within 28 days prior to the start of the first protocol cycle), all patients will 
undergo either a CT scan with intravenous contrast or an MRI. For patients who cannot tolerate iodine-
based contrast agents, CTs may be performed without contrast, or an MRI may be utilized. Visible skin 
lesions and palpable subcutaneous tumours will be measured through physical examination using a 
ruler or callipers. Ultrasound should not be used for measuring disease sites. 
Local imaging during screening and at the end of treatment (EOT) should be performed in line with initial 
imaging method of tumor and metastases site(s).  Where FDG-PET-CT/MRI was already indicated to 
detected burden of disease during initial diagnosis, it is highly recommended to perform same method 
during screening and at EOT within the trial. All imaging methods are expected to be performed 
according to local practice and cover all known tumour sites. 
Subsequent disease evaluations will be conducted only if regular patient care necessitates imaging. 
After the last cycle, a disease evaluation must be performed on Day 15 (±7 days), and before initiating 
any further treatment (including additional chemotherapy, local therapy, or radiation therapy), or sooner 
if there is clinical evidence of disease progression. If local protocol includes a disease evaluation at 
EOT, these data can be additionally recorded. If the last disease evaluation was within 28 days of EOT 
or if there is already documented evidence of disease progression, repeat evaluations at EOT are not 
necessary. 
Disease evaluations following the screening will include all disease sites identified at baseline, using the 
same methods as at the screening. Regions without evidence of disease at baseline do not need to be 
imaged in subsequent assessments unless there is clinical concern for a new lesion in that region. 
Reference Evaluation of Images: 
All images obtained during the clinical trial and follow-up will be reviewed by a radiology reference panel 
appointed by the sponsor. Disease will be assessed according to RECIST v1.1 at a central review for 
CT and MRI and will determine disease response and progression. 
10. TREATMENT 
10.1. 
Study Treatment 
All dosages of the treatment cycles prescribed and dispensed to the patient and all dose changes during 
the trial must be recorded on the Dosage Administration Records within the eCRF. 
Alternating cycles of VDC/IE + dinutuximab beta should be given at 21-day intervals +/- 7 days and upon 
haematological recovery to absolute neutrophil count (ANC) ≥ 0.75*109/L and platelets ≥ 75*109/L. 
Average treatment time of 21 days is assumed and begin of next cycle should be made by local 
investigator if starting criteria of haematological recovery are met and no other laboratory findings are 
present, which could in investigators view increase patients’ risk or require any intervention. 
Time between day1 of two cycles should not be less than 14 days and not longer than 28 days. Therapy 
should be continued as soon as starting criteria for the next cycle are fulfilled.  

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Treatment Plan for VDC + Dinutuximab beta 
DRUG 
DAILY DOSE 
APPLICATION 
DAY IN CYCLE 
CUMULATIVE 
DOSE 
PER CYCLE 
ROUTE 
AND 
DURATION 
OF 
ADMINISTRATION 
Vincristine 
2 mg/m2/d, max. 
2 mg/single dose 
d1 
2 mg/m2/cycle 
IV push or short 
infusion 
Doxorubicin 
37.5 mg/m2/d 
d1, d2 
75 mg/m2/cycle 
IV infusion, 24 h 
Cyclophosphamide 1200 mg/m2/d 
d1 
1200 mg/m2/cycle 
IV infusion, 1 h 
Dinutuximab beta 
See Section 
10.1.1 
d3-12 
See Section 10.1.1 
IV infusion, 24 h 
 
Continuation with IE upon haematological recovery to white blood cell count (WBC) ≥ 2.0*109/L with 
ANC ≥ 1.0*109/L and platelets ≥ 80*109/L. 
 
Treatment Plan for IE + Dinutuximab beta 
DRUG 
DAILY DOSE 
APPLICATION 
DAY IN CYCLE 
CUMULATIVE 
DOSE 
PER CYCLE 
ROUTE 
AND 
DURATION 
OF 
ADMINISTRATION 
Ifosfamide 
1800 mg/m2/d 
d1-d5 
9 g/m2/cycle 
IV infusion, 4 h 
Etoposide 
100 mg/m2/d 
d1-d5 
500 mg/m2/cycle 
IV infusion, 2 h 
Dinutuximab beta 
See Section 
10.1.1 
d6-d15 
See Section 10.1.1 
IV infusion, 24 h 
 

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10.1.1. 
Dosing Regimen  
 
Doses will be escalated in a 3+3 design with three pre-defined dose levels, namely Level 1: 50%, 
Level 2: 75%, Level 3: 100%.  
Dinutuximab beta dose will be assessed in a 3+3 design. 
Dose level 1   
5 mg/m²/d 10-day continuous infusion once daily as an IV infusion over 24 hours 
Infusions starts at the end of the respective standard chemotherapy i.e. VDC day 3 and IE day 6.  
Dose level 2  
7,5 mg/m²/d 10-day continuous infusion once daily as an IV infusion over 24 hours.  
Infusions starts at the end of the respective standard chemotherapy i.e. VDC day 3 and IE day 6. 
Dose level 3 
10 mg/m²/d 10-day continuous infusion once daily as an IV infusion over 24 hours.  
Infusions start at the end of the respective standard chemotherapy VDC day 3 and IE day 6. 
Starting dose will be 5 mg/m²/d, which equals 50% of the final dose. At each level at least 3 at max. 6 
patients will be included depending on the occurrence of DLT. At Level 1 a toxicity-adjusted dose 
escalation is implemented based on the observed Common Toxicity Criteria (CTCAE Version 5) grades. 
Specifically, a CTC grades of ≤ 1 will result in a 100% dose escalation (=Level 3). At least one CTC 
grade=2 will result in a 50% dose escalation (=Level 2). 
10.1.2. 
Treatment Duration of Dinutuximab Beta 
Dinutuximab beta will be administered as a continuous intravenous infusion over a period of 10 days. 
Each infusion will be administered over 24 hours following the last day of the standard induction 
chemotherapy cycle. Dinutuximab beta will be administered in addition to the last 5 cycles of induction 
chemotherapy, consisting of alternating cycles of Vincristine, Doxorubicin and Cyclophosphamide and 
Ifosfamide and Etoposide. 
 
10.2. 
Dose Escalation Guidelines 
 
10.2.1. 
Starting Dose Rationale 
Doses will be escalated in a 3+3 design with three pre-defined dose levels. Starting dose will be 5 
mg/m²/d, which equals 50% of the final dose. 
 
10.2.2. 
Provisional Dose Levels 
The dose escalation will continue until the MTD and/or the RDE dose is reached, based on the schedule 
given in Section 10.1.1. Following completion of the dose escalation in this clinical trial, a dose can be 
chosen for the expansion part within a phase II clinical trial. The dose for a potential expansion will be 
opened at either the MTD, or a lower dose that is determined to be the RDE. 
 

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10.2.3. 
Guidelines for dose escalation and determination of 
Maximum Tolerated Dose (MTD) 
For the purposes of dose escalation decisions, each cohort will consist of 3 to 6 newly enrolled patients 
who will be treated at the specified dose level. The first cohort will be treated with the starting dose of 5 
mg/m2/d.  
Patients must complete a minimum of 1 cycle of treatment with the minimum safety evaluation and drug 
exposure or have had a DLT within the first cycle of treatment to be considered evaluable for dose 
escalation decisions. Dose escalation decisions will occur when the cohort of patients has met these 
criteria. 
Dose escalation decisions will be made by DSMC and GPOH trial team. Decisions will be based on a 
synthesis of all relevant data available from all dose levels evaluated in the ongoing study, including 
safety information, DLTs, all CTCAE Grade ≥ 2 toxicity data during Cycle 1. 
Within CESS-GD2 the dose escalation involves treating small cohorts of patients with increasing doses 
of the dinutuximab beta, monitoring for dose-limiting toxicities (DLTs), and deciding whether to escalate, 
de-escalate, or stop dose escalation based on observed toxicities. The trial will be conducted according 
to the following dose escalation schedule to determine the MTD and RDE: 
Initial Cohort at Dose Level 1: 5 mg/m²/day 
Cohort 1 (3 patients) 
Observation: 
Treatment of 3 patients at the starting dose of 5 mg/m²/day. 
 
Outcome: 
• 
If 0 out of 3 patients experience a DLT:  
o 
CTC ≤ 1 Escalate to 100% dose level (10 mg/m²/day) 
o 
CTC ≥ 2 Escalate to 75% dose level (7.5 mg/m²/day) 
• 
If 1 out of 3 patients experience a DLT: Enroll 3 more patients at the 
same dose level 
• 
If 2 or more out of 3 patients experience a DLT: stop the trial 
Expansion Cohort 1 (if needed) 
Observation: 
Treatment of 3 additional patients at the dose level of 5 mg/m²/day. 
 
Outcome: 
• 
If 1 or fewer out of these 6 patients experience a DLT in total: Escalate 
to the next dose level (7,5 mg/m²/day) 
• 
If 2 or more out of these 6 patients experience a DLT: stop the trial 
 
Second Cohort at 7.5 mg/m²/day 
Cohort 2 (3 patients) 
Observation: 
Treatment of 3 patients at the second dose level of 7.5 mg/m²/day. 
 
Outcome: 
• 
If 0 out of 3 patients experience a DLT 
• 
If 1 out of 3 patients experience a DLT: Enroll 3 more patients at the 
same dose level 
• 
If 2 or more out of 3 patients experience a DLT: stop the trial 
Expansion Cohort 2 (if needed) 
Observation: 
Treatment of 3 additional patients at the dose level of 7,5 mg/m²/day. 
 
Outcome: 
• 
If 1 or fewer out of these 6 patients experience a DLT in total: Escalate 
to the next dose level (10 mg/m²/day) 
• 
If 2 or more out of these 6 patients experience a DLT: stop the trial 

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Third Cohort at 10 mg/m²/day 
Cohort 3 (3 patients) 
Observation: 
Treatment of 3 patients at the second dose level of 10 mg/m²/day. 
 
Outcome: 
• 
If 0 out of 3 patients experience a DLT: This dose level may be 
considered safe, and potentially, no further escalation is possible 
• 
If 1 out of 3 patients experience a DLT: Enroll 3 more patients at the 
same dose level 
• 
If 2 or more out of 3 patients experience a DLT: stop the trial  
Expansion Cohort 3 (if needed) 
Observation: 
Treatment of 3 additional patients at the dose level of 10 mg/m²/day. 
 
Outcome: 
• 
If 1 or fewer out of these 6 patients experienced a DLT, 10 mg/m²/day 
can be regarded as MTD  
• 
If 2 or more out of these 6 patients experience a DLT: stop the trial 
 
Summary of Decisions Making 
Observation 
Decision 
No DLTs 
Escalate to the next dose level 
1 DLT in 3 patients 
Expand cohort to 6 patients 
2 or more DLTs per cohort 
stop the trial 
 
The aim is to determine the highest dose at which fewer than 2 out of 6 patients experience a DLT, 
which will be considered the MTD. 
The dosage will start at 5 mg/m² per day, which is 50% of the target final dose. In Level 1, a toxicity-
adjusted dose escalation will be applied based on the severity of side effects observed according to the 
Common Toxicity Criteria (CTCAE Version 5). If the observed toxicity is Grade 1 or lower, the dose will 
be escalated directly to the full final dose (Level 3), skipping the intermediate dose level. However, if a 
Grade 2 toxicity is observed, the dose will only be increased to 75% of the final dose (Level 2), without 
skipping any levels. 
10.2.4. 
Definitions of dose limiting toxicities (DLTs) 
All dose levels of dinutuximab beta will be evaluated for the occurrence of dose limiting toxicities (DLT). 
A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, 
disease progression, inter-current illness, or concomitant therapies that occurs within the first 21 days 
(Cycle 1) of treatment with the protocol compliant treatment and meets any of the criteria included in 
listing below. 
A study participant will be considered evaluable for a DLT if at least one cycle of dinutuximab beta in 
combination with chemotherapy (VDC/IE) is administered. 
Participants who discontinue treatment in the first cycle for reasons unrelated to the IMPs toxicity, are 
not evaluable for DLT and will be replaced in enrolment (maximum number of replacement subjects will 
be 3 per dose level). In case of doubt, the DSMC will determine whether toxicity qualifies as DLT.  

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DLTs will be assessed within the Common Toxicity Criteria for Adverse Events (CTCAE Version 5.0). 
The following are considered drug-related DLTs: 
• 
allergic reaction grade ≥3, 
• 
any immune mediated adverse event, regardless of grade, which requires discontinuation of 
study treatment, 
• 
serum sickness grade ≥3, 
• 
severe, unrelenting neuropathic pain (grade ≥3) unresponsive to continuous infusion of 
morphine and gabapentin, 
• 
any of the following neurotoxicities: 
o 
sensory changes grade ≥3 interfering with daily activities >2 weeks after completing 
dinutuximab beta therapy, 
o 
objective motor weaknesses grade ≥3, 
o 
vision toxicity grade ≥3,  
o 
prolonged grade ≥3 peripheral motor neuropathy; 
• 
hyponatremia grade ≥3 (125-129 mmol/L symptomatic; 120-124 mmol/L regardless of 
symptoms) lasting >24 hours despite appropriate fluid management, 
• 
capillary leak syndrome grade ≥3, 
• 
cardiac toxicity grade ≥3, 
• 
any grade ≥4 toxicity requiring any mechanical ventilation/inotropic support/hemofiltration and 
therefore, intensive care unit hospitalization, except for sepsis as an expected side effect of 
chemotherapy,  
• 
any toxic death (grade 5 toxicity). 
10.3. 
Dose Modifications 
For vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide: In patients < 10 kg, 
the calculation of dosage is converted from m² BSA to kg BW divided by 30.  
For dinutuximab beta: No dose modifications are allowed, beside those described in section 10.2.3 .  
NOTE: The maximum single dose for vincristine is 2 mg.  
Symptom specific dose modifications are outlined below. 
10.3.1. 
Hematological Toxicity 
Dose / time intensity is regarded as an essential aspect of induction part. In case of significant bone 
marrow toxicity, preference is given to early G-CSF support rather than dose reduction in order to 
maintain dose intensity.  
If significant toxicity continues as defined by hematological recovery delayed > 6 days: 
• 
if hematological recovery to ANC ³ 0.75*109/L and platelets ³ 75*109/L is delayed > 6 days 
before VDC: Reduce doxorubicin and cyclophosphamide dose by 20% in the next cycle. If ANC 
recovers in the next cycle until day 18, increase doses by 20%, 
• 
if hematological recovery to white blood cell count (WBC) ³ 2.0*109/L with ANC ³ 1.0*109/L and 
platelets ³ 80*109/L is delayed > 6 days before IE: Reduce isocyanides and etoposide dose by 
20% in the next cycle. If ANC recovers in the next cycle until day 18, increase doses by 20%. 

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If neutropenic sepsis CTCAE grade ≥ 3 occurs: 
• 
if neutropenic sepsis CTCAE grade ≥ 3 occurs before VDC: Reduce doxorubicin and 
cyclophosphamide dose by 20% in the next cycle. If ANC recovers in the next cycle until day 
18, increase doses by 20%, 
• 
if neutropenic sepsis CTCAE grade ≥ 3 occurs before IE: Reduce ifosfamide and etoposide 
dose by 20% in the next cycle. If ANC recovers in the next cycle until day 18, increase doses 
by 20%. 
In the event of further episodes of toxicity, the dose is to be reduced by an additional 20%. If necessary, 
it is advised to omit etoposide completely rather than reducing the doses of the other four drugs. 
10.3.2. 
Mucositis / Gastrointestinal Toxicity CTCAE Grade ≥ 3 
If mucositis / gastrointestinal toxicity CTCAE grade ≥ 3 occurs: 
• 
If mucositis / gastrointestinal toxicity CTCAE grade ≥ 3 occurs and persists beyond day 18 after 
start of VDC: Reduce doxorubicin dose by 20% in the next cycle. 
• 
If mucositis / gastrointestinal toxicity CTCAE grade ≥ 3 occurs and persists beyond day 21 after 
start IE: Reduce ifosfamide and etoposide dose by 20% in the next cycle. 
10.3.3. 
Nephrotoxicity / Renal Function Monitoring 
It is recommended to monitor serum creatinine prior to each cycle of ifosfamide. Glomerular function is 
to be assessed according to national group guidelines, applying either isotope clearance or calculated 
creatinine clearance. 
Schwartz's Formula (1-18 years) 
According to Schwartz's formula (Schwartz et al., 1987), creatinine clearance (Ccrea) can be calculated 
from single serum samples:  
 
where F is proportional to body muscle mass, hence depending on age and sex:  
Infants (< 1 year of age)  
F = 0.45  
Males, 1-16 years  
 
F = 0.55  
Females, 1-21 years 
 
F = 0.55  
Males, > 16-21 years 
 
F = 0.70  
Normal values [ml/min/1.73 m²]:  
Infants (7 days):  
 
45  
Infants (6 months):  
 
60-80  
> 1 year:  
 
 
120 
Cockroft-Gault Formula (> 18 years)  
Females  
 
      or      
 
 
 
 
73m²]
[mL/min/1.
 
[mg/dL]
 
Crea
[cm]
Height 
 x 
F
C
 
serum
crea =
 
mol/L]
 [
 
Crea
 wt(kg)
(yrs))
 
age
-
(140
 
1.05
 
serum 
 
[mg/dL]
 
Crea
 x 
72
 wt(kg)
(yrs))
 
age
-
(140
  
0.85
 
serum

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Males  
 
      or      
 
NOTE: These equations are not confirmed in patients receiving repeated cycles of intensive 
chemotherapy or in adolescents. Renal function may be overestimated by these methods. 
 
Tubular Function (Tp/Ccrea or Tmp/GFR) 
Tubular function may be assessed using serum electrolyte and bicarbonate levels and the calculation 
of fractionated phosphate reabsorption, relative amino acid reabsorption and / or fractionated sodium 
excretion from single urine samples (Rossi et al., 1994; Rossi et al., 1995) 
Fractionated phosphate reabsorption:  
Reference values in three age groups. "limit" refers to mean – 2 SD for TP/Ccrea  
 
< 1 month 
1-12 months > 1 year 
 
mean limit mean limit mean limit 
TP/Ccrea [µmol/ml] 2.13 
1.90 2.10 
1.00 1.50 
1.07 
 
Ifosfamide Adjustment to Renal Function: 
If either glomerular filtration rate (GFR) or Tp/Ccrea (Tmp/GFR) or HCO3 is reduced, classify toxicity as 
grade 0/1, 2, or 3/4 and adjust ifosfamide treatment as indicated: 
Toxicity 
grade* 
GFR  
(ml/min/1.73 m2) 
Tp/Ccrea 
(Tmp/GFR) (mmol/L) 
HCO3# 
(mmol/L) 
Action (apply worst grade) 
0 / 1 
≥ 60 
≥ 1.00 
≥ 17.0 
Continue ifosfamide dose at 
100%  
2 
40-59 
0.80 - 0.99 
14.0 - 16.9 
Reduce ifosfamide dose by 
30%  
3 / 4 
≤ 40 
≤ 0.80 
≤ 1 4.0 
Use cyclophosphamide instead, 
1500 mg/m²/d, d1  
* Toxicity is graded from 0 to 4, analogous to the CTCAE system; however, for the purpose of modifying 
treatment, grades 0 and 1 and grades 3 and 4 are considered together. 
# Low values of HCO3 may be re-checked when the patient is clinically stable (to rule out infection as a 
cause, etc.) before modifying ifosfamide dose / treatment. 
Etoposide Adjustment to Renal Function: 
If GFR < 60 ml/min/1.73 m2, reduce etoposide dose by 30%. 
 
mol/L]
[
 
Crea
 wt(kg)
(yrs))
 
age
-
(140
 
1.25
 
serum 
 
[mg/dL]
 
Crea
 x 
72
 wt(kg)
(yrs))
 
age
-
(140
 
 
serum

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10.3.4. 
Cardiac Toxicity 
If SF < 28% or left ventricular ejection fraction < 40% or parameters decrease by an absolute value of ³ 
10 percentile points from previous tests, delay chemotherapy cycle for seven days and repeat 
echocardiography: 
• 
if SF has recovered to ≥ 29%, proceed to next cycle, 
• 
if SF remains < 29%, omit doxorubicin and substitute actinomycin D of 0.75 mg/m2/d (d1, d2) 
(IV push) (1.5 mg/m2/cycle) (max. single dose/d: 1.5 mg/d). 
Repeat cardiac tests prior to next doxorubicin-containing cycle. If results have normalised, apply 
doxorubicin at normal dosage. If SF remains abnormal, please see paragraph above. 
10.3.5. 
Neurotoxicity CTCAE Grade ≥ 3 
Ifosfamide-induced Encephalopathy:  
If ifosfamide-induced encephalopathy occurs supportive care may be given according to institutional 
guidelines. Ifosfamide infusion may be prolonged to 4-8 hours according to institutional guidelines. 
If repetitive CTCAE grade ≥ 3 central neurotoxicity occurs in association with ifosfamide, consider 
withholding ifosfamide and substitute cyclophosphamide 1500 mg/m² BSA/cycle on day 1. Substitution 
with cyclophosphamide is only on day 1.  
10.4. 
Follow up for toxicities 
Beside the regular trial follow up of 3 months after the last dose of an IMP, patients whose treatment is 
interrupted or permanently discontinued due to an adverse event (AE) or an abnormal laboratory value 
deemed treatment-related must be followed until the toxicity resolves or stabilizes. The follow-up 
procedures for patients experiencing specific dose-limiting toxicities are detailed in the table below. In 
addition to the parameters listed in the table, other relevant clinical and laboratory metrics should be 
monitored as clinically appropriate. 
 
In general, toxicities should be followed until they resolve to grade 1 or the patient's baseline value. 
However, frequent follow-up as outlined in table may be discontinued if the toxicity has stabilized at a 
higher level and is considered irreversible. 
 
Toxicity 
Follow-up assessment 
Hematology 
If CTCAE grade 4 neutropenia, thrombocytopenia, or anaemia, or grade 3 or 
4 febrile neutropenia occurs, white blood cell count with differential (including 
neutrophil count), platelet count, and haemoglobin must be measured after 3 
days, and then at least once a week until the condition resolves to ≤ CTCAE 
grade 2 or returns to baseline. 
Hepatic/Liver 
Toxicitiy  
If a hepatic DLT occurs, ALT, AST, and total bilirubin levels must be 
measured at least once a week until they resolve to ≤ CTCAE grade 1 or 
return to baseline. For patients with total bilirubin levels ≥ grade 2 (regardless 
of duration), bilirubin should be fractionated into total/direct or indirect/direct 
components, and any additional evaluations indicated by these results should 
be conducted. 
Gastrointestinal  
If vomiting or diarrhoea DLTs occur, blood electrolytes must be measured at 
least once a week until the symptoms resolve to ≤ CTCAE grade 1 or return 
to baseline. If a nausea DLT occurs without clinically relevant vomiting or 
diarrhoea, the patient must be monitored weekly, as clinically appropriate, 
until the condition resolves to ≤ CTCAE grade 2 or baseline. 

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Lung 
Monitor patients for pulmonary symptoms indicative of pneumonitis and hold 
treatment during diagnostic evaluation. Exclude infectious causes and follow 
the dose modification guidelines outlined in Section 10.3. 
Cardiac 
If QTc exceeds 500 ms, blood electrolytes, including calcium, magnesium, 
phosphorus, and potassium, should be measured and any abnormalities 
corrected. Concomitant medications should be reviewed for other potential 
causes of QTc prolongation. An ECG should be repeated daily until the QTc 
prolongation resolves to grade 1 or less, and the patient should be evaluated 
by a qualified physician before leaving the trial site. 
Other Toxicities 
Patients who experience other DLTs must be evaluated at least once a week, 
including appropriate laboratory assessments, until the condition resolves to 
CTCAE grade 1 or the patient’s baseline. 
 
Please note: Follow-up for toxicities ends either when the toxicities decrease as described in the table, 
when the patient receives further therapy outside the trial (whether chemotherapy, local therapy, or 
radiation), or when the regular follow-up period has concluded. Whichever occurs first. 
11. CONCOMITANT THERAPY 
11.1. 
Required Concomitant Therapy as part of supportive care 
An anticipated side effect of the treatment with dinutuximab beta is neuropathic pain. Therefore, in the 
first cycles patients will be treated with gabapentin p.o. and morphine i.v. (Barone et al., 2021). The 
treatment in the following cycles can be adapted.  
 
Gabapentin 
Gabapentin should be administered before every infusion cycle of dinutuximab beta. Patients should 
begin with an oral gabapentin medication three days prior to the dinutuximab beta cycle. Recommended 
oral dose of gabapentin is 1x10 mg/kg/d three days prior to the dinutuximab beta administration and 
should be increased to 2x10 mg/kg/d 2 days before the start of dinutuximab beta administration and, if 
required by the patient, further increased to 3x10 mg/kg/d during the antibody infusion. The treatment 
with gabapentin should be decreased and finally stopped in the reverse order starting on the first day 
after the end of dinutuximab beta infusion (i.e. day 1 after dinutuximab beta treatment: 2 × 10 mg/kg 
p.o.; day 2 after dinutuximab beta treatment: 1 × 10 mg/kg p.o.; day 3 after dinutuximab beta treatment: 
stop). 
 
Morphine 
As a prevention of severe visceral and neuropathic pain opioids are the standard medications given with 
dinutuximab beta. Doses of morphine should be started and then gradually increase. Side effects 
include: respiratory depression and sedation, nausea, vomiting, constipation, pruritus, urinary retention, 
lowered seizure threshold.  
During the first cycle i.v. morphine should be given as follows: 
- morphine loading infusion (30 μg/kg/h) over 60 minutes before the start of the continuous infusion of 
dinutuximab beta.  
- afterwards, administration of morphine sulfate as a continuous infusion on the first day with a rate of 
30 μg/kg/h. Morphine boluses can be given as required. Depending on the individual patient’s pain 
tolerance, treatment with morphine can then be decreased and doses can be adapted in the following 
cycles. 
Other opioids are allowed in the decreasing phase and after continuous morphine infusion, i.e.: 
• 
oral morphine; administered at a dose of 0.2 to 0.4 mg/kg every 4-6 hours, 
• 
oral tramadol, if pain is well-controlled on low doses of p.o. morphine. 

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11.2. 
Permitted concomitant Therapy 
Expected inflammatory side effects may require a treatment with antipyretic drugs. An 
antihistaminergic prophylaxis and prevention of gastritis is recommended. All concomitant therapy is 
permitted according to institutional guidelines as not stated otherwise in this protocol.  
11.3. 
Prohibited concomitant therapy 
Below prohibited medications are listed. The use of these medications is a protocol violation and must 
be recorded in the electronic case report form (eCRF).  
Intravenous Immunoglobulins 
Due to the risk of interference with dinutuximab beta-dependent cellular cytotoxicity, the treatment with 
intravenous immunoglobulins is not allowed. 
Vaccination 
Vaccinations are not allowed during administration of dinutuximab beta until 10 weeks after the last 
treatment course, due to the risk for neurological toxicities due to immune stimulation through 
dinutuximab beta. 
Other medications   
Furthermore, treatment with any other systemic anticancer treatments not described in this protocol 
are not allowed.  
11.4. 
Contraceptive Requirements 
To this protocol, methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly are considered as highly effective birth control methods. Such methods include: 
• 
combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation1: 
o 
oral 
o 
intravaginal 
o 
transdermal 
• 
progestogen-only hormonal contraception associated with inhibition of ovulation1: 
o 
oral 
o 
injectable 
o 
implantable2 
• 
intrauterine device (IUD) 2 
• 
intrauterine hormone-releasing system (IUS) 2 
• 
bilateral tubal occlusion 2 
• 
vasectomised partner 2,3 
• 
sexual abstinence4 
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy 
of the contraception method 
2 Contraception methods that in the context of this guidance are considered to have low user 
dependency. 

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3 Vasectomised partner is a highly effective birth control method if partner is the sole sexual partner of 
the WOCBP trial participant and that the vasectomised partner has received medical assessment of the 
surgical success. 
4 In the context of this guidance sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject. 
For male subjects with WOCBP the following methods must be considered: 
• 
condom, 
• 
consider contraception for non-pregnant WOCBP partner, 
• 
contraception during treatment and until the end of relevant systemic exposure in the male 
subject. 
Duration of Contraconception/Contraception methods in subjects should be at least 6 months. 
Duration might be extended depending on further treatment or according to local procedure. Due to the 
potential impact on fertility, patients and care givers should seek advice on fertility preservation, prior to 
treatment given by the investigator. 
12. OTHER SUPPORTIVE CARE 
The outlined therapeutic regimen within this trial protocol is intensive and aggressive and will be followed 
by severe bone marrow depression. Hence, treatment according to this protocol should be restricted to 
institutions with knowledge in both the administration of intensive, aggressive combinational 
chemotherapy and the handling and feasibility of full supportive care.  
In paediatric patients only those preparations should be used that are either approved for use in children 
(according to the SmPC) or whose dose-precise and safe use complies with current guidelines. 
13. STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
If a patient stops CESS-GD2 protocol treatment, the reason should be recorded in the patient’s 
medical records and be reported on the appropriate CRF whether it is due to either the patient’s, 
parent/legal guardian’s or clinician’s decision. Reasons for stopping protocol treatment include, but are 
not limited to: 
• 
the patient and/or patient’s parent/guardian does not wish to continue with further trial 
treatment, 
• 
unacceptable toxicity/DLT, 
• 
disease progression whilst on therapy or other important medical events, 
• 
pregnancy. 
In case of the listed criteria treatment must be discontinued. 
CESS-GD2 will be analysed on an intention-to-treat (ITT) basis and all patients who stop trial treatment 
will remain in the trial for follow-up unless the patient and/or parent/legal guardian explicitly withdraws 
consent for data collection.  

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13.1. 
Patient replacement 
Patients who have not received dinutuximab beta will be replaced. If a patient is deemed as non-
evaluable for the Dose-determining set, enrolment of a new patient to the current cohort will be 
considered if there is less than the required number of evaluable patients. Enrolment of new patients 
may be considered until at least the minimum number (3) or at most the maximum number (6) of 
evaluable patients is achieved within the cohort. Minimum and maximum numbers of evaluable patients 
per cohort are defined in Section 15.2. 
13.2. 
Withdrawal of consent to data collection 
The patient and/or parent/legal guardian may withdraw consent at any time during the study. For the 
purposes of this trial, withdrawal is defined as: 
The patient would like to withdraw from trial medication and is not willing to be followed up for the 
purposes of the trial at any further visits (i.e. only data collected prior to the withdrawal of consent can 
be used in the trial analysis). 
The details of withdrawal should be clearly documented in the patient’s medical records. A patient’s 
wishes with respect to their data must be respected. 
13.3. 
Lost to follow-up 
If a patient is lost to follow-up, every effort should be made to contact the patient’s primary physician to 
obtain information on the patient’s status. Similarly, if a patient’s care is transferred to another 
clinician, the Sponsor should be informed, and follow-up information be obtained. 
14. SAFETY MONITORING AND REPORTING 
14.1. 
Definition and Reporting of Adverse Events (AE) 
 
An adverse event is defined as the onset of, or an increase in, any unwanted sign(s), symptom(s), or 
medical condition(s) that occur after the patient and/or guardian has signed the informed consent form 
(ICF). 
AEs will be assessed continuously and graded according to NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0. 
Abnormal laboratory values or test results that arise after informed consent has been given are 
considered adverse events only if they cause clinical signs or symptoms, are deemed clinically 
significant, require medical intervention (such as a transfusion or haematological stem cell support), or 
necessitate changes to the study medication(s). See for details section 14.1.1. 
Except for screening failures, adverse events that begin or worsen after informed consent should be 
recorded in the Adverse Events CRF. Pre-existing conditions at the time of informed consent should be 
documented in the Relevant Medical History/Current Medical Conditions section of the patient’s CRF. 
Adverse event monitoring should continue for at least 30 days following the final dose of the last cycle 
within the protocol. Adverse events, including lab abnormalities constituting AEs, should be described 
using a diagnosis whenever possible, rather than listing individual signs and symptoms. If a clear 
diagnosis cannot be determined, each sign or symptom should be reported as a separate adverse event. 
If CTCAE grading is unavailable for an adverse event, the severity will be classified as mild, moderate, 
severe, or life-threatening, corresponding to Grades 1 through 4. CTCAE Grade 5 (death) requires 
detailed information about the event and will be recorded on the End of Treatment (EOT) or death form. 
Adverse events should be identified through non-directive questioning of the patient or guardian during 
the screening process after informed consent has been obtained and at each subsequent visit during 
the study. Adverse events may also be identified if reported voluntarily by the patient during the 
screening process or between visits, or through physical examination, laboratory tests, or other 
assessments.  

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Adverse events will be systematically recorded and presented in the form of a classic line listing for 
thorough and clear analysis. The line listing will contain the following information for each reported AE: 
• 
Event Term/Description – According to NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 
• 
Duration – The time period over which the adverse event persisted, including both onset and 
resolution dates or categorized as “Ongoing” at EoT, 
• 
Severity – According to NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 (grading from 1-5) 
• 
Relationship to Trial Treatment – The investigator's assessment of the relationship to trial 
treatment; reasonable possibility that AE is related: “yes” or “no”. 
 
• 
Action Taken – Documentation of any action taken with respect to investigational treatment: 
“none”, “dose decreased”, “dose increased”, “temporarily interrupted”, “permanently 
discontinued”, “unknown”, “not applicable” 
 
• 
Seriousness – Classification of the event as serious or non-serious, in accordance with meet 
a seriousness criterion as defined in Section 14.2 
 
• 
Concomitant Medications – A list whether medication or therapy was given:” No concomitant 
medication/non-drug therapy”, “concomitant medication/non-drug therapy” 
 
 
All adverse events should be managed appropriately. If concomitant therapy is administered, this should 
be documented on the Adverse Event CRF. Once an adverse event is identified, it must be monitored 
until resolution or deemed permanent. At each visit (or more frequently, if necessary), the severity, 
suspected relationship to trial treatment, required interventions, and outcome should be assessed. 
Progression of the underlying Ewing sarcoma, including fatal outcomes, documented using appropriate 
methods (RECIST 1.1 criteria) should not be reported as a serious adverse event. However, adverse 
events separate from the malignancy progression should be reported according to standard guidelines, 
with proper attribution regarding their relation to the trial treatment. 
14.1.1. 
Handling of Laboratory test abnormalities 
Laboratory abnormalities that are considered adverse events (i.e., those that are clinically significant, 
induce clinical signs or symptoms, require concomitant therapy, or necessitate changes in protocol 
compliant treatment) should be documented in the Adverse Events CRF. Whenever possible, provide a 
diagnosis rather than a symptom (e.g., anaemia instead of low haemoglobin). Such laboratory 
abnormalities should be monitored until they return to normal, or an adequate explanation is found. If 
an abnormal laboratory or test result corresponds to a sign/symptom of an already reported adverse 
event, it is not necessary to record the lab/test result as an additional event. 
Laboratory abnormalities that do not meet the criteria for an adverse event should not be reported as 
such. A Grade 3 or 4 event (severe) according to CTCAE 5.0 does not automatically qualify as a serious 
adverse event (SAE) unless it meets the definition of serious as described below or as determined by 
the investigator. If the protocol requires a dose hold or medication for the lab abnormality, the lab 
abnormality must be reported as an adverse event. 
14.2. 
Definition and Reporting of Serious Adverse Events (SAE) 
A Serious Adverse Event (SAE) is defined as regarding to the “Detailed guidance on the collection, 
verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal 
products for human use – 2011/C 172/01 CT-3” and Article 2(33) (EU) No 536/2014 as: 

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A Serious Adverse Event (SAE) is any untoward medical occurrence or effect that at any dose 
• 
results in death, 
• 
is life-threatening, 
• 
requires hospitalization or prolongation of existing hospitalization, 
• 
results in persistent or significant disability or incapacity, or 
• 
is a congenital anomaly or birth defect. 
Any important medical event (defined as a medical event(s) that may not be immediately life threatening 
or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require intervention [e.g. medical, surgical] to prevent one of the other 
serious outcomes listed in the definition above.) should also be considered as an SAE.  
Examples of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.) 
Suspected transmission of an infectious agent (e.g. pathogenic or non-pathogenic) via the trial treatment 
should be also considered as an SAE.  
Although pregnancy, overdose and cancer are not always serious by regulatory definition, but these 
events should be handled as SAEs. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome 
and, where applicable, offspring information must be reported on the Pregnancy Surveillance Form. An 
overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as 
an SAE.  
The following reasons for hospitalizations should be not considered as SAEs due to clinical situation the 
regular patient care: 
• 
a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event), 
• 
elective surgery, planned prior to signing consent, 
• 
admissions as per protocol for a planned medical/surgical procedure, 
• 
routine health assessment requiring admission for baseline/trending of health status, 
• 
medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases, 
• 
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g. lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason), 
• 
admission for administration of anticancer therapy in the absence of any other SAEs (applies to 
the nature of this oncology protocol) 
To ensure patient safety, every SAE, regardless of suspected causality, occurring from the timing given 
in section 14.2.1 until at least 30 days after last dose of protocol therapy must be reported within 24 
hours of becoming aware of its occurrence. For further details please see section 14.2.1. 
Recurring episodes, complications, or progression of the initial SAE must be reported as follow-up to 
the original incident within 24 hours of receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise deemed completely unrelated to a previously reported one should be reported 
separately as a new event. 
14.2.1. 
Timing of SAE Reporting 
SAE reporting starts after the patient and/or guardian has signed the informed consent form (ICF), but 
no earlier than the administration of the first protocol-compliant therapy in the 1st cycle. Adverse Events 
that occur before this time point and meet a seriousness criterion will not be reported as SAEs to clearly 
distinguish them from pre-treatment events.  

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This also applies to events that already exist when the patient enters the study, and the SAE is already 
present. If an existing AE worsens after the first administration in the first cycle, this worsening must be 
reported as an SAE. 
The SAE reporting ends either 30 days after last dose of protocol therapy, when the patient receives 
further therapy outside the trial (whether chemotherapy, local therapy, or radiation), or when the regular 
follow-up period has concluded. Whichever occurs first. 
Any SAEs experienced beyond this period should only be reported if the investigator suspects a causal 
relationship to dinutuximab beta.  
14.2.2. 
Serious Adverse Event Reporting  
Information on all SAEs must be collected and documented on the Serious Adverse Event Report Form 
within the trial database. All relevant sections of the form should be completed to ensure a 
comprehensive clinical report. The investigator is responsible for assessing and recording the 
relationship of each SAE to the protocol treatment. If the completed SAE Report cannot be done in the 
clinical trial database, a signed fax form can be sent to the safety desk within 24 hours. 
Safety Desk 
Holsterhauser Platz 2, 45147 Essen Germany 
Phone: +49 201 7494 96-0 
Fax: +49 201 8777 5484 
E-Mail: safety@gpoh-trials.org 
The FAX needs to include the patient´s pseudonymized patient ID and the main information regarding 
the SAE. The original SAE Report Form and fax confirmation sheet must be kept with the case report 
form documentation at the study site. In case of using fax, trial staff must enter the SAE report into the 
database as soon as possible. 
Follow-up information should be sent to the same contact(s) who received the original SAE Report Form, 
using a new form indicating it is a follow-up and referencing the date of the original report. Each 
recurrence, complication, or progression of the original event should be reported as a follow-up, 
regardless of when it occurs. The follow-up should detail whether the event has resolved or is ongoing, 
how it was treated, and whether the patient continued or withdrew from the study. 
The assessment of causality (relationship with the study medication: related/not related) and 
expectedness (expected/not expected) is essential to identify SUSARs (Suspected Unexpected Serious 
Adverse Reactions). This causality assessment must be performed by the reporting investigator and will 
be re-evaluated by the sponsor's delegate's representative. If the reporting investigator determines a 
potential causality, the sponsor's delegate's representative cannot downgrade this assessment; any 
discrepancies will be documented. All other events categorized as SUSARs will be reported within the 
legal timeframe. 
The sponsor will report individual events categorized as SUSARs to the EudraVigilance database. 
Timelines for SUSAR reporting are as follows: 
• 
initial fatal or life-threatening SUSARs will be reported to the competent authorities as soon as 
possible but no later than 7 calendar days from initial receipt of SAE by Sponsor. A completed 
follow-up will be submitted within an additional 8 calendar days. 
• 
all other SUSARs will be reported to the competent authorities as soon as possible but no later 
than 15 calendar days from initial receipt of SAE by Sponsor. 
 
All safety related information collected within the trial will be summarized in an Annual Safety Report 
(ASR) annually from the date of receipt of the first Clinical Trial Authorization for the trial to the 
submission of the End of Trial Declaration. This ASR will cover all IMPs, as due to consecutive 
administration of the IMPs, adverse events cannot be identified as related to a single IMP. 
 

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14.3. 
Serious Breach Reporting 
 
According to CTR 536/2014 any deviation of the approved protocol version or the clinical trial regulation 
that is likely to affect the safety, rights of trial participants and/or data reliability and robustness to a 
significant degree in a clinical trial needs to be reported as serious breach.  
The sponsor will perform the assessment of a (suspected) serious breach in a timely manner from the 
moment they have received this information.  
Reporting will be done by the sponsor or its delegated parties within seven calendar days after becoming 
aware via the clinical trial information system (CTIS). Sponsor will also report (suspected) serious 
breaches as defined above which occur outside the EU/EEA. 
14.4. 
Reporting of Pregnancy 
For subjects who receive protocol compliant treatment, pregnancies and suspected pregnancies 
(including a positive pregnancy test regardless of age or disease state) of a female subject occurring 
while the subject is on protocol compliant treatment or until EoT visit of the subject are considered 
immediately reportable events. In case that a pregnant patient is on protocol compliant treatment, the 
treatment is to be discontinued immediately.  
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Safety Desk 
immediately using the Pregnancy Initial Report Form.  
The female subject may be referred to an obstetrician-gynaecologist or another appropriate healthcare 
professional for further evaluation.  
The investigator will follow the female subject until completion of the pregnancy and must notify Safety 
Desk immediately about the outcome of the pregnancy (either normal or abnormal outcome) using the 
Pregnancy Follow-up Report Form.  
If the outcome of the pregnancy was abnormal (e.g., spontaneous abortion), the investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious criteria, it 
must be reported as an SAE in accordance with the details given in section 14.2.  
All neonatal deaths that occur within 28 days of birth should be reported, without regard to causality, as 
SAEs (“Other important medical event”). In addition, any infant death after 28 days that the investigator 
suspects is related to the in utero exposure to the protocol compliant treatment should also be reported 
to Safety Desk within 24 hours of the investigator’s knowledge of the event using the SAE Report Form. 
If a female partner of a male subject taking part in this trial becomes pregnant, the male being treated 
should notify the investigator, and the pregnant female partner should be advised to call their healthcare 
provider immediately. 
15. STATISTICAL CONSIDERATIONS  
The sections below describe the statistical methods as planned at time of protocol finalization. Statistical 
analyses will however be described in detail in a statistical analysis plan (SAP) which will be finalized 
before the enrolment of the first patient. 
15.1. 
Statistical Hypotheses  
No formal hypothesis will be stated and statistically tested. All parameters will be descriptively analysed 
using standard statistical methods. 
15.2. 
Sample Size Determination  
No formal sample size calculation has been undertaken for this phase I trial. In this dose-finding trial 
using a 3+3 design to determine the recommended phase II dose (RPD2) of dinutuximab beta in 
combination with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide, the sample 
size will be determined by the following steps: 
 

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Initial Dose Cohorts: 
• 
each dose level will start with 3 patients. 
 
The trial will follow the following Dose Escalation Rules: 
• 
if 0 out of 3 patients of the initial dose cohort at dose level 1 experience a dose-limiting toxicity 
(DLT), the trial will escalate to the next higher or highest dose level, depending on when CTC 
levels ≤1 or at least one CTC level =2 is present, respectively. 
• 
If 1 out of 3 patients experience a DLT, an additional 3 patients will be enrolled at the same 
dose level into an expansion cohort. 
• 
If 1 out of 6 patients experience a DLT, the dose escalation will proceed to the next level, if a 
higher level available. 
• 
If 2 or more out of 3 or 6 patients experience a DLT, the current dose will be considered above 
the MTD (maximum tolerated dose), and dose escalation will stop. The previous dose will be 
considered the RPD2. 
 
The trial will follow the following Stopping Rules: 
• 
  The trial will continue to enrol patients up to the maximum number of 6 patents per dose level 
and escalate doses until the MTD or RP2D is identified. 
Based on the guidelines for dose escalation and determination in section 10.2.3, the trial will enroll 
between n=3 and n=18 patients. 
 
15.3. 
Populations for Analyses 
 
 
15.3.1. 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) comprises all patients who have received at least one dose of dinutuximab 
beta. Patients will be categorized according to the treatment they were assigned to receive. The FAS 
will be used for all raw data listings.   
15.3.2. 
Safety Set (SAF) 
The safety set consists of all patients who have received at least one dose of any IMP and have at least 
one valid safety assessment after baseline. A statement indicating no adverse events (AEs) on the 
Adverse Event CRF qualifies as a valid safety assessment. 
For patients on the specified regimen, classification by dose level received will be as follows: 
1. the assigned dose level, if received at least once. 
2. The initial dose level received in the study, if the assigned dose level was never administered. 
As it is unlikely that a treated patient would provide no safety data at all; therefore, the Safety Set (SAF) 
should be equal to the Full Analysis Set (FAS). Typically, the FAS is equal to or a subset of the SAF, 
but it should never exceed the SAF.  
The FAS will be used for efficacy analyses, while the SAF will be used for safety analyses. 
15.3.3. 
Per-protocol set 
Not applicable. 

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15.3.4. 
Dose-Determining Analysis Set (DDS) 
The Dose Determining Set (DDS) includes all patients from the safety set who either meet the minimum 
exposure criterion with sufficient safety evaluations or discontinue early due to a dose-limiting toxicity 
(DLT). A patient is considered to have met the minimum exposure criterion if they have received at least 
1 full cycle out of the 5 planned treatment cycles.  
Patients who do not experience a DLT during the first cycle are considered to have sufficient safety 
evaluations if they have been observed for at least 21 days following the first dose and are deemed by 
both the Sponsor and Investigators to have enough safety data to conclude that a DLT did not occur. 
Patients failing to meet these minimum safety evaluation requirements will be regarded as ineligible for 
the DDS. DDS is to be considered as subset of SAF. 
15.4. 
General Approach 
 
The sponsor or a designated collaborator will analyse the data from this study. Any independent data 
analysis by the investigator must be submitted to GPOH prior to publication or presentation. The data 
will be summarized using descriptive statistics for quantitative data and contingency tables for qualitative 
data, covering demographic and baseline characteristics, efficacy observations and measurements, and 
safety observations and measurements. The analysis and reporting will include data from all patients 
up to the point when all have either completed the five treatment cycles or discontinued the study. 
Patients treated with the MTD, or RDE if different, during the dose escalation phase will be pooled with 
those receiving the same dose and regimen in the expansion cohort. A treatment group is defined by 
the dose level. 
15.5. 
Statistical Analyses 
 
Detailed statistics will be described in the statistical analysis plan (SAP).  
15.5.1. 
Study Treatment 
The clinical study report will detail the actual dose of dinutuximab beta and number of cycles of all 
protocol compliant treatment. Additionally, it will include the dose intensity, calculated as the ratio of the 
actual dose received to the actual duration, and the relative dose intensity, calculated as the ratio of 
dose intensity to the planned dose received and planned duration. These metrics will be listed and 
summarized using descriptive statistics. The summary data will be presented separately for each 
treatment cycle and collectively for all study days. The Full Analysis Set (FAS) will be utilized for these 
analyses. Definitions of actual dose and actual duration will be given in the SAP. 
15.5.2. 
Protocol Compliance 
Compliance with the protocol will be evaluated by counting and calculating the proportion of patients 
with protocol deviations. These deviations will be identified before the database lock, listed, and 
summarized accordingly. 
15.6. 
Analysis of the Primary Endpoint(s) 
 
The primary objective of this study is to determine the recommended dose of dinutuximab beta in 
combination with standard chemotherapy agents, based on the incidence of dose-limiting toxicities 
(DLTs) observed during the trial. The primary endpoint is the incidence of dose limiting toxicities (DLTs). 
Listing/summary of DLTs 
DLTs will be listed, and their incidence summarized by primary system organ class, worst grade based 
on the CTCAE version 5.0, type of adverse event (serious or non-serious), and by treatment. The DDS 
will be used for these summaries. 

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15.6.1. 
Handling of Missing Values, Censoring, and 
Discontinuations 
During dose-escalation, patients who are deemed ineligible for the dose-determining set may be 
replaced if necessary. However, patients in the safety expansion phase will not be replaced. 
Missing data will not be replaced. 
As of the data cut-off date for the primary Clinical Study Report (CSR) for reporting purposes: 
• 
patients continuing treatment: Time-to-event data related to response (e.g., progression-free 
survival) will be censored at the date of the last radiological disease assessment before the cut-
off date. 
• 
ongoing Events (e.g., Adverse Events): These will be summarized using the cut-off date as the 
date of completion, with an indication in the listings that the event is ongoing. 
For patients who discontinue the study while experiencing ongoing events related to secondary efficacy 
endpoints, these events will be censored at the discontinuation date. 
The reasons for study discontinuation will be summarized and listed, along with the dates of first and 
last dinutuximab beta administration, duration of exposure to dinutuximab beta, and the date of 
discontinuation for each patient. 
15.7. 
Analysis of the Secondary Endpoint(s)  
15.7.1. 
Early Efficacy signals 
The anti-tumor activity of dinutuximab beta in combination with standard chemotherapy agents will be 
assessed through centralized tumor response, using RECIST 1.1 criteria. This assessment will be 
summarized in terms of duration of response (DOR), event-free survival (EFS) and progression-free 
survival (PFS).  
Kaplan-Meier analyses of progression-free survival (PFS), event-free survival (EFS) and duration of 
response (DOR) will be conducted both overall and by dose level, provided there is a sufficient number 
of patients.  
15.8. 
Safety Analyses  
For all safety analyses, the safety set will be utilized. Unless specified otherwise, all listings and tables 
in the clinical study report will be presented by dose level, with patients classified according to the 
treatment received, as described in Section15.3. Data from patients in the expansion cohort will be 
combined with data from patients in the initial cohort who received the same dose. 
A minimum of safety analyses, at least SAE reporting, will be done for all patients, even if they were 
replaced and do not qualify for the safety set. This will be described in detail in the SAP. 
15.8.1. 
Analysis of Adverse Events (AEs) 
All adverse events (AEs) reported during the course of the study will be documented, assessed, and 
managed according to regulatory guidelines and institutional policies. An AE is defined as stated above. 
Adverse events will be systematically recorded and presented in the form of a line listing for thorough 
and clear analysis. The cumulative data will be analyzed periodically to identify any safety concerns or 
trends, and appropriate actions will be taken to ensure patient safety. 
 
Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and categorized by primary 
system organ class, type of adverse event, and treatment group. Additional collected information, such 
as start/end dates, duration of the adverse event, severity, or relation to the study medication, will be 
listed as appropriate. 

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15.8.2. 
Analysis of Laboratory Abnormalities 
All laboratory values will be converted into SI units where applicable, and their severity will be graded 
using CTCAE version 5.0. Parameters without existing CTCAE grading will be categorized as low, 
normal, or high based on laboratory normal ranges. 
For each laboratory test (e.g., hematology, biochemistry), a detailed listing of values will be provided, 
organized by laboratory parameter, patient, and dose level. The occurrence of significant lab 
abnormalities (newly occurring CTCAE grade 3 or 4 laboratory toxicities) will be reported by parameter, 
cycle, and dose level. Additionally, the frequency of all laboratory abnormalities will be tabulated by 
parameter, the worst CTCAE 5.0 grade experienced, and dose level. Laboratory data will be 
summarized using grade shift tables for parameters that can be classified according to CTCAE version 
5.0. Remaining data will be summarized using shift tables based on normal ranges. 
Laboratory data will also be presented through summary statistics of raw data and changes from 
baseline values, including means, medians, standard deviations, and ranges. 
15.8.3. 
Analysis of Tolerability 
The tolerability of dinutuximab beta in combination with standard chemotherapy agents will be evaluated 
by summarizing the frequency of tolerated cycles, dose interruptions and dose modifications. The 
reasons for these dose adjustments will be documented for each patient and then summarized. 
Additionally, cumulative dose, dose intensity, and relative dose intensity of dinutuximab beta will be 
listed and summarized for each patient. 
15.9. 
Planned Interim Analyses 
 
No formal interim analyses are planned. However, the dose-escalation design requires decisions to be 
made based on the current data before the study concludes. Specifically, after each cohort within the 
dose escalation levels, the decision is contingent on the observed data and needs to be taken and 
confirmed by the DSMC. 
The analyses necessary to discuss dose escalation with the DSMC do not constitute a temporary halt 
of the study in the regulatory sense and therefore will not be reported as such, even if recruitment has 
to be temporarily suspended for this reason. 
Exploratory analyses, including the analysis of exploratory endpoints, as well as any additional analyses, 
will be detailed in the Statistical Analysis Plan (SAP). 
16. DATA HANDLING AND RECORD KEEPING  
16.1. 
Data Management 
Data will be collected via case report forms (CRF) and entered into the clinical database. This 
information will be electronically verified using programmed edit checks defined by the clinical team. 
Any discrepancies identified in the data will be communicated to the clinical team and, if necessary, to 
the investigational site personnel. Resolutions to these issues will be documented and reflected in the 
database. 
As this trial is utilizing Electronic Data Capture (EDC), designated investigator staff will enter the 
protocol-required data usually directly into the Electronic Case Report Forms (eCRF). These eCRFs are 
constructed using fully validated, secure web-enabled software that adheres to 21 CFR Part 11 
requirements. Investigator site staff will receive training before gaining access to the EDC system.  
The Principal Investigator is responsible for ensuring that the data entered into the eCRF is complete, 
accurate, and updated in a timely manner. Besides the data entered into the eCRFs, requisition forms 
may also need to be completed for biomarker sample collection or imaging.  
Source Data Documentation 
In accordance with ICH E6 (R2) guidelines, all data entered into the electronic Case Report Form (eCRF) 
must be supported by corresponding source documentation recorded in the patient's medical records. 

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No data will be entered directly into the eCRF without prior written or electronic record in the source 
documents. 
This includes all clinical, laboratory, and procedural data collected during the study. Investigators are 
required to ensure that all data points reflected in the eCRF are substantiated by appropriate and 
contemporaneous entries in the patient's medical record or equivalent source documents, in line with 
the Good Clinical Practice (GCP) guidelines. 
The study does not foresee any instances where data would be recorded directly onto the eCRF without 
an associated source document. This policy applies uniformly across all study sites and for all data 
collection processes. 
16.2. 
Record Retention 
The investigator must retain all essential documents in accordance with local laws or requirements. 
Essential documents include, but are not limited to: 
• 
signed informed consent/assent documents for all subjects, 
• 
subject identification code list, screening log (if applicable), and enrolment log, 
• 
 approval letters of all local/national competent authorities and ECs, 
• 
record of all communications between the investigator, GPOH, and their authorized 
representative(s), 
• 
list of sub-investigators and other appropriately qualified persons to whom the investigator has 
delegated significant study-related duties, along with their roles in the study, curriculum vitae, 
and signatures, 
• 
copies of CRFs and documentation of corrections for all subjects, 
• 
investigational medical product (IMP) accountability records, 
• 
record of any retained body fluids or tissue samples, 
• 
all other source documents (subject records, hospital records, laboratory records, etc.), 
• 
all other documents as listed in Section 8 of the ICH (International Conference on 
Harmonization) consolidated guideline on GCP (Essential Documents for the Conduct of a 
Clinical Trial). 
The investigator must notify GPOH if they wish to assign the essential documents to someone else, 
relocate them, or are unable to retain them for a specified period. Written approval from GPOH must be 
obtained before destroying any records. If the investigator cannot meet this obligation, they must request 
permission from GPOH to make alternative arrangements and document the details of these 
arrangements. 
All study documents should be made available if required by relevant health authorities. Measures 
should be taken to prevent accidental or premature destruction of these documents. 
16.3. 
Archiving 
It is the responsibility of the Principal Investigator at each site to ensure all essential trial documentation 
and source records (e.g. signed Informed Consent Forms, Investigator Site Files, Pharmacy Files, 
patients’ hospital notes, copies of (e)CRFs etc.) at their site are securely retained the legally outlined 
period after the end of the trial. 
16.4. 
End of Trial Definition 
The trial will remain open until the date of the last patient’s last visit. The sponsor will notify the relevant 
Competent Authority and Ethics Committee that the trial has ended at the appropriate time and will 
provide them with a summary of the clinical trial report within 12 months of the end of trial. 
The sponsor confirms that for this trial which include minors, Regulation (EC) No 1901/2006 Article 41, 
Para. 2; Guideline 2009/C 28/01 EC 4.2 as well as Ethical Considerations for Clinical Trials on Medicinal 

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Products Conducted with the Paediatric Population, Final 2008, 19.1, apply, with possibly shorter 
timelines to submit the clinical study report, in case that is necessary by this legal background. 
17. OPERATIONAL CONSIDERATIONS 
17.1. 
Regulatory, Ethical, and Study Oversight Considerations  
The accepted basis for the conduct of clinical trials in humans is founded on the protection of human 
rights and the dignity of human beings regarding the application of biology and medicine and requires 
compliance with the principles of GCP and detailed guidelines in line with those principles. GCP is a set 
of internationally recognized ethical and scientific quality requirements which must be observed for 
designing, conducting, recording and reporting clinical trials that involve the participation of human 
subjects. Compliance with GCP provides assurance that the rights, safety and well-being of trial subjects 
are protected, and that the results of the clinical trials are credible. All involved parties agreed on GCP 
principles, especially in line with Art. 47 Eu No. 536/2014. 
All involved parties shall consider all relevant guidance and applicable laws with respect to commencing 
and conducting a clinical trial. 
The conduct of the trial shall be based on the following international ethical and statutory sources: 
• 
the WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human 
Subjects,  
• 
if the region has adopted the Convention for the Protection of Human Rights and Dignity of the 
Human Being regarding the Application of Biology and Medicine: Convention on Human Rights 
and Biomedicine (CETS No.: 164), 
• 
regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on 
clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, 
• 
directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good 
clinical practice as regards investigational medicinal products for human use, as well as the 
requirements for authorization of the manufacturing or importation of such products (Official 
Journal L 91, 09/04/2005 P. 0013 – 0019), 
• 
directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the 
protection of individuals with regard to the processing of personal data and on the free 
movement of such data (Official Journal L 281, 23/11/1995 P. 0031 – 0050), 
• 
scientific guidelines relating to the quality, safety and efficacy of medicinal products for human 
use, as agreed upon by the CHMP and published by the Agency, as well as the other 
pharmaceutical Community guidelines published by the Commission in the different volumes of 
the rules governing medicinal products in the European Community (Directive 2005/28/EC (9)). 
 
17.1.1. 
Statement on the future use of biological samples  
The compliance with the applicable regulations for the future use of biological samples from clinical trial 
subjects will be made overall according to  
• 
regulation [EU] No 536/2014 Annex I, section D, No. 17, lit. s  
• 
the WMA Declaration of Taipei on ethical considerations regarding health databases and 
biobanks 
As the future use of biological samples from clinical trial subjects will be regulated according to the given 
ICFs, the patient information sheet covers national legal requirements, which may apply. 
 

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17.2. 
Study Discontinuation and Closure 
 
 
Additionally, to the criteria described in section 13 of this protocol, the following events, if applicable, 
will/must cause premature termination of the clinical trial: 
a) unjustifiable risk and/or toxicity in risk-benefit analysis (decision taken by sponsor), e.g. when 
adverse events occur, unknown to date in respect of their nature, severity, duration or frequency 
in relation to the current established safety profile (substantial changes in risk-benefit 
considerations), and therefore medical and/or ethical reasons affect the continued performance 
of the trial; 
 
b) new scientific evidence becomes available during the study that could affect the patient's safety 
(benefit-risk analysis no longer positive), e.g. new insights from other clinical trials; 
 
c) request of the sponsor or regulatory agency, e.g. as a consequence of monitoring or inspection; 
favourable opinion withdrawn by ethics commission the clinical trial as a whole, either in all 
participating countries or also in a specific participating country;  
 
d) in case of difficulties in the recruitment of the planned number of subjects in the indicated time 
(insufficient recruitment rate); 
 
e) permanently unavailability of an IMP or withdrawal of the license to manufacture or of the 
permission to import an IMP. 
 
The decision will be made by the sponsor or its representatives in consultation with the DSMC.  If there 
is an imminent risk of harm to the enrolled patients, the sponsor will immediately discontinue the 
enrolment and verify the applicability of the above listed criteria. 
 
17.2.1. 
Temporary Halt 
 
According to Expert Group on Clinical Trials: “Regulation (EU) No 536/2014 Questions & Answers”, 
May 2022, Nos. 427-429 
A temporary halt implies that the sponsor makes unforeseen stops of this clinical trial activity of a sub 
study described in the protocol (i.e. recruitment only or recruitment and treatment) or its sub studies 
(cohorts) or a cohort (arm), due to unexpected circumstances that could affect the benefit/risk ratio or 
not. In case of safety issues subjects need to be monitored/followed up, please refer to the respective 
protocol sections.  
During the temporary halt the issues of concern are assessed together with the need for possible 
changes in the clinical trial. After this analysis is completed, and reassurance that any potential 
problem may be solved or mitigated, the sponsor could either restart or end the clinical trial or its sub 
studies (cohorts) or a cohort (arm).  
In case the reasons for the temporary halt have the potential to affect the benefit/risk balance (i.e. 
concern related to safety, lack of efficacy or IMP quality defect), the sponsor will request a restart of 
the clinical trial or its sub studies (cohorts) or a cohort (arm) through a substantial modification subject 
to authorization, providing the justification for the restart, including conclusions of the analysis, the 
mitigation measures if applicable and an updated benefit/risk assessment.  
A restart will be considered as substantial modification.  
The protocol compliant conduct of this clinical trial as it is described in section 15.9 is not affected by 
this section. 
 

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17.3. 
Confidentiality and Privacy  
GPOH affirms the subject's right to protection against invasion of privacy and to be in compliance with 
ICH and other local regulations (whichever is most stringent). GPOH requires the investigator to 
permit GPOH´s representatives and, when necessary, representatives from regulatory authorities, to 
review and/or copy any medical records relevant to the study in accordance with local laws.  
Should direct access to medical records require a waiver or authorization separate from the subject’s 
signed informed consent/assent document, it is the responsibility of the investigator to obtain such 
permission in writing from the appropriate individual.  
Personal data of all subjects i.e. date of birth and data regarding the disease, treatment and follow-
up will be collected. All investigational materials and data will be pseudonymized in accordance with 
data protection legislation before scientific processing. The investigators and all members of a site or 
other persons involved in the study are obliged to keep study data and information confidential. 
Access to data is strictly limited to authorized persons. All legal requirements concerning the safety 
and confidentiality of data and prevention of data loss will be respected. All involved individuals are 
sworn to secrecy. Subjects will be informed that their pseudonymized data will be passed on in 
accordance with the documentation and notification obligations pursuant to GCP requirements to the 
recipients described there. Subjects who do not agree that the information may be passed on in this 
way will not be enrolled into the trial. All international and national data protection laws will be 
considered in the respective countries. 
Details will be described in the data protection concept. 
A description of measures that will be implemented in case of data security breach to mitigate the 
possible adverse effects required by Regulation [EU] No 536/2014 Annex I, section D, No. 7, lit. am. 
outlined in Appendix 3. 
17.4. 
Key Roles and Study Governance  
17.4.1. 
Sponsor   
The German Society of Pediatric Oncology and Hematology (GPOH) is the Sponsor for this clinical 
trial. In addition, the GPOH will transfer different responsibilities to a qualified CRO.   
17.4.2. 
Data Safety Monitoring Committee (DSMC)   
Such a committee has been installed. Members of the DSMC are experienced researchers not 
involved in the trial who will be responsible for providing the principal investigators with guidance on 
the trial conduction and, in case of problems, on whether the trial should be stopped, modified or 
continued (for details see the DSMC Charter in its actual version).  
The DSMC closed meetings will take place at least once a year through e-mail communications and 
possibly conference calls. Additional meetings will be possible and can be scheduled in case the 
DSMC judges that these are needed.  
The DSMC will receive from the trial statistician a report at time intervals defined in the charter, starting 
from the international birthday of the clinical trial. All reports will be focused on recruitment/trial 
integrity and safety, as well as patient safety and quality of trial..  
Before reporting on the safety and results of the trial the DSMC will consider not only the interim 
results of the study but also any major new information from other sources considered to be relevant 
to the trial. In this perspective, the DSMC will be guided by the pre-assigned statistical rules for dose 
modification stated in this protocol but will not apply them automatically.  
The DSMC will be set up according to EMEA/CHMP/EWP/5872/03 Corr. 
  

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17.4.3. 
Quality Management  
All aspects of the study will be carefully monitored by GPOH or its authorized representative for 
compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.  
 
17.4.4. 
Clinical Monitoring 
 
All aspects of the study will be carefully monitored by GPOH or its authorized representative for 
compliance with applicable government regulations with respect to current GCP and standard 
operating procedures. 
GPOH ensures that appropriate monitoring procedures are performed before, during and after the 
study. All aspects of the study are reviewed with the investigator and the staff at a study initiation visit, 
conference call and/or at an investigator meeting.   
Monitoring will include on-site visits with the investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone. During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the GPOH representative in accordance with the Study 
Monitoring Plan.  
Accuracy will be checked by performing source data verification that is a direct comparison of the 
entries made onto the CRFs against the appropriate source documentation. Any resulting 
discrepancies will be reviewed with the investigator and/or his/her staff. Any necessary corrections 
will be made directly to the CRFs or via queries by the investigator and/or his/her staff. Monitoring 
procedures require that informed consent/assents, adherence to inclusion/exclusion criteria and 
documentation of SAEs and their proper recording be verified. Additional monitoring activities may be 
outlined in a study-specific monitoring plan.  
 
17.4.5. 
Quality Assurance and Quality Control 
Each clinical site will conduct internal quality management for conduct, data collection, biological 
specimen collection, documentation, and completion. A tailored quality management plan will be 
developed to outline the trials specific quality management procedures. 
Quality control (QC) procedures will be implemented, starting with the data entry system, and data 
QC checks will be run on the generated database. Any missing data or anomalies will be 
communicated to the respective site(s) for clarification and resolution. 
Monitors will follow written Standard Operating Procedures (SOPs) to verify that the clinical trial is 
conducted, data is generated, and biological specimens are collected, documented, and reported in 
compliance with the protocol, International Conference on Harmonization Good Clinical Practice (ICH 
GCP), and applicable regulatory requirements such as Good Laboratory Practices (GLP) and Good 
Manufacturing Practices (GMP). 
The investigational site will provide direct access to all trial-related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
17.5. 
Publication and Data Sharing Policy 
 
The definition and scope of work for a new manuscript, abstract, poster, oral presentation, or other 
publication should be determined by the sponsor, the lead author, with input from the Study 
statistician(s) and DSMC and further team members as appropriate. All proposed publications must fulfil 
ethics and GCP criteria. 

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Guidelines for multi-centre publication of a study under the terms of this protocol: 
The lead author shall determine the appropriate co-authors of the Study in accordance with ICMJE 
guidelines for authorship (http://www.icmje.org/icmje-recommendations.pdf).  The author/co-author 
must:  
• 
demonstrate substantial contributions to the conception or design of the proposed publication; 
or the acquisition, analysis, or interpretation of data for the proposed publication; and  
• 
participate in drafting the proposed publication or revising it critically for important intellectual 
content; and  
• 
give final approval of the version to be published; and  
• 
agree to be accountable for all aspects of the proposed publication in ensuring that questions 
related to the accuracy or integrity of any part of the proposed publication are appropriately 
investigated and resolved.  
Each author is expected to comply with their own institutional authorship guidelines and collaborative 
group guidelines. 
Authorship of multi-centre publication of Study under the terms of this protocol: 
Shared first authorship for Investigators participating in the study should be the goal of each manuscript.  
Listing of other authors should be based on contribution and confirmed by the Sponsor.  Senior 
authorship will be shared by the lead Investigators overseeing the study and should be confirmed at the 
completion of enrolment. The study statistician and anyone responsible for ancillary studies 
(pharmacology, biology) whose results are reported in the publication should be considered for 
authorship. All participating sites who register at least one subject on study should be listed as an annex 
of the publication. If third parties have played a substantial role in the concept of the study, having one 
representative author is to be discussed.  
 
 

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I. APPENDIX 1 LANSKY AND ECOG SCALE 
LANSKY SCALE FOR PATIENTS <16 YEARS OF AGE (LANSKY ET AL., 1987) 
Performance status 
Definition 
100 
Fully active, normal 
90 
Minor restrictions in strenuous physical activity 
80 
Active, but gets tired more quickly 
70 
Greater restriction of play and less time spent in play activity 
60 
Up and around, but active play minimal; keeps busy by being involved in 
quieter activities 
50 
Lying around much of the day, but gets dressed; no active playing 
participates in all quiet play and activities 
40 
Mainly in bed; participates in quiet activities 
30 
Bedbound; needing assistance even for quiet play 
20 
Sleeping often; play entirely limited to very passive activities 
10 
Doesn't play; does not get out of bed 
0 
Unresponsive 
 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS FOR PATIENTS ≥16 YEARS 
OF AGE (ZUBROD ET AL., 1960) 
Performance status  
Definition 
0  
Fully active; no performance restrictions. 
1  
Strenuous physical activity restricted; fully ambulatory and able to carry 
out light work. 
2  
Capable of all self-care but unable to carry out any work activities. Up 
and about >50% of waking hours. 
3  
Capable of only limited self-care; confined to bed or chair >50% of 
waking hours. 
4  
Completely disabled; cannot carry out any self-care; totally confined to 
bed or chair. 
5 
Dead 
 
 

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II. APPENDIX 2 PROTOCOL CONTENT ACCORDING TO ANNEX 1 
(EU) NO 536/2014 
 
Protocol section/ 
Comment 
The protocol shall be identified by: 
 
• 
the title of the clinical trial; 
Title page; protocol 
information; synopsis 
• 
the EU trial number; 
• 
the sponsor's protocol code number specific for all versions of it (if 
relevant); 
• 
the date and number of the version, to be updated when it is 
amended; 
• 
a short title or name assigned to the protocol; and 
• 
the name and address of the sponsor, as well as the name and 
function of the representative or representatives of the sponsor 
authorised to sign the protocol or any substantial modification to 
the protocol. 
 
Protocol information 
The protocol shall, when possible, be written in an easily accessible 
and searchable format, rather than scanned images. 
 
Protocol is a converted 
document and OCR 
compliant 
The protocol shall at least include: 
 
• 
a statement that the clinical trial is to be conducted in compliance 
with the protocol, with this Regulation and with the principles of 
good clinical practice; 
Regulatory, ethical 
and study oversight 
• 
a comprehensive list of all investigational medicinal products and 
of all auxiliary medicinal products 
 
Investigational 
medicinal product 
• 
a summary of findings from non-clinical studies that potentially 
have clinical significance and from other clinical trials that are 
relevant to the clinical trial 
 
Background 
• 
a summary of the known and potential risks and benefits including 
an evaluation of the anticipated benefits and risks to allow 
assessment in accordance with Article 6; for subjects in a clinical 
trial in an emergency situation, the scientific grounds for expecting 
that the participation of the subjects has the potential to produce a 
direct clinically relevant benefit shall be documented 
 
Assessment of 
potential risks and 
burden 
• 
where patients were involved in the design of the clinical trial, a 
description of their involvement 
 
Not applicable  
• 
a description of, and justification for, the dosage, the dosage 
regime, the route and mode of administration, and the treatment 
period for all investigational medicinal products and auxiliary 
medicinal products 
Justification for dosing 
• 
a statement of whether the investigational medicinal products and 
auxiliary medicinal products used in the clinical trial are authorised; 
if authorised, whether they are to be used in the clinical trial in 
accordance with the terms of their marketing authorisations, and, if 
not authorised, a justification for the use of non-authorised auxiliary 
medicinal products in the clinical trial 
Investigational 
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• 
a description of the groups and subgroups of the subjects 
participating in the clinical trial, including, where relevant, groups of 
subjects with specific needs, for example. age, gender, 
participation of healthy volunteers, subjects with rare and ultra-rare 
diseases 
 
Study design; 
Rationale for the 
inclusion of minors 
• 
references to literature and data that are relevant to the clinical trial, 
and that provide background for the clinical trial 
References 
• 
a discussion of the relevance of the clinical trial to allow 
assessment in accordance with Article 6; 
Study rationale; 
Background; 
Risk/Benefit 
Assessment 
• 
a description of the type of clinical trial to be conducted and a 
discussion of the trial design (including a schematic diagram of trial 
design, procedures and stages, if relevant) 
Overall Design 
• 
a specification of the primary endpoints and the secondary 
endpoints, if any, to be measured during the clinical trial 
Objectives and 
endpoints 
• 
a description of the measures taken to minimise bias, including, if 
applicable, randomisation and blinding 
TBD 
• 
a description of the expected duration of subject participation and 
a description of the sequence and duration of all clinical trial 
periods, including follow-up, if relevant 
Synopsis (trial 
duration) 
• 
a clear and unambiguous definition of the end of the clinical trial in 
question and, if it is not the date of the last visit of the last subject, 
a specification of the estimated end date and a justification thereof; 
Synopsis; End of trial 
definition 
• 
a description of the criteria for discontinuing parts of the clinical trial 
or the entire clinical trial; 
Study intervention 
discontinuation and 
participant 
discontinuation 
• 
arrangements for the maintenance of clinical trial treatment 
randomisation codes and procedures for breaking codes, if 
relevant; 
Not applicable 
• 
a description of procedures for the identification of data to be 
recorded directly on the Case Report Forms considered as source 
data; 
Data handling and 
record keeping 
• 
a description of the arrangements to comply with the applicable 
rules for the collection, storage and future use of biological samples 
from clinical trial subjects, where applicable, unless contained in a 
separate document 
Statement on the 
future use of biological 
samples 
• 
a description of the arrangements for tracing, storing, destroying 
and 
returning 
the 
investigational 
medicinal 
product 
and 
unauthorised auxiliary medicinal product in accordance with Article 
51 
Preparation and 
precautions for 
disposal 
A description of the statistical methods to be employed, including, if 
relevant: 
 
• 
timing of any planned interim analysis and the number of subjects 
planned to be enrolled; 
Planned interim 
analyses 
• 
reasons for choice of sample size; 
Sample size 
determination 
• 
calculations of the power of the clinical trial and clinical relevance; 
Statistical 
considerations 
• 
the level of significance to be used; 

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• 
criteria for the termination of the clinical trial; 
Dose-limiting toxicities 
• 
procedures for accounting for missing, unused, and spurious data 
and for reporting any deviation from the original statistical plan; and 
Handling of missing 
values 
• 
the selection of subjects to be included in the analyses; 
Populations for 
analyses 
A description of the subject inclusion and exclusion criteria, 
including criteria for withdrawing individual subjects from treatment 
or from the clinical trial. 
Study population 
A description of procedures relating to the withdrawal of subjects 
from treatment or from the clinical trial including procedures for the 
collection of data regarding withdrawn subjects, procedures for 
replacement of subjects and the follow-up of subjects that have 
withdrawn from treatment or from the clinical trial. 
 
Study intervention 
discontinuation and 
participant 
discontinuation 
A justification for including subjects who are incapable of giving 
informed consent or other special populations, such as minors. 
 
Rationale for the 
inclusion of minors 
A justification for the gender and age allocation of subjects and, if a 
specific gender or age group is excluded from or underrepresented 
in the clinical trials, an explanation of the reasons and justification 
for these exclusion criteria. 
 
Only age below 12 
months excluded 
A detailed description of the recruitment and informed consent 
procedure, especially when subjects are incapable of giving 
informed consent. 
 
Screening and 
informed consent 
A description of the treatments, including medicinal products, which 
are permitted or not permitted, before or during the clinical trial. 
 
Concomitant therapy 
A description of the accountability procedures for the supply and 
administration of medicinal products to subjects including the 
maintenance of blinding, if applicable. 
 
Not applicable 
A description of procedures for monitoring subject compliance, if 
applicable. 
 
Not applicable 
A description of arrangements for monitoring the conduct of the 
clinical trial. 
 
Clinical monitoring 
A description of the arrangements for taking care of the subjects 
after their participation in the clinical trial has ended, where such 
additional care is necessary because of the subjects' participation in 
the clinical trial and where it differs from that normally expected for 
the medical condition in question. 
 
Follow-up for toxicities 
A specification of the efficacy and safety parameters as well as the 
methods and timing for assessing, recording, and analysing these 
parameters. 
 
Safety monitoring and 
reporting 
A description of ethical considerations relating to the clinical trial if 
those have not been described elsewhere. 
 
Regulatory, ethical 
and study oversight 
A statement from the sponsor (either in the protocol or in a separate 
document) confirming that the investigators and institutions 
Separate document: 
financial arragement 

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involved in the clinical trial are to permit clinical trial-related 
monitoring, audits and regulatory inspections, including provision of 
direct access to source data and documents. 
 
(within site 
agreements) 
A description of the publication policy. 
Publication and data 
sharing policy 
Duly substantiated reasons for the submission of the summary of 
the results of the clinical trials after more than one year. 
 
Not applicable. 
A description of the arrangements to comply with the applicable 
rules on the protection of personal data; in particular organisational 
and technical arrangements that will be implemented to avoid 
unauthorised access, disclosure, dissemination, alteration or loss of 
information and personal data processed 
 
Appendix: Description 
of measures in case of 
data security breach 
A description of measures that will be implemented to ensure 
confidentiality of records and personal data of subjects 
 
A description of measures that will be implemented in case of data 
security breach in order to mitigate the possible adverse effects 
 
If a clinical trial is conducted with an active substance available in the 
Union under different trade names in a number of authorised 
medicinal products, the protocol may define the treatment in terms of 
the active substance or Anatomical Therapeutic Chemical (ATC) code 
(level 3-5) only and not specify the trade name of each product. 
 
Declaration of IMP and 
AxMP 
With regard to the notification of adverse events, the protocol shall 
identify 
the 
categories 
of: 
 
 
• 
adverse events or laboratory anomalies that are critical to safety 
evaluations and must be reported by the investigator to the 
sponsor, and 
Definition and 
reporting of adverse 
events 
• 
serious adverse events which do not require immediate reporting 
by the investigator to the sponsor. 
Definition and 
reporting of serious 
adverse events 
The 
protocol 
shall 
describe 
the 
procedures 
for: 
 
 
• 
eliciting and recording adverse events by the investigator, and the 
reporting of relevant adverse events by the investigator to the 
sponsor; 
Definition and 
reporting of adverse 
events 
• 
reporting by the investigator to the sponsor of those serious 
adverse events which have been identified in the protocol as not 
requiring immediate reporting; 
Definition and 
reporting of serious 
adverse events 
• 
reporting of suspected unexpected serious adverse reactions by 
the sponsor to the Eudravigilance database; and 
Serious adverse event 
reporting 
• 
follow-up of subjects after adverse reactions including the type and 
duration of follow-up. 
Definition and 
reporting of adverse 
events 
In case the sponsor intends to submit a single safety report on all 
investigational medicinal products used in the clinical trial in 
accordance with Article 43(2), the protocol shall indicate the reasons 
Reporting of serious 
adverse events 

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thereof. 
 
Issues regarding labelling and the unblinding of investigational 
medicinal products shall be addressed in the protocol, where 
necessary. 
Formulation, 
Appearance, 
Packaging, and 
Labelling 
The protocol shall be accompanied by the Charter of the Data Safety 
Monitoring Committee, if applicable. 
DSMC Charter 
submitted as separate 
document 
The protocol shall be accompanied by a synopsis of the protocol 
Synopsis 
 
 

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III. APPENDIX 3 - DESCRIPTION OF MEASURES IN CASE OF DATA 
SECURITY BREACH 
The sponsor and/or its representatives provide organizational, contractual, and technical security 
measures to guarantee the protection of patient’s privacy. Therefore, to provide safeguards for 
organizational risks, a set of dataflow rules and processes have been established. Those include:  
 
Organizational measures  
• 
Internal guidelines and policies, that define what data use is allowed and prohibited. The 
supervision of queries to patient related data sets will be always performed by the sponsor or 
its representatives.  
 
• 
Processes ensuring controlled environment of data handling, which guarantees data’s 
traceability. The quality of the trial data, appropriate to the proposed objectives, and the absence 
of identifiers will be checked by the sponsor or its representatives.  
 
Contractual measures  
• 
Agreements with data providers are regulated by means of a contract. The contractual 
relationship established between data providers and the sponsor, or its representatives sets out 
the conditions for the use of the data and exploitation by the third parties in comply with the 
contracts minimum content established by the GDPR.  
 
Technical measures  
To prevent access to data, sets of measures implementing several restrictions are established. These 
effective means guarantee that datasets within all trial related data bases will not be linked or combined 
to the original datasets within the data provider. Technical controls include safeguards and 
countermeasures, for an information system that are implemented and executed primarily by the 
information system through mechanisms contained in the system’s software, hardware or firmware 
components.  
• 
Access control includes access control policy, procedures and enforcement, account 
management, information flow enforcement, separation of duties, least privilege, unsuccessful 
logon attempts, system use notification, concurrent session control, session lock, session 
termination, permitted actions without identification or authentication, remote access, wireless 
access, access control for mobile devices, use of external information systems, information 
sharing, publicly accessible content. 
 
• 
Physical (access keys) and electronic (personal tag) – established policy, procedures and 
controlled mechanisms to access the security perimeters where the trial-related data bases or 
data sets are set. Employees must go through the registration process, which includes 
specifying identity (name, employer organization), dates and duration of access (start and end 
time) to grant a specific access authorization.  
 
• 
Network and host access controls - only authorized employees and registered users are granted 
access to the network and servers with the absolute minimum permissions necessary to perform 
their duties. The information system enforces a limit of consecutive invalid log in attempts by a 
user and automatically locks the account/node until released by an administrator; delays next 
log in, when the maximum number of unsuccessful attempts is exceeded. Additionally, all 
access to high-security servers is monitored and logged, with access logs stored on a dedicated 
log server. Access to servers and program source code is controlled and granted only to 

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authorized entities. Special procedures are in place for assigning passwords and creating and 
managing users during operations.  
 
• 
Network communication protection - the information security system has only the most important 
ports open for incoming and outgoing communications, with all traffic filtered by a switch firewall.  
 
• 
Security monitoring - will be assessed using software and new information from reliable sources. 
Any newly discovered security vulnerability will be logged on the management site, assigned to 
a responsible person and resolved as soon as possible. Proper risk assessment will be 
performed in accordance with risk assessment procedures. Continuous monitoring program 
facilitate ongoing awareness of vulnerabilities, threats and information security to support risk 
management decisions. The security controls and information security-related risks are 
analyzed at a frequency sufficient to support organizational risk-based decisions. The results of 
continuous monitoring programs generate appropriate risk response actions and allow to 
maintain the security authorizations over time with changing program needs, threats, 
vulnerabilities, and technologies. Having access to security-related information on a continuing 
basis through reports and frequent updates to security authorization packages, hardware, 
software, firmware inventories, and other system information gives the capability to make more 
effective and timely risk management decisions, including ongoing security authorization 
decisions. 
 
In case of data security breaches all organizational, contractual, and technical security measures to 
guarantee the protection of patient’s privacy will be reassessed to mitigate the possible adverse effects. 
 
 

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