Clinical trial NCT04560166
Conditions: Neuroblastoma Recurrent
Sponsor: Y-mAbs Therapeutics
Start date: 2021-11-08; Completion date: 2022-09-21
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
An International, Single-Arm, Multicenter Phase 2 Trial.

Detailed description:
This is an international, single-arm, multicenter phase 2 trial, in patients ≥ 12 months of age with high-risk NB with primary refractory disease or in first relapse. Patients will receive naxitamab + GM-CSF + irinotecan/temozolomide. The Follow-Up period ends 2 years after End of Treatment.

Arms: arm 1: A treatment cycle is 21 days. The patients will receive irinotecan 50 mg/m2/day IV and temozolomide 100 mg/m2/day orally (both on Days 1-5) in combination with naxitamab 2.25 mg/kg/day IV (Days 2, 4, 8 and 10) (total 9 mg/kg per cycle), and GM-CSF 250 ug/m2/day sc, (Days 6-10).

Patients will receive up to 18 IT cycles after enrollment. Naxitamab and GM-CSF will be given for at least 8 cycles.
Interventions: intervention 1: Naxitamab and GM-CSF in combination with irinotecan and temozolomide
Intervention descriptions: intervention 1: * Irinotecan, solution for infusion (20 mg/mL)
* Temozolomide, capsules (5 mg, 20 mg and 100 mg)
* The humanized immunoglobulin isotype G (IgG1) monoclonal antibody (mAb) naxitamab, solution for infusion (4 mg/mL)
* Sargramostim (GM-CSF), lyophilized 250 µg single use vial (250 µg/vial)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
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Clinical Trial Protocol
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CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
Naxitamab and Granulocyte-Macrophage Colony Stimulating Factor in 
Combination with Irinotecan and Temozolomide in Patients with High-Risk 
Neuroblastoma with Primary Refractory Disease or in First Relapse. An 
International, Single-Arm, Multicenter Phase 2 Trial 
 
 
Clinical Trial ID: 203 
EudraCT No: 2020-003068-21   
IND No: 132793 
Version 4.0_16-Nov-2021 
 
 
 
 
This trial protocol is the property of Y-mAbs Therapeutics A/S and is a confidential document. It is not 
to be copied or distributed to other parties without written approval from Y-mAbs Therapeutics A/S. 


 
 
 
 
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Approval of Clinical Trial Protocol 
 
 Protocol Author 
 
 
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Y-mAbs Therapeutics A/S 
 
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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................. 9 
2 
PROTOCOL SYNOPSIS .................................................................................................. 14 
3 
FLOW CHART .................................................................................................................. 19 
4 
INTRODUCTION .............................................................................................................. 22 
4.1 
Medical Background ....................................................................................................... 22 
4.2 
Rationale for antibody therapy for High-Risk NB .......................................................... 22 
4.3 
Naxitamab profile ............................................................................................................ 23 
4.3.1 
Non-clinical data for naxitamab ................................................................................. 23 
4.3.2 
Clinical data for naxitamab......................................................................................... 23 
4.3.3 
Choice of chemotherapy regimen as backbone treatment .......................................... 25 
4.3.4 
Combining naxitamab with irinotecan and temozolomide ......................................... 26 
4.3.5 
Naxitamab dose selection and infusion rate ............................................................... 27 
4.3.6 
Use of GM-CSF in combination with naxitamab ....................................................... 27 
4.3.7 
Choice of trial population ........................................................................................... 28 
4.3.8 
Choice of trial design .................................................................................................. 28 
4.4 
Benefit-risk assessment ................................................................................................... 28 
5 
TRIAL OBJECTIVES ....................................................................................................... 30 
5.1 
Primary Objective ........................................................................................................... 30 
5.2 
Secondary Objective ....................................................................................................... 30 
6 
ENDPOINTS ...................................................................................................................... 31 
6.1 
Primary Endpoint ............................................................................................................ 31 
6.2 
Secondary Endpoints ....................................................................................................... 31 
6.3 
Exploratory Endpoints..................................................................................................... 32 
7 
DESCRIPTION OF DESIGN AND TRIAL POPULATION ........................................ 33 
7.1 
Overall Trial Design ........................................................................................................ 33 
7.2 
Overall Trial Plan ............................................................................................................ 33 
7.2.1 
Treatment .................................................................................................................... 33 
7.3 
Recruitment Period .......................................................................................................... 34 
7.4 
Screening/Pre-treatment Evaluation ................................................................................ 34 
7.5 
Patient Replacement ........................................................................................................ 34 
7.6 
Screening Failures and Re-screening .............................................................................. 34 
7.7 
Enrollment ....................................................................................................................... 35 
7.8 
Follow-up ........................................................................................................................ 35 
7.9 
End of Trial ..................................................................................................................... 35 
7.10 
Number of Patients .......................................................................................................... 35 
7.11 
Patient Selection .............................................................................................................. 35 
7.11.1 
Inclusion Criteria ........................................................................................................ 36 
7.11.2 
Exclusion Criteria ....................................................................................................... 37 
7.12 
Premature Discontinuation of Treatment ........................................................................ 38 
7.13 
Withdrawal ...................................................................................................................... 40 


 
 
 
 
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TREATMENTS .................................................................................................................. 41 
8.1 
Investigational Medicinal Products (IMPs)..................................................................... 41 
8.1.1 
Administration of IMP for Each Patient ..................................................................... 41 
8.1.2 
Treatment schedule ..................................................................................................... 41 
8.1.2.1 
Temozolomide ....................................................................................................... 42 
8.1.2.2 
Irinotecan ............................................................................................................... 42 
8.1.2.3 
Naxitamab .............................................................................................................. 42 
8.1.2.4 
GM-CSF................................................................................................................. 43 
8.1.3 
Treatment delays and missed dosing .......................................................................... 43 
8.1.4 
Treatment after Discontinuation of IMP .................................................................... 44 
8.1.5 
Drug Accountability and Compliance Check ............................................................. 44 
8.1.6 
Packaging and Labelling ............................................................................................ 44 
8.1.7 
Storage and Handling ................................................................................................. 44 
8.2 
Medication Errors, Misuse and Abuse ............................................................................ 45 
8.3 
Technical complaint ........................................................................................................ 45 
8.4 
Concomitant Therapy ...................................................................................................... 45 
8.4.1 
Pre-medications Prior to Naxitamab Infusions ........................................................... 46 
8.4.2 
Supportive therapy to be readily available during naxitamab .................................... 48 
8.4.3 
Pre-medication prior to administration of irinotecan ................................................. 48 
8.4.4 
Management of selected IT adverse reactions ............................................................ 49 
8.4.4.1 
Management of hematologic toxicities .................................................................. 49 
8.4.4.2 
Management of non-hematologic toxicities .......................................................... 50 
8.4.5 
Management of selected naxitamab adverse reactions ............................................... 51 
8.4.5.1 
Management of bronchospasm and hypoxia ......................................................... 51 
8.4.5.2 
Management of hypotension .................................................................................. 51 
8.4.5.3 
Management of hypertension................................................................................. 52 
8.4.5.4 
Management of infusion-related reactions ≥ CTCAE Grade 2, other than hypoxia, 
bronchospasm, hypotension, and hypertension ..................................................... 53 
8.4.6 
Management of GM-CSF (sargramostim) Adverse Reactions................................... 54 
8.4.7 
Therapy and Procedures Allowed During Trial ......................................................... 54 
8.4.8 
Prohibited Therapy/Procedures During the Trial ....................................................... 54 
9 
PROCEDURES AND ASSESSMENTS ........................................................................... 56 
9.1 
Efficacy Assessments ...................................................................................................... 56 
9.1.1 
Response Assessments ............................................................................................... 56 
9.1.1.1 
Response assessment of BM MRD43: .................................................................... 58 
9.1.2 
Timing of response assessment .................................................................................. 59 
9.2 
Safety Assessment ........................................................................................................... 59 
9.2.1 
Physical Examination ................................................................................................. 59 
9.2.2 
Vital Signs .................................................................................................................. 59 
9.2.3 
Naxitamab Discharge Criteria .................................................................................... 60 
9.2.4 
Echocardiography ....................................................................................................... 60 
9.2.5 
Pulmonary Function Test and Oxygen Saturation ...................................................... 60 
9.2.6 
ECG ............................................................................................................................ 60 


 
 
 
 
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Pain Assessment ......................................................................................................... 60 
9.2.8 
Non-child-bearing Potential/Pregnancy Test.............................................................. 61 
9.2.9 
Clinical Laboratory Assessments ............................................................................... 62 
9.3 
Other Assessments .......................................................................................................... 62 
9.3.1 
Demographics and Other Baseline Characteristics .................................................... 62 
9.3.2 
Height and Body Weight ............................................................................................ 62 
9.3.3 
Medical and Surgical History ..................................................................................... 62 
9.3.4 
Performance Test ........................................................................................................ 63 
9.3.5 
Unscheduled Visits ..................................................................................................... 63 
10 
ADVERSE EVENTS ......................................................................................................... 64 
10.1 
Definition of Adverse Events .......................................................................................... 64 
10.2 
Definition of Serious Adverse Events ............................................................................. 64 
10.3 
Definition of Non-Serious Adverse Events ..................................................................... 65 
10.4 
Definition of Predefined Adverse Events of Special Interest ......................................... 65 
10.5 
Adverse Event Reporting ................................................................................................ 65 
10.5.1 
Non-Serious Events .................................................................................................... 65 
10.5.2 
Serious Adverse Events .............................................................................................. 65 
10.5.3 
Adverse Events during Follow-up .............................................................................. 65 
10.5.4 
Adverse Events with Onset after End of Trial ............................................................ 66 
10.5.5 
Recording of Adverse Events ..................................................................................... 66 
10.5.6 
Diagnosis of Adverse Events ...................................................................................... 66 
10.5.7 
Onset Date and Time .................................................................................................. 66 
10.5.8 
End Date and Time ..................................................................................................... 66 
10.5.9 
Severity ....................................................................................................................... 66 
10.5.10 
Outcome ..................................................................................................................... 66 
10.5.11 
Relationship to Investigational Medicinal Product .................................................... 67 
10.5.12 
Action Taken with Investigational Medicinal Product ............................................... 67 
10.6 
Events Requiring Immediate Reporting .......................................................................... 68 
10.6.1 
Pregnancy ................................................................................................................... 68 
10.7 
Timelines for Initial Reporting of AEs ........................................................................... 68 
10.7.1 
Contact details for reporting: ...................................................................................... 68 
10.8 
Follow-up on Adverse Events ......................................................................................... 69 
10.9 
Reporting of SUSARs ..................................................................................................... 69 
10.10 
Communication of Significant Safety Issues .................................................................. 69 
10.11 
Data Monitoring Committee ........................................................................................... 70 
11 
LABORATORIES ............................................................................................................. 71 
11.1 
Clinical Laboratory Assessments .................................................................................... 71 
11.2 
Immunogenicity .............................................................................................................. 72 
12 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ............. 73 
12.1 
General Overview ........................................................................................................... 73 
12.2 
Sample Size ..................................................................................................................... 73 
12.3 
Populations of Interest ..................................................................................................... 73 


 
 
 
 
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Efficacy Analysis ............................................................................................................ 73 
12.4.1 
Primary endpoint: ORR at or before completion of four cycles ................................ 74 
12.4.2 
ORR after 2 cycles, CR rate after 2 and 4 cycles, MR rate and “MR or better” rate . 74 
12.4.3 
Duration of response ................................................................................................... 74 
12.4.4 
Rate of patients who obtain CR in BM and convert to MRD negative ...................... 74 
12.4.5 
Time to First Subsequent Therapy.............................................................................. 75 
12.4.6 
PFS and OS ................................................................................................................. 75 
12.4.7 
Exploratory Endpoints ................................................................................................ 75 
12.5 
Safety Analysis ................................................................................................................ 75 
12.5.1 
Adverse events ............................................................................................................ 75 
12.5.2 
Safety laboratory data ................................................................................................. 76 
12.5.3 
Vital signs ................................................................................................................... 76 
12.6 
Pain assessments during naxitamab infusions ................................................................. 76 
12.7 
Analysis of ADA Formation ........................................................................................... 76 
12.8 
Hospitalization days ........................................................................................................ 76 
12.9 
Naxitamab infusions in out-patient setting...................................................................... 76 
12.10 
Interim Analysis .............................................................................................................. 76 
12.10.1 
Multiplicity adjustments ............................................................................................. 76 
12.11 
Subgroup Analyses .......................................................................................................... 76 
12.12 
Handling of Missing Data ............................................................................................... 77 
12.13 
Statistical Analysis Plan .................................................................................................. 77 
12.14 
Reporting of trial results .................................................................................................. 77 
13 
ETHICS .............................................................................................................................. 77 
13.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .................. 77 
13.2 
Ethical Conduct of the Trial ............................................................................................ 78 
13.3 
Patient Information and Informed Consent ..................................................................... 78 
13.4 
Confidentiality ................................................................................................................. 79 
14 
MONITORING AND QUALITY ASSURANCE ........................................................... 80 
14.1 
Compliance with Good Clinical Practice ........................................................................ 80 
14.2 
Protocol Compliance ....................................................................................................... 80 
14.2.1 
COVID related protocol deviations ............................................................................ 80 
14.3 
Changes to the Protocol................................................................................................... 80 
14.3.1 
Training of Personnel ................................................................................................. 80 
14.4 
Monitoring ....................................................................................................................... 80 
14.4.1 
Monitoring of Pharmacies .......................................................................................... 81 
14.5 
Source Data Verification ................................................................................................. 82 
14.5.1 
Source Data................................................................................................................. 82 
14.5.2 
Direct Access to Source Data/Documents .................................................................. 82 
14.5.3 
Access to Information for Monitoring ........................................................................ 82 
14.5.4 
Access to Information for Auditing or Inspections .................................................... 82 
14.5.5 
Quality Assurance ...................................................................................................... 83 
15 
DATA HANDLING AND RECORD KEEPING ............................................................ 84 


 
 
 
 
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15.1 
Electronic Case Report Forms......................................................................................... 84 
15.2 
eCRF................................................................................................................................ 84 
15.2.1 
Corrections to Data ..................................................................................................... 84 
15.2.2 
Data Entry Timelines .................................................................................................. 84 
15.3 
Trial Documents at Site and Record Retention ............................................................... 84 
15.4 
Data Management ........................................................................................................... 85 
16 
PREMATURE TERMINATION OF THE TRIAL ........................................................ 86 
16.1 
Criteria for Halting Patient Enrolment ............................................................................ 86 
16.2 
Criteria for Termination of the Trial ............................................................................... 86 
17 
REPORTING AND COMMUNICATION OF RESULTS ............................................ 87 
17.1 
Publication ....................................................................................................................... 87 
17.2 
Use of Information .......................................................................................................... 87 
18 
INSURANCE ...................................................................................................................... 88 
19 
REFERENCES ................................................................................................................... 89 
20 
APPENDICES .................................................................................................................... 93 
Appendix 1 Creatine-based 2009 revised Bedside Schwartz Equation ............................... 93 
Appendix 2 Flowchart and assessment for patients who discontinues IT treatment due to 
toxicity ................................................................................................................... 94 
Appendix 3 Temozolomide dosing (100mg/m2/day) Nomogram .......................................... 99 
Appendix 4 Nomogram for Reduced Dosing (80 mg/m2/day ) of Temozolomide ............. 100 
Appendix 5 Nomogram for Reduced Dosing (60 mg/m2/day) of Temozolomide .............. 101 
Appendix 6 Temozolomide 10 mg/mL suspension .............................................................. 102 
Appendix 7 Recommendations for administration of Temozolomide ............................... 103 
Appendix 8 Wong-Baker FACES® Pain Rating Scale ........................................................ 104 
Appendix 9 FLACC Behavioral Scale .................................................................................. 105 
Appendix 10 Performance tests ............................................................................................... 107 
 
List of Tables 
Table 1 Schedule of time and events: screening, treatment and follow-up ................................... 19 
Table 2 Efficacy results for interim analyses of Trials 12-230 and 201 ....................................... 24 
Table 3 IMPs provided by Y-mAbs .............................................................................................. 41 
Table 4 Treatment schedule........................................................................................................... 42 
Table 5 Primary (soft tissue) Tumor response .............................................................................. 56 
Table 6 Tumor response at metastatic soft tissue and bone sites .................................................. 57 
Table 7 BM metastasis response ................................................................................................... 57 
Table 8 Determination of overall response ................................................................................... 58 
Table 9 Protocol required laboratory assessments ........................................................................ 71 
Table 10 ADA samples ................................................................................................................. 72 


 
 
 
 
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Table 11 Sample sizes, assumptions and power ............................................................................ 73 
Table 12 Schedule of time and events: screening, treatment and follow-up for patients in 
treatment with naxitamab + GM-CSF alone .......................................................... 94 
Table 13 Treatment with naxitamab + GM-CSF alone ................................................................. 96 
Table 14 Protocol required laboratory assessments for patient treated with naxitamab + 
GM-CSF alone ....................................................................................................... 97 
 
List of Figures 
Figure 1 Trial design ................................................................................................................... 34 
 
Attachment I Key Contact Information 


 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACE 
Angiotensin-converting enzyme 
ADA 
Anti-Drug Antibody  
ADCC 
Antibody-Dependent Cellular Cytotoxicity  
ADCP 
Antibody dependent cellular phagocytosis  
AE 
Adverse Event  
AESI 
Adverse event of special interest  
allo-SCT 
Allogeneic hematopoietic stem cell transplantation  
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
ASCT 
Autologous stem cell transplant 
AST 
Aspartate aminotransferase 
BM 
Bone Marrow 
BP 
Blood Pressure 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
C 
Cycle 
CBC 
Complete Blood Count 
CDC 
Complement-Dependent Cytotoxicity 
CI 
Confidence Interval 
CNS 
Central Nervous System  
COG 
Childrens Oncology Group 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CSR 
Clinical Study Report 
D 
Day 
DLT 
Dose-Limiting Toxicity 


 
 
 
 
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DMC 
Data Monitoring Committee 
DoR 
Duration of Response 
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
EFS 
Event-Free Survival  
eGFR 
estimated Glomerular Filtration Rate 
EOT 
End of Treatment  
ES 
Ewing Sarcoma 
FAS 
Full Analysis Set 
FDA 
The Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography  
FLACC 
Face, Legs, Activity, Cry, Consolability 
FPFT 
First Patient First Treatment 
FSH 
Follicle-Stimulating Hormone 
FU 
Follow-Up 
GCP 
Good Clinical Practice 
GD2 
Disialoganglioside 
GM-CSF 
Sargramostim - Granulocyte-Macrophage Colony Stimulating Factor  
HACA 
Human Anti-Chimeric Antibody  
HITS 
Naxitamab + GM-CSF + irinotecan +temozolomide 
HPC 
Hematopoietic Progenitor Cell  
IB 
Investigator’s Brochure 
ICF 
Patient Information and Informed consent form 
ICH 
International Council on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ID 
Identifier 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IHC 
immunohistochemistry  
IL-2 
Interleukin-2 


 
 
 
 
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IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IND  
Investigational New Drug 
INRC 
International Neuroblastoma Response Criteria  
INRG 
International Neuroblastoma Risk Group  
IQR 
Interquartile range  
IRB 
Institutional Review Board 
IT 
Irinotecan and temozolomide 
ITCC 
Innovative Therapies for Children with Cancer 
IU 
International Unit 
IV 
Intravenous 
kg 
Kilogram(s) 
L 
Liter 
LDH 
Lactate Dehydrogenase 
mAb 
Monoclonal Antibody 
MeDRA 
Medical Dictionary for Regulatory Activities 
MD 
Minimal disease  
µg 
Microgram 
mg 
Milligram 
MIBG 
Metaiodobenzylguanidine  
min 
Minute(s) 
mL 
Milliliter(s) 
mmol 
Millimol 
MR 
Minor Response  
MRD 
Minimal residual disease  
MRI 
Magnetic Resonance Imaging  
MSK 
Memorial Sloan Kettering Cancer Center  
MYCN 
Myelocytomatosis Viral-Related Oncogene, Neuroblastoma Derived 
N 
Number of subjects 
NB 
Neuroblastoma  


 
 
 
 
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NCI 
National Cancer Institute 
NE 
Not Evaluable 
NIH 
National Institutes of Health 
NOAEL 
No-observed-adverse-effect-level 
OR 
Objective Response 
ORR 
Overall Response Rate  
OS 
Overall Survival 
PD 
Progressive Disease  
PFS 
Progression Free Survival  
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PO 
Per Os (by mouth) 
PPS 
Per Protocol Analysis Set 
PR 
Partial Response 
PRES 
Posterior reversible encephalopathy syndrome  
PRN 
When necessary (pro re nata) 
RT 
Radiation therapy  
RTqPCR 
Reverse transcriptase-quantitative polymerase chain reaction  
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
sc 
Subcutaneous 
SD 
Stable disease 
SIOPEN 
International Society of Paediatric Oncology Europe Neuroblastoma  
SmPC 
Summary of Product Characteristics 
SoC 
Standard of Care 
SPECT 
Single-Photon Emission Computed Tomography 
SpO2 
Peripheral Oxygen Saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 


 
 
 
 
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TFST 
Time to First Subsequent Therapy 
UNL 
Upper Normal Limit 
WBC 
White Blood Cells 
W 
Week 
WHO 
World Health Organization 
WOCBP 
Woman of child-bearing potential 
 


 
 
 
 
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PROTOCOL SYNOPSIS 
Title 
Naxitamab and Granulocyte-Macrophage Colony Stimulating Factor in 
Combination with Irinotecan and Temozolomide in Patients with High-
Risk Neuroblastoma with Primary Refractory Disease or in First 
Relapse. An International, Single-Arm, Multicenter Phase 2 Trial 
EudraCT number 
2020-003068-21   
Investigational 
New Drug (IND) 
132793 
Sponsor 
Y-mAbs Therapeutics A/S 
Agern Allé 11 
2970 Hoersholm 
Denmark 
Trial ID 
203 
Trial design 
This is an international, single-arm, multicenter phase 2 trial, in patients 
≥ 12 months of age with high-risk NB with primary refractory disease or 
in first relapse. Patients will receive naxitamab + GM-CSF + 
irinotecan/temozolomide. The Follow-Up period ends 2 years after End 
of Treatment. 
Patient population The trial will include patients with high-risk neuroblastoma with 
measurable and/or evaluable disease and with either primary refractory 
disease or first relapse following induction and consolidation therapy. 
Objectives 
Primary objective: 
• To investigate the efficacy of naxitamab + GM-CSF in 
combination with irinotecan/temozolomide as assessed by overall 
response rate in patients with high-risk neuroblastoma with 
primary refractory disease or in first relapse 
Secondary objectives: 
• To further investigate the efficacy and safety of naxitamab + GM-
CSF in combination with irinotecan/temozolomide in patients 
with high-risk neuroblastoma with primary refractory disease or 
in first relapse. 
Endpoints 
Primary Endpoint: 
Overall response rate, defined as the proportion of patients obtaining a 
centrally assessed complete or partial response according to the 
International Neuroblastoma Response Criteria at or before completion 
of four cycles 
Key Secondary Endpoints: 


 
 
 
 
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• Overall response rate after 2 cycles defined as the proportion of 
patients obtaining a centrally assessed complete response or 
partial response according to the International Neuroblastoma 
Response Criteria at completion of two treatment cycles  
• Duration of response, defined as the time from first centrally 
assessed overall response (complete response or partial response 
according to the International Neuroblastoma Response Criteria) 
to progressive disease or death 
• Complete Response rate, defined as the proportion of patients 
obtaining a centrally assessed complete response according to the 
International Neuroblastoma Response Criteria at or before 
completion of four treatment cycles 
• Time to First Subsequent Therapy (defined as the time from 
initiation of treatment with investigational medicinal product until 
death or start of new anti-cancer treatment (prohibited as per 
protocol)) 
• Progression Free Survival defined as the time from first 
investigational medicinal product administration until centrally 
assessed Progressive Disease or death, whichever comes first  
• Overall survival defined as the time from first investigational 
medicinal product administration until death  
• 1- and 2-years Progression Free Survival defined as the 
proportion of patients alive and with no centrally assessed 
Progressive Disease at 1- and 2 year, respectively after first 
investigational medicinal product administration 
• 1- and 2-years overall survival defined as the proportion of 
patients alive at 1- and 2 years after first investigational medicinal 
product administration 
Patient selection 
criteria 
Key inclusion criteria: 
• Documented neuroblastoma at time of initial diagnosis defined 
as: 
o Histopathological verification of neuroblastoma or 
ganglioneuroblastoma nodular, or  
o Bone Marrow aspirate or biopsy indicative of 
neuroblastoma (according to International 
Neuroblastoma Response Criteria and high blood or 


 
 
 
 
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urine catecholamine metabolite levels (> 2 x upper limit 
of normal)  
• Documented high-risk disease at time of initial diagnosis 
defined as: 
o MYCN-amplified any stage (according to International 
Neuroblastoma Risk Group) of any age or 
o MYCN-nonamplified with stage M (according to 
International Neuroblastoma Risk Group) and diagnosed 
at ≥18 months of age  
• Patient should have received standard of care (SoC) frontline 
induction/ consolidation therapy (surgery, chemotherapy, 
autologous stem cell transplant, MIBG, radiotherapy, 
immunotherapy, or retinoids) 
• Patients must have active disease despite previous aggressive 
multi-drug chemotherapy (≥ 2 agents, including an alkylating 
agent and a platinum containing compound) defined as one of 
the following:  
o Verified first progression during multi-drug frontline 
treatment or  
o Verified first episode of relapse, defined as recurrence 
after response to frontline treatment, or  
o Verified first designation of refractory disease, defined 
as persistent metastatic disease (SD or minor response by 
International Neuroblastoma Response Criteria and 
MIBG curie score ≥3) detected at conclusion of at least 4 
cycles of multi-drug induction chemotherapy on or 
according to a high-risk NB treatment protocol  
• The patients must have one of the following (locally assessed) 
obtained within 3 weeks prior to enrollment and at least 10 
calendar days after end of any prior anti-cancer treatment: 
o Measurable tumor on CT/MRI scan that is MIBG-avid or 
demonstrates increased FDG uptake on PET scan  
o MIBG scan with positive uptake at a minimum of one 
site. This site must represent disease recurrence after 
completion of therapy, progressive disease on therapy, or 
refractory disease during induction 
• Aged ≥ 12 months at enrollment 


 
 
 
 
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• Written informed consent from legal guardian(s) and/or child 
obtained in accordance with local regulations. Pediatric patients 
must provide assent as required by local regulations 
Key Exclusion criteria: 
• Any systemic anti-cancer therapy, including chemotherapy, or 
immunotherapy, within 3 weeks prior to enrollment 
• Autologous Stem Cell Transplantation within 6 weeks prior to 
enrollment or ongoing toxicity due to the stem cell transplant at 
the discretion of the investigator 
• Therapeutic 131I-MIBG within 6 weeks prior to enrollment 
• Radiation therapy within 4 weeks prior to enrollment at the site 
of any lesion that will be identified as a target lesion to measure 
tumor response. Lesions that have been previously radiated 
cannot be used as target lesions unless there is radiographic 
evidence of progression at the site following radiation or a 
biopsy done following radiation shows viable neuroblastoma. 
There are no time restrictions following prior radio therapy for 
non-target lesions or for palliative radiation to sites that will not 
be used for response assessment  
• Prior treatment with anti-GD2 therapy if the patient experienced 
progressive disease while on anti-GD2 treatment 
• Patients with neuroblastoma in bone marrow only 
• Neuroblastoma in the CNS or leptomeningeal disease within 6 
months prior to enrollment 
• Performance status of < 50% as per the Lansky scale (patients 
less than 16 years of age) or Karnofsky scale (for patients aged 
16 years or older) 
• Life expectancy of less than 6 months, as judged by the 
Investigator 
• Allogeneic hematopoietic stem cell transplantation or donor-
lymphocyte-infusion (defined as any kind of active allogeneic 
lymphocyte suspension)  
o within 6 months of 1st dose of GM-CSF or  
o with a lymphocyte count < 0.2 x109/L 
• Treatment with Hematopoietic Progenitor Cell boost within 2 
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Methodology 
The efficacy and safety of naxitamab + GM-CSF in combination with 
irinotecan/temozolomide will be evaluated using a single-arm trial 
design in patients with high-risk neuroblastoma with either primary 
refractory disease or in first relapse. At the discretion of the investigator 
patients may receive treatment for up to 70 weeks. Each patient will 
have a long-term follow-up for 2 years after End of Treatment. 
Number of 
patients (planned) 
Approximately 70 patients will be screened to achieve the planned 52 
enrolled patients who have all received at least 1 dose of IMP. 
Investigational 
Medicinal 
Product (IMP) 
The following investigational medicinal products are supplied by Y-
mAbs: 
• Irinotecan, 20 mg/mL, solution for infusion, IV infusion 
• Temozolomide, 5 mg, 20 mg and 100 mg, capsules, orally  
• The humanized immunoglobulin isotype G (IgG1) monoclonal 
antibody (mAb) naxitamab, 4 mg/mL, solution for infusion, IV 
infusion 
• Sargramostim (GM-CSF), 250 µg/vial, lyophilized 250 µg single 
use vial, subcutaneous 
Trial period(s) 
and duration 
Each patient will receive up to 70 weeks of treatment. End of Treatment 
will be 6 weeks after last treatment. Each patient will have a long-term 
follow-up up for 2 years after end-of-treatment. 
Statistical 
considerations 
Results will be presented by appropriate descriptive statistics.   
With the statistical analysis methodology of the primary endpoint and a 
drop-out rate of 20%, in mind: 52 patients are needed to, with 82% 
power, demonstrate that the overall response rate is statistically 
significantly higher than 20%.  
The null hypothesis that the probability of the centrally assessed 
response rate after 4 cycles is equal to 20% will be tested against the 
two-sided alternative using the two-sided exact binomial test on the 5% 
significance level.  
Secondary endpoints based on INRC responses, based on both central 
and local assessments, will be presented using descriptive statistics. 
Responses based on investigators’ local assessments are used as 
sensitivity analyses. Duration of response, PFS and OS will be estimated 
using Kaplan-Meier methodology.   
Two-sided 95% confidence intervals will be presented. 
Safety data will be summarized and where relevant, presented in graphs.  


 
 
 
 
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3 
FLOW CHART 
Table 1 Schedule of time and events: screening, treatment and follow-up  
Please refer to Appendix 2 for flowchart for patients who have discontinued treatment with irinotecan and temozolomide due to toxicity.  
Treatment / Measurements / 
Evaluations 
Screening 
First treatment cycle 
 
 
 
D -24 to -4 
D -3 to 0 
D1  
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D15 
Next cycles3 
EOT4 
Long-term FU5 
Informed consent (13.3)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check (7.11.1, 7.11.2) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and baseline 
characteristics (9.3.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical history 
(9.3.3) 
X 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (9.2.1) 
X 
X8 
X8 
 
 
 
 
 
 
 
 
 
 
X8 
X 
 
Height and weight (9.3.2) 
X 
X8 
X8 
 
 
 
 
 
 
 
 
 
 
X8 
 
 
Serum pregnancy test, if 
applicable (9.2.8 ) 
X 
X9 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Vital signs (9.2.2) 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Echocardiography (9.2.4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function tests and 
oxygen saturation1 (9.2.5)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 2 (9.2.6) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical laboratory assessments 
(11.1) 
X 
X8 
X8 
 
X 
 
X 
 
 
X 
 
 
X10 
X8 
X 
 
Anti-drug antibodies (11.2) 
 
X8 
X8 
 
 
 
 
 
 
 
 
 
 
X8 
X 
 


 
 
 
 
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Treatment / Measurements / 
Evaluations 
Screening 
First treatment cycle 
 
 
 
D -24 to -4 
D -3 to 0 
D1  
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D15 
Next cycles3 
EOT4 
Long-term FU5 
Bone marrow biopsy/aspirates         
(9.1.1, 9.1.1.1, 9.1.2) 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
X11 
X13 
X14 
Imaging (9.1.1, 9.1.2) 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
X12 
X13 
X14 
Performance test (9.3.4) 
X 
X8 
X8 
 
 
 
 
 
 
 
 
 
 
X8 
X 
 
Pain assessment (9.2.7) 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Pre-treatment (8.4.1, 8.4.3) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Treatment (8.1.1, 8.1.2)  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Drug accountability and 
compliance check (8.1.5)  
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
Hand out diary (8.1.5) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Adverse events (10) 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X10 
X 
X 
X 
Concomitant medication(s) (8.4) 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X10 
X 
X 
X 
1 If clinically indicated, please see exclusion criteria 13. 
2 Local assessment of electrocardiogram (ECG) during screening and at end of treatment (EOT). If the patient needs sedation before ECG, the ECG can be performed in connection with imaging. 
3 The next cycle may be postponed up to 3 weeks in case of irinotecan and temozolomide toxicities: Please refer to Section 8.4.4. 
4 EOT visit should take place 6 (up to 10) weeks after last treatment. If treatment is discontinued due to progressive disease (PD), initiation of new anti-NB treatment prohibited as per protocol, withdrawal from the 
trial or investigator judges it warranted due to medical reasons/non-compliance, the patient should be called for EOT visit as soon as possible and subsequently be followed for safety and new anti-cancer therapy 
for 6 weeks after last treatment, and herafter continue in the long-term follow-up. 
5 Long-term follow-up (FU) evaluations should take place approximately every 4 months until 2 years after End of Treatment. During long-term FU, information on death, PD, serious adverse events (SAEs) ongoing 
at EOT, new SAEs at least possibly related to naxitamab, new onset of secondary malignancies and autoimmune diseases should be collected. Furthermore, new anti-cancer therapy should be collected as concomitant 
medication. (see Section 9.1). 
6 Screening imaging and BM examination must be obtained at least 10 calendar days after any prior anti-cancer treatment. 
7 Only applicable for D-3 to 0 in cycle 1. 
8 Height, weight, physical examination, clinical laboratory assessments, anti-drug antibodies (ADA) and performance test must be performed prior to dosing in each cycle; prior to day (D)1 or at D1. 
9 Serum pregnancy test must be done on D-3 prior to gabapentin administration for women of childbearing potential 
10 Should only be performed at D15 during C1.  
11 Bilateral aspirates and bone marrow (BM) biopsies (2+2), performed at screening and after C2, C4, C8, C13, and EOT. In addition, for patients who achieve a first CR or PR after C4 or a first CR or PR after C8 
a confirmatory response assessment should be performed within 4-6 weeks after detection of the overall response. Samples for RTqPCR should be taken at Screening and after C2 and C4. See section section 9.1.2 


 
 
 
 
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12 Imaging schedule follows timing of BM biopsies (see #11 above). For a Fluorodeoxyglucose Positron Emission Tomography/ Computed Tomography (FDG PET/CT) scan, the patient must be in fasting state 
for at least 4 hours prior to the scan. If the patient is not fasting serum glucose determination must be performed prior to the administration of FDG. Please refer to the imaging acquisition guideline for more details. 
13 Not to be performed at EOT if the patient discontinue treatment due to PD, provided that PD is documented by scan and/or biopsy. See section section 9.1.2 
14 For patients who have not experienced PD, response assessment should be performed approximately every 4 months after EOT during long-term FU. See section section 9.1.2 


 
 
 
 
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4 
INTRODUCTION 
4.1 
Medical Background 
Neuroblastoma (NB) is a rare cancer but is the most common extracranial solid tumor of 
childhood. It has a varied prognosis, ranging from spontaneous regression to aggressive 
metastatic tumors with fatal outcomes despite multimodality therapy. The prognosis of 
NB correlates closely with numerous biological and clinical factors such as age, tumor 
stage and histology, genetic and chromosomal abnormalities1. At diagnosis, more than 50 
percent of patients present with metastatic disease (stage 4), typically in the bone marrow 
(BM)2-4. BM invasion is associated with a very poor prognosis3, 5. Despite advances in 
frontline multimodality therapy, approximately 50% of patients with high-risk NB have 
persistence of disease or develop progressive disease (PD)6. After relapse, the outcome 
has been poor for decades, with 10-year overall survival (OS) of <15%7. The 
disappointing prognosis is supported by a meta-analysis of 3 Phase 2 trials (71 patients), 
conducted by Innovative Therapies for Children with Cancer (ITCC)/ International 
Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) European, showing a 
median progression free survival (PFS) for all patients, patients with primary refractory 
disease, and patients with relapsed disease of 6.4, 12.5, and 5.7 months, respectively. The 
corresponding numbers for OS were 16.1, 27.9, and 11.0 months, respectively8. 
Moreover, another meta-analysis of 35 phase 1-2 trials from Children's Oncology Group 
(COG) from 2002 to 2014 (383 patients) in recurrent or refractory NB revealed 1-year 
and 4-year PFS rates of 21% and 6%, respectively, and 1-year and 4-year OS rates of 
57% and 20%, respectively9.  
Thus, there is a high unmet medical need for more efficacious treatments for patients 
with high-risk NB with primary refractory or relapsed disease. 
4.2 
Rationale for antibody therapy for High-Risk NB 
The disialoganglioside GD2 is an adhesion molecule abundantly expressed in NB10. This 
genetically stable antigen is rarely lost and relatively inert on the cell membrane. 
Monoclonal antibodies (mAbs) that target GD2 have shown clinical efficacy in the 
treatment of GD2 expressing tumors. This includes metastatic cancer in well-
vascularized sites of metastases, such as BM infiltrated by NB cells10, 11. Three anti-GD2 
mAbs are currently approved for the treatment of high-risk NB. Dinutuximab 
(Unituxin®) and naxitamab (Danyelza®) are approved in the United States (US) for the 
treatment in the post-consolidation setting and of relapsed/refractory NB in the bone 
and/or BM, respectively12, 13. Dinutuximab beta (Qarziba®) is approved in the European 
Union (EU) for the treatment in the post-consolidation setting and of relapsed or 
refractory NB14. Dinutuximab and dinutuximab beta contain significant murine fractions 
and represent so called chimeric antibodies. Rapid production of human anti-chimeric 
antibody (HACA) can develop in patients and can delay treatment, prevent further 
cycles, and compromise anti-tumor effects of the mAb treatment. Furthermore, treatment 
with these antibodies requires long time infusions; dinutuximab is administered over 10 


 
 
 
 
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to 20 hours for 4 consecutive days; dinutuximab beta is administered over 8-hours for 5 
days or during continuous infusion with a pump for 10 days. Treatments are typically 
performed or initiated in the in-patient setting. Humanization of the anti-GD2 antibody 
reduces or eliminates the mouse epitopes and has the potential to reduce development of 
such anti-drug-antibody (ADA) responses. Furthermore, a shorter infusion time may 
decrease the treatment burden for patients and their families. Naxitamab represent such 
an approach.  
4.3 
Naxitamab profile 
4.3.1 
Non-clinical data for naxitamab 
Naxitamab (humanized 3F8) is a humanized anti-GD2 mAb with approximately ten-fold 
higher binding affinity to GD2 compared to dinutuximab and dinutuximab beta primarily 
due to a slower dissociation rate. Naxitamab has preferential affinity for NB tissue. In 
normal tissues naxitamab binding is observed in cerebellum, cerebral cortex, spinal cord, 
peripheral nerves, 
. The 
effect of naxitamab is mediated through antibody-dependent cellular cytotoxicity 
(ADCC), and complement-dependent cytotoxicity (CDC) (see the current version of the 
Investigator’s Brochure (IB) and any updates hereof). 
No adverse findings were observed after administration of naxitamab as a single dose of 
 to mice or after two cycles of three doses of 
, amounting 
to a maximum of 
, in a 
toxicity study in nude rats. Moreover, 
in a 
 repeat-dose toxicity study in nude rats, naxitamab was well tolerated 
clinically when administered over 4 cycles of 3 treatment days, and up to 
 
. Up to moderate hyperplasia accompanied by inflammatory changes 
 
 
were considered adverse. Complete recovery occurred in 
males with partial recovery in females. In view of the severity of these stomach changes, 
 
(see the current version of the IB and any updates 
hereof). 
4.3.2 
Clinical data for naxitamab 
Two ongoing, open-label, single arm, phase 2 clinical trials (trials 12-230 and 201, 
interim analyses) have proven naxitamab to be efficacious (Table 2) with a manageable 
safety profile as single anti-cancer agent in combination with granulocyte-monocyte 
colony stimulating factor (GM-CSF) in patients with high-risk refractory or relapsed NB 
in bone and/or BM (the current version of the IB and any updates hereof). In these trials, 
naxitamab was administered intravenously (IV) over 30 minutes (min) on Days 1, 3 and 
5 at 3.0 mg/kg/infusion (9.0 mg/kg/cycle) in combination with GM-CSF (Sargramostim) 
subcutaneously (sc) at 250 ug/m2/day on Days -4 to 0 and at 500 ug/m2/day on Days 1 to 
5. Treatment cycles were repeated every 4 weeks until complete response (CR) or partial 
response (PR), followed by 5 additional cycles every 4 weeks. In Trial 201, in which 


 
 
 
 
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detailed information on infusions was captured, the vast majority (95%) of naxitamab 
infusions were administered in the outpatient setting. The duration of infusions was short, 
at a median of 37 minutes and all infusions were <2 hours15. 
 
Table 2 Efficacy results for interim analyses of Trials 12-230 and 201 
 
ORR (%) 
CR (%) 
PR (%) 
Trial 201 (N=22) 
68 [95% CI: 45 to 86] 
59 
9 
 
 
  
 
Note. CR = complete response; ORR = overall response rate; PR = partial response. N = number of subjects. CI = 
confidence interval.  
  
In terms of safety across Trials 12-230 and 201, naxitamab was found to be generally 
well tolerated with a manageable safety profile. The acute toxicities/infusion related 
adverse events (AEs) included mainly Common Terminology Criteria for Adverse 
Events (CTCAE) Grade 1-2 events. Treatment-Emergent AEs (TEAE) occurring in ≥ 
50% of patients in at least one of the 2 trials included hypotension, urticaria, abdominal 
pain, pyrexia, tachycardia, bronchospasm, cough, flushing, nausea, vomiting, decreased 
appetite, diarrhoea, pain in extremity and pruritus. Across the 2 trials, TEAEs of CTCAE 
grade 3 or higher were reported in 
 to 92% of patients. TEAEs of grade 3 or higher 
reported in ≥10% of the patients in at least one of the trials were pain, hypotension, 
urticaria, bronchospasm, stridor, depressed level of consciousness and neutropenia The 
acute toxicities/infusion related AEs were generally managed by pre-medications 
(opioids, corticosteroids, antipyretics, and antihistamines) along with concomitant 
administration of normal saline, opioids, nebulized beta-2 agonists, and oxygen as 
applicable during the naxitamab infusion. 
, 2 events of posterior reversible 
encephalophathy syndrome (PRES) (CTCAE grade 3) with onset 2 and 7 days after the 
last dose in Cycle 1 were reported in connection with hypertension in 
. No 
new events of PRES have been reported after the implementation  of mitigations for 
hypertension. One (1) case of transverse myelitis (CTCAE Grade 3) has been reported in 
a single patient treated under single patient use 
 
. The patient was treated with high dose methylprednisolone and recovered 
subsequently. The event is seen as a possible class effect with anti-GD2 antibodies. 
In trials 12-230 and 201, 23.1% and 8.3%, respectively, developed ADAs. 
 
 As only 2 subjects developed ADA in 201 at the 
time of the interim analysis, very limited information was available regarding efficacy 
and safety in this subgroup. 
Based on the above data, naxitamab (Danyelza®) received accelerated regulatory 
approval on 25Nov 2020 by the FDA in the US for the treatment in combination with 


 
 
 
 
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GM-CSF of patients ≥ 1 year of age with relapsed or refractory high-risk NB in the bone 
or BM demonstrating a PR, minor response (MR), or stable disease (SD) to prior therapy 
for NB. 
4.3.3 
Choice of chemotherapy regimen as backbone treatment  
No single-agent induction chemotherapy regimen has proven superior in obtaining 
response in high-risk NB. Therefore, induction and consolidation regimens employ 
intensive multi-agent chemotherapy including platinum and alkylating agents, as well as 
topoisomerase-inhibitors, most often followed by surgical resection, high-dose 
chemotherapy with autologous cell rescue and radiation therapy (RT)6. 
When the induction chemotherapy regimen fails, an alternative approach to second line 
therapy is needed. No SoC currently exists for the treatment of patients with primary 
refractory or first relapse of high-risk NB.  
Irinotecan and temozolomide (IT) are widely used as salvage chemotherapy supported by 
clinical trials data.  
Wagner et al assessed the effect of IT treatment in a small phase 1 study including 12 
evaluable heavily pretreated patients with refractory solid tumors (incl 2 patients with 
NB). Oral temozolomide at 100 mg/m2/day for 5 days and IV irinotecan at either 10 
mg/m2/day (n = 6) or 15 mg/m2/day (n = 6) was given daily for 5 days for 2 consecutive 
weeks. Median number of courses was 4. One patient had CR (Ewing Sarcoma (ES), 
dose level 1), two had PR (NB and ES at dose levels 1 and 2, respectively), and one had 
minor response (MR) (ES, dose level 1)16. 
A phase 2, single-arm, single center study by Kushner et al, included 36 assessable 
heavily pre-treated patients with high-risk stage 4 refractory (N=19) or relapsed (N=17) 
NB17. Patients received IV irinotecan 50 mg/m2/day over 1 hour and temozolomide 150 
mg/m2/day orally at Days 1-5. The median number of cycles was 5 (range 1-15). Overall, 
of the 36 patients assessable for response, 12 patients (33%) had disease regressions, 
including three patients (8%) with CR or PR, and nine patients with objective responses  
(i.e., less than PR). The safety profile was associated with manageable adverse effects 
and no unexpected toxicities. 
A phase 2, multi-center, single arm study by Bagatell et al, included patients with 
primary refractory (25%) or first relapsed NB18. IT was administered in 6 cycles of 21 
days with irinotecan given IV at 10 mg/m2/dose on Days 1-5 and 8-12 and temozolomide 
orally at 100 mg/m2/dose on Days 1-5. Of the 55 evaluable patients, 28 (stratum 1) had 
measurable disease by cross-sectional imaging and 27 (stratum 2) had disease only 
assessable by BM aspirate/biopsy or metaiodobenzylguanidine (MIBG) scan. The 
objective response rate was 15% overall, 11% on stratum 1, and 19% on stratum 2. 
Furthermore, 50% on stratum 1 and 56% on stratum 2 had stable disease (SD). Two-year 
event-free survival (EFS) and OS rates in the overall cohort were 13% ± 9% and 30% ± 
10%, respectively. IT therapy was generally well tolerated and with acceptable AEs: Less 


 
 
 
 
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than 6% of patients experienced > Grade 3 diarrhea. Although > Grade 3 neutropenia was 
observed, less than 10% of patients developed evidence of infection while neutropenic. 
Finally, in the BEACON study in patients with high-risk refractory/relapsed NB, 
temozolomide was administered at 100mg/m2/day orally and irinotecan at 50mg/m2/day 
IV on Days 1 to 5 of a 3-week cycle, for 6 cycles or until progression (NCT02308527). 
With a median follow-up time of 15.4 months, irinotecan + temozolomide ± 
bevacizumab (N=60) vs. temozolomide ± bevacizumab (N=61) improved PFS and OS: 
Hazard ratios of 0.66 [95%CI 0.43-1.00] and 0.63 [95%CI 0.41-0.99], respectively19. 
Based on the above data, IT will serve as backbone chemotherapy in Trial 203. 
4.3.4 
Combining naxitamab with irinotecan and temozolomide 
Although IT therapy may result in disease stabilization in patients with primary 
refractory or first relapse of NB, response rates remain relatively low with CR rates of 5-
10%17, 18. To improve the outcome for these patients, the IT regimen could serve as a 
backbone on which mAb targeting GD2 is added. Although IT have known 
myelosuppressive adverse effects, anti-GD2 mAb therapy may be effective in this IT 
chemotherapy setting when combined with GM-CSF; ADCC and CDC are dependent on 
complement and myeloid cells such as neutrophils, which recover faster than 
lymphocytes20. 
In support of these considerations, a significant and early anti-tumor activity was 
observed in a small, randomized phase II trial by Mody et al. with dinutuximab + GM-
CSF vs temsirolimus both as add-on to IT therapy in patients with primary refractory or 
first relapse of NB. All patients received oral temozolomide (100 mg/m2/dose) and IV 
irinotecan (50 mg/m2/dose given over 90 min) on Days 1–5. Treatments were repeated in 
cycles of 21 days. Median number of treatment courses were 3 [interquartile range (IQR) 
2–10]) and 6 [IQR 3–17] in the temsirolimus and dinutuximab arm, respectively. Of the 
17 patients randomized to IT + dinutuximab, 9 (53%, 95% CI: [29.2%, 76.7%]) had 
objective response (OR)(5 CR, 4 PR,). In the temsirolimus arm, 1 PR was observed 
(5.6%, 95% CI: [0.0%, 16.1%]). These responses appeared to be irrespective of disease 
status (relapsed vs. refractory disease, measurable vs. evaluable disease)21. A follow-up 
study including additional 36 patients non-randomly assigned to IT + dinutuximab + 
GM-CSF confirmed the favorable results. Of 53 patients overall, 22 had OR (41.5%, 
95% CI: [28.2%, 54.87%]; 11 CR, 11 PR) and 22 patients had SD22. This IT dosing 
regimen has been applied as backbone therapy with median number of cycles around 4 in 
several other NB clinical trial settings23-25. 
Preliminary and promising results have also been obtained with naxitamab + GM-CSF in 
combination with irinotecan and temozolomide (human3F8, irinotecan, temozolomide, 
sargramostim; HITS). One study included 46 (23 enrolled on protocol and 23 on 
compassionate use basis) heavily prior-treated patients with high-risk NB refractory to 
induction chemotherapy (N=7) or prior relapse (N=39). Each cycle comprised of 
irinotecan 50 mg/m2/day IV plus temozolomide 150 mg/m2/day IV or orally (Days 1-5); 


 
 
 
 
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naxitamab 2.25 mg/kg/day IV over 30 minutes, Days 2, 4, 8 and 10 (total 9 mg/kg or 270 
mg/m2 per cycle) and GM-CSF 250 mg/m2/day sc, Days 6-10. Median age at enrollment 
was 6.6 years and median number of prior relapses was 2. Early responses, assessed after 
2 cycles, were documented in 18 (39%) patients and were complete (N = 9), partial (N = 
8), and mixed (N = 1); 13 patients had SD26. Another study included 44 (36 evaluable 
and 8 non-evaluable) heavily prior-treated patients with NB treated with the same 
IT/naxitamab treatment regimen as above under compassionate use in the outpatient 
setting in Spain27. The median number of cycles was 5 (range 1-15). Median age at 
enrollment was 6 years, 16 patients had high-risk NB refractory to induction 
chemotherapy and 28 patients had previously ≥1 relapse (median number of prior 
relapses was 2). Early responses, assessed after 2 cycles, were documented in 17 (47.2%) 
of the 36 evaluable patients; 11 patients had CR (30.5%), and 6 patients had PR (16.7%). 
Ten patients had SD. One-year PFS was 37.0% (95% CI: 21.8% to 62.9%), median time 
to progression was 9.2 months. One-year OS was 55% (95% CI: 39.4% to 76.9%). In 
both studies, toxicities included myelosuppression and diarrhea as expected with IT, and 
pain and hypertension as expected with naxitamab. No other >Grade 2 related toxicities 
occurred.  
In all the above studies the safety profile of the IT regimen was manageable.  
Based on these data, naxitamab may have the potential to improve outcomes when used 
as second line therapy in combination with IT in patients with high-risk NB with primary 
refractory disease or first relapse. In line with the study by Mody et al., IT will be 
administered on Days 1 to 5 at cycles of 21 days for up to 18 cycles: irinotecan IV at 50 
mg/m2/dose/day over 90 min and temozolomide orally at 100 mg/m2/dose.  
4.3.5 
Naxitamab dose selection and infusion rate 
The efficacy and safety of naxitamab has been substantiated in Trials 12-230 and 201 at 
3.0 mg/kg/infusion over a 30-minute infusion period on Days 1, 3 and 5 (9.0 
mg/kg/cycle) every 28 days. In Trial 203, naxitamab will be administered in combination 
with GM-CSF in combination with IT in cycles of 21 days (see 4.3.4). To reduce the risk 
of naxitamab associated AEs in this treatment regimen, a slightly slower naxitamab 
dosing regimen per cycle will be applied at 2.25 mg/kg/day on Days 2, 4, 8 and 10 (total 
9 mg/kg per cycle) as described by Mora J et al. (see Section 4.3.4)26, 27. Furthermore, to 
reduce the risk of infusion related toxicity, naxitamab will be administered over 
minimum 60 min for the first infusion and 30 min for subsequent infusions.  
If patients discontinue IT treatment due to toxicity, the naxitamab+GM-CSF regimen can 
be continued: naxitamab will then be administered IV at 3.0 mg/kg/day on Days 1, 3 and 
5 (9.0 mg/kg/cycle) in cycles of 28 days in accordance with the regimen applied in the 
naxitamab clinical development program (see Section 4.3.2) . 
4.3.6 
Use of GM-CSF in combination with naxitamab 
During the naxitamab clinical development program, naxitamab has been administered in 
combination with GM-CSF (sargramostim) (see Section 4.3.2). Furthermore, naxitamab 


 
 
 
 
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is approved for combination treatment with GM-CSF in the US and dinutuximab 
(Unituxin®) is approved for use in combination with IL-2 and GM-CSF in the US12, 13. In 
the clinical setting, GM-CSF increases neutrophil production and maturation of 
monocytes to macrophages and can amplify the anti-NB activity of naxitamab via effects 
on these cells28, 29. Moreover, GM-CSF has been found to be well tolerated compared to 
other cytokines such as interleukin-2 (IL-2)26, 27. Based on these considerations, 
naxitamab will be administered in combination with GM-CSF in this trial. GM-CSF 
(sargramostim) will be administered at 250 ug/m2/day sc on Days 6-10, in accordance 
with a dosing regimen found to be efficacious and with a manageable safety profile11, 29, 
30 and in an ongoing clinical trial at MSK (NCT03189706). If patients discontinue IT 
treatment due to toxicity, the naxitamab+GM-CSF regimen can be continued: GM-CSF 
will be administered sc at 250 ug/m2/day on Days -4 to 0 and at 500 ug/m2/day on Days 1 
to 5 in cycles of 28 days in accordance with the regimen applied in the naxitamab clinical 
development program. 
4.3.7 
Choice of trial population 
The trial will include patients with high-risk NB with measurable and/or evaluable 
disease and either with primary refractory disease or in first relapse following induction 
and consolidation therapy. Primary refractory disease or first relapse following induction 
therapy is associated with poor outcomes and no approved SoC exists for treatment of 
this patient population. Thus, there is a high unmet medical need for more efficacious 
treatments. The age cut-off of 12 months is applied, as most infants with disseminated 
disease have a favorable outcome following treatment with chemotherapy and surgery31-
33. 
4.3.8 
Choice of trial design 
Trial 203 is an open label, uncontrolled, multicenter trial. Due to the devasting nature of 
refractory and relapsed high-risk NB with 10-years OS of less than 15% and the only 
modest effect of IT treatment alone, a single arm trial design is applied. The primary 
endpoint ORR is an endpoint accepted for single arm trials by regulatory authorities for 
efficacy evaluation of anti-cancer therapies34, 35.  
The assessment of the primary endpoint after completion of 4 cycles is considered 
appropriate based on published clinical trials on IT treatment and on completed trials on 
naxitamab17, 18, 21, 22. The long-term follow-up of 2-years after End of Treatment is to gain 
data on long-term efficacy and safety of naxitamab in combination with IT. 
4.4 
Benefit-risk assessment 
Chemo resistant and relapsed disease are major obstacles to curing high-risk NB. Despite 
intensive frontline therapy, approximately 50% of patients with high-risk NB experience 
persistence of disease or develop PD6. The prognosis for patients with recurrent or 
refractory NB is extremely poor with 10-years OS of less than 15%7. Thus, more 
efficacious treatments for this patient population remains a large unmet medical need. 


 
 
 
 
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Naxitamab is a mAb targeting GD2 widely expressed on NB cells. Across Trials 12-230 
and 201 in patients with high-risk refractory or relapsed NB in bone and/or BM, 
naxitamab in combination with GM-CSF was found to provide a statistically significant 
and clinically relevant ORR ranging from 
to 68% and CR rates ranging from 
 to 
59%. In these trials, naxitamab was found to be overall well tolerated with acute 
toxicities/infusion related AEs that could be managed by pre-medications (opioids, 
corticosteroids, antipyretics, and antihistamines) along with concomitant administration 
of normal saline, opioids, nebulized beta-2 agonists, and oxygen as applicable. In further 
support of a manageable safety profile, 95% of all infusions were performed in the out-
patient setting with similar rates across cycles and infusions in Trial 201. Moreover, 
treatment of patients with naxitamab + GM-CSF in combination with IT indicated 
promising anti-cancer effect also with a manageable safety profile26, 27.  
Based on the above, naxitamab + GM-CSF in combination with IT has the potential to 
improve outcomes earlier during the high-risk NB disease course and thereby address the 
important unmet medical need in this patient population. 
 


 
 
 
 
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5 
TRIAL OBJECTIVES 
5.1 
Primary Objective 
To investigate the efficacy of naxitamab + GM-CSF in combination with IT as assessed 
by ORR in patients with high-risk NB with primary refractory disease or in first relapse. 
5.2 
Secondary Objective 
To further investigate the efficacy and safety of naxitamab + GM-CSF in combination 
with IT in patients with high-risk NB with primary refractory disease or in first relapse. 


 
 
 
 
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6 
ENDPOINTS 
6.1 
Primary Endpoint 
ORR, defined as the proportion of patients obtaining a centrally assessed CR or PR 
according to the International Neuroblastoma Response Criteria (INRC) at or before 
completion of four cycles. 
6.2 
Secondary Endpoints 
1. ORR after 2 cycles defined as the proportion of patients obtaining a centrally 
assessed CR or PR according to the INRC at completion of two treatment cycles 
2. Duration of response (DoR), defined as the time from first centrally assessed OR 
(CR or PR according to the INRC) to PD or death 
3. CR rate, defined as the proportion of patients obtaining a centrally assessed CR 
according to the INRC at or before completion of four treatment cycles  
4. CR rate after two cycles defined as the proportion of patients obtaining a centrally 
assessed CR according to the INRC at completion of two treatment cycles 
5. Minor response (MR) rate, defined as the proportion of patients obtaining a 
centrally assessed MR according to the INRC at or before completion of four 
treatment cycles 
6. ”MR or better” rate, defined as the proportion of patients obtaining a centrally 
assessed CR, PR or MR according to the INRC at or before completion of four 
treatment cycles 
7. Proportion of patients with disease in BM at enrollment who obtain centrally 
assessed CR in BM and convert to minimal residual disease (MRD) negative 
(assessed by reverse transcriptase-quantitative polymerase chain reaction 
(RTqPCR)) at or before completion of four cycles 
8. Time to First Subsequent Therapy or death (defined as the time from initiation of 
treatment with investigational medicinal products (IMP) until death or start of 
new anti-cancer treatment (prohibited as per protocol)) 
9. PFS defined as the time from first IMP administration until centrally assessed PD 
or death, whichever comes first  
10. OS defined as the time from first IMP administration until death 
11. 1- and 2-years PFS defined as the proportion of patients alive and with no 
centrally assessed PD at 1- and 2 year, respectively after first IMP administration 
12. 1- and 2-year OS defined as the proportion of patients alive at 1- and 2 years after 
first IMP administration 
13. Safety incl. incidence of AEs and SAEs graded according to Common 
Terminology Criteria for AEs (CTCAE) version 5.0 
14. Pain during naxitamab infusions as assessed by Wong Baker- and FLACC scales  
15. Incidence of ADA (including assessment for neutralizing potential and time to 
first positive ADA assessment from first day of naxitamab administration) 
16. Number of naxitamab infusions done in an out-patient setting defined as infusions 
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6.3 
Exploratory Endpoints 
1. Confirmed ORR after 2 cycles defined as the proportion of patients obtaining a 
centrally assessed confirmed CR or PR according to the INRC at completion of 
two treatment cycles 
2. Duration of confirmed response, defined as the time from first centrally assessed 
confirmed OR (CR or PR according to the INRC) to PD or death 
3. Confirmed CR rate, defined as the proportion of patients obtaining a centrally 
assessed confirmed CR according to the INRC at or before completion of four 
treatment cycles  
4. Confirmed CR rate after two cycles defined as the proportion of patients 
obtaining a centrally assessed confirmed CR according to the INRC at completion 
of two treatment cycles 
5. Primary endpoint and secondary efficacy endpoints (number 1-7, 9 and 11) based 
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7 
DESCRIPTION OF DESIGN AND TRIAL POPULATION 
7.1 
Overall Trial Design  
This is an open label, single-arm, multicenter, phase 2 trial, in patients ≥ 12 months of age 
with high-risk NB with primary refractory disease or in first relapse. 52 patients who have all 
received at least 1 dose of IMP will be enrolled. Response assessment of images and BM 
biopsies and aspirates will undergo central review by independent external experts. An 
independent Data Monitoring Committee (DMC) will oversee trial safety. 
7.2 
Overall Trial Plan 
The trial includes a screening visit to assess the patient’s eligibility. Patients fulfilling the 
eligibility criteria will receive up to 70 weeks of treatment with naxitamab and GM-CSF in 
combination with IT. End of Treatment (EOT) will be 6 (up to 10) weeks after last treatment. 
After EOT the patient will enter a long-term FU up to 2 years. Please refer to Figure 1 in 
7.2.1. 
7.2.1 
Treatment 
Each treatment cycle is 21 days. Patients will receive irinotecan 50 mg/m2/day IV and 
temozolomide 100 mg/m2/day orally (both on Days 1-5) in combination with naxitamab 2.25 
mg/kg/day IV (Days 2, 4, 8 and 10) (total 9 mg/kg per cycle), and GM-CSF 250 ug/m2/day 
sc, (Days 6-10). Patients will receive up to 18 IT cycles after enrollment. Naxitamab and 
GM-CSF will be given for at least 8 cycles.   
Patients who discontinue IT due to unacceptable toxicity will be offered treatment with 
naxitamab + GM-CSF alone. The treatment will be administered in 28-days cycles with 
naxitamab 3.0 mg/kg/infusion at Days 1, 3 and 5 and GM-CSF 250 µg/m2/day for 5 days 
from Days -4 to 0, and at 500 µg/m2/day for 5 days from Day 1 to Day 5. The total number of 
naxitamab treatment cycles will be at least 8 cycles (including the cycles given in the HITS 
regimen.  
Patients who discontinue GM-CSF due to unacceptable toxicity should continue naxitamab 
treatment. 
Patients achieving a CR or PR (both patients receiving HITS or naxitamab + GM-CSF alone) 
should receive 8 naxitamab cycles or 5 additional naxitamab cycles following the objective 
response, whichever provides the longest treatment with naxitamab. Patients who have 
achieved a MR or SD at completion of the 8 cycles (both patients receiving HITS or 
naxitamab + GM-CSF alone) may receive naxitamab + GM-CSF consolidation treatment for 
5 cycles administered at every 6 weeks (in the HITS regimen) or 8 weeks (in the naxitamab + 
GM-CSF alone regimen). The total number naxitamab cycles to be administered includes the 
treatment cycles administered in the HITS regimen. 


 
 
 
 
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Figure 1 Trial design 
 
7.3 
Recruitment Period 
It is estimated that ~18 months will be needed to recruit the planned number of patients. 
7.4 
Screening/Pre-treatment Evaluation 
Pre-treatment evaluations should be completed within 21 days prior to start of trial treatment 
on Day -3. Please refer to the screening visit in the flowchart (Section 3) Procedures (except 
BM biopsies/aspirates and imaging) performed by site as part of SoC within the screening 
period may be used for the evaluation of patient eligibility even if the evaluation is performed 
prior to patient information and ICF signature. 
7.5 
Patient Replacement 
No patient replacement is allowed. 
7.6 
Screening Failures and Re-screening 
Screen failures are defined as patients who consent to participate in the clinical trial but are 
not eligible according to in/exclusion criteria. 
Individuals who do not meet the criteria for participation in this trial may be re-screened 
under the following circumstances: 
• If the time elapsed since occurrence of a treatment/procedure would otherwise 
qualify for an exclusion criterion 
• If the laboratory parameters defined in the exclusion criteria are met but are 
expected to improve and not meet the exclusion criteria at the discretion of the 
investigator. 
• Age < 12 months 
• Stabilization or improvement of a clinical condition that would otherwise 
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If a patient is re-screened the patient should receive a new patient identifier (ID), i.e., a 
patient can have multiple screening IDs, but only one treatment ID. If a patient is re-screened 
the parents/patient must sign a new informed consent form (ICF). 
7.7 
Enrollment 
A patient is defined as enrolled, when the patient is confirmed eligible according to 
in/exclusion criteria and ready to start pre-treatment Day-3. 
7.8 
Follow-up 
EOT assessments should take place minimum 6 weeks (up to 10 weeks) after last treatment. 
If treatment is discontinued due to PD, planned initiation of new anti-NB treatment 
prohibited as per protocol, withdrawal from the trial or investigator judges it warranted due to 
medical reasons/non-compliance, the patient should be called for EOT visit as soon as 
possible and before initiation of new anti-NB treatment. The patients should subsequently be 
followed for safety and new anti-cancer therapy for a total of 6 weeks after last treatment (see 
flowchart in Section 3 and treatment discontinuation criteria in Section 7.12). 
 
After EOT, a long-term FU period will start. The patient will attend long-term FU visits 
approximately every 4 months for up to 2 years after EOT.  
The investigator will perform response assessments (if the patient has not experienced PD) 
(see Section 3, 9.1.1, 9.1.2 and Appendix 2), report death and PD (as applicable) and collect 
information on SAEs ongoing at EOT visit, new SAEs at least possibly related to naxitamab 
treatment, secondary malignancies, and autoimmune diseases. Furthermore, new anti-cancer 
therapy should be collected as concomitant medication. Please refer to flowcharts in Section 
3 and Appendix 2. 
 
Trial period completion is defined as when the patient has completed the final scheduled visit 
(long-term FU visit 2 years after EOT).  
7.9 
End of Trial 
End of Trial is defined as last patient’s last visit or death. “Date of trial completion” is the 
date the patient completed the final scheduled visit. 
7.10 Number of Patients 
With an estimated screen failure rate of 25% approximately 70 patients will be screened to 
achieve the planned 52 patients.  
7.11 Patient Selection 
The trial will include patients with high-risk NB who have received SoC frontline 
chemotherapy with or without autologous stem cell transplant (ASCT) and have been 
designated primary refractory disease or have experienced first relapse following frontline 
SoC, comparable to the following protocols for frontline therapy: 
• Childrens Oncology Group (COG) protocol 0532,  
• COG-US protocol A3973  
• GPOH based induction (as per the NB 2004) 
• MSKCC N5 or N7 (MSK-US) 
• Rapid Cojec (SIOPEN) 


 
 
 
 
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To be eligible, the patient must meet all inclusion criteria and must not violate any of the 
exclusion criteria. Patient eligibility must be approved by the sponsor before the patient 
receives IMP in the trial. This is done by completing the patient eligibility form. 
7.11.1 
Inclusion Criteria 
1. Documented NB at time of initial diagnosis36 defined as: 
o Histopathological verification of NB or ganglioneuroblastoma nodular, or  
o BM aspirate or biopsy indicative of NB (according to INRC)37 and high blood 
or urine catecholamine metabolite levels (> 2 x upper limit of normal)  
2. Documented high-risk disease at time of initial diagnosis defined as33, 38:  
o MYCN-amplified any stage (according to International Neuroblastoma Risk 
Group (INRG)) of any age or 
o MYCN-nonamplified with stage M (according to INRG) and diagnosed at ≥ 
18 months of age  
3. Patient should have received SoC frontline induction/consolidation therapy (surgery, 
chemotherapy, ASCT, MIBG, radiotherapy, immunotherapy, or retinoids) 
4. Patients must have active disease despite previous aggressive multi-drug 
chemotherapy (≥ 2 agents, including an alkylating agent and a platinum containing 
compound) defined as one of the following:  
o verified first progression during multi-drug frontline treatment or  
o verified first episode of relapse, defined as recurrence after response to 
frontline treatment, or  
o verified first designation of refractory disease, defined as persistent metastatic 
disease (SD or minor response by INRC37, 39 and MIBG curie score ≥339) 
detected at conclusion of at least 4 cycles of multi-drug induction 
chemotherapy on or according to a high-risk NB treatment protocol as defined 
above (7.11). 
5. The patients must have one of the following (locally assessed) obtained within 3 
weeks prior to enrollment and at least 10 calendar days after end of any prior anti-
cancer treatment: 
o Measurable tumor on CT/MRI scan that is MIBG-avid or demonstrates 
increased FDG uptake on PET scan  
o MIBG scan with positive uptake at a minimum of one site. This site must 
represent disease recurrence after completion of therapy, progressive disease 
on therapy, or refractory disease during induction 
6. Aged ≥ 12 months at enrollment 
7. Written informed consent from legal guardian(s) and/or patient obtained in 
accordance with local regulations. Pediatric patients must provide assent as required 
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7.11.2 
Exclusion Criteria 
1. A diagnosis of myelodysplastic syndrome or any malignancy other than NB 
2. Any systemic anti-cancer therapy, including chemotherapy, or immunotherapy, within 
3 weeks prior to enrollment 
3. ASCT within 6 weeks prior to enrollment or ongoing toxicity due to the stem cell 
transplant at the discretion of the investigator 
4. Therapeutic 131I-MIBG within 6 weeks prior to enrollment 
5. RT within 4 weeks prior to enrollment at the site of any lesion that will be identified 
as a target lesion to measure tumor response. Lesions that have been previously 
radiated cannot be used as target lesions unless there is radiographic evidence of 
progression at the site following radiation or a biopsy done following radiation shows 
viable NB. There are no time restrictions following prior RT for non-target lesions or 
for palliative radiation to sites that will not be used for response assessment 
6. Prior treatment with anti-GD2 therapy if the patient experienced PD while on anti-
GD2 treatment 
7. Receipt of second line chemotherapy after designation of primary refractory disease 
or first relapse or PD 
8. Patients with NB in BM only 
9. NB in the CNS or leptomeningeal disease within 6 months prior to enrollment 
10. Performance status of < 50% as per the Lansky scale (patients less than 16 years of 
age) or Karnofsky scale (for patients aged 16 years or older) 
11. Life expectancy of less than 6 months, as judged by the Investigator 
12. Left ventricular ejection fraction < 50% by echocardiography 
13. Inadequate pulmonary function defined as evidence of dyspnea at rest, exercise 
intolerance, and/or chronic oxygen requirement. In addition, room air pulse oximetry 
< 94% and/or abnormal pulmonary function tests if these assessments are clinically 
indicated  
14. Patients with ≥ Grade 2 diarrhea 
15. Treatment with long-acting myeloid growth factor within 14 days or short-acting 
myeloid growth factor within 7 days prior to first dose of GM-CSF 
16. Treatment with immunosuppressive treatment (local steroids excluded) within 4 
weeks prior to enrollment 
17. Life threatening infection(s) 
18. Patients with uncontrolled seizure disorders despite anticonvulsant therapy (defined as 
a seizure event within 3 months prior to enrollment)  
19. Treatment with enzyme-inducing anticonvulsants including phenytoin, phenobarbital, 
or carbamazepine for at least 7 days prior to enrollment 
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21. Allogeneic hematopoietic stem cell transplantation (allo-SCT) or donor-lymphocyte-
infusion (defined as any kind of active allogeneic lymphocyte suspension)  
a. within 6 months of 1st dose of GM-CSF or  
b. with a lymphocyte count < 0.2 x109/L 
22. Treatment with Hematopoietic Progenitor Cell (HPC) boost within 2 months prior to 
enrollment 
23. History of allergy or known hypersensitivity to GM-CSF, yeast-derived products, or 
any component of GM-CSF, naxitamab, irinotecan or temozolomide  
24. History of anaphylactic reactions CTCAE Grade 4 related to prior anti-GD2 antibody 
therapy 
25. Unacceptable hematological status at screening (hematological support is allowed if 
administered ≥1 week before screening procedure), defined as one of the following: 
a. Hemoglobin <5.0 mmol/L (<8 g/dL) 
b. White blood cell count <1000/µL 
c. Absolute neutrophil count <750/µL  
d. Platelet count < 75,000/µL 
26. Unacceptable liver function at screening, defined as one of the following: 
a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >5 
times upper normal limit (UNL)  
b. Total bilirubin >1.5 x UNL 
27. Unacceptable kidney function at screening, defined as: 
o Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 calculated 
by the 2009 revised Bedside Schwartz Equation (Appendix 1) 
28. Inability to comply with protocol 
29. Patients with a significant intercurrent illness (any ongoing serious medical problem 
unrelated to cancer or its treatment) that is not covered by the detailed exclusion 
criteria and that is expected to interfere with the action of IMPs or to significantly 
increase the severity of the toxicities experienced from trial treatment 
30. Females of childbearing potential (as defined in Section 9.2.8) who are pregnant, 
breast feeding, intend to become pregnant, or are not using adequate contraceptive 
methods as defined in 9.2.8 or males who are not using adequate contraceptive 
methods as defined in 9.2.8. Contraception must be used for 6 months after last IT 
treatment or 42 days after last naxitamab treatment whichever comes last for both 
genders 
 
7.12 Premature Discontinuation of Treatment   
General discontinuation criteria  


 
 
 
 
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A patient should be discontinued from treatment with all IMPs if any of the following 
situations occur: 
1. Grade 4 anaphylaxis related to naxitamab 
2. Grade 3 anaphylaxis related to naxitamab not responding to medical intervention at 
the discretion of the investigator 
3. Grade 4 sensory neuropathy or Grade 3 sensory neuropathy that interferes with daily 
activities for more than 2 weeks at the discretion of the investigator 
4. CTCAE Grade 3 pain unresponsive to maximum supportive measures at the 
discretion of the investigator 
5. Grade 4 bronchospasm 
6. Grade 3 bronchospasm not responding to medical intervention at the discretion of the 
investigator 
7. Posterior reversible encephalopathy syndrome (PRES) 
8. The investigator judges it necessary for medical reasons/non-compliance 
9. The patient receives prohibited therapy and/or procedures during the trial, see Section 
8.4.8 
10. Pregnancy 
11. Patient/legal guardian withdraw consent to treatment 
12. PD  
Discontinuation criteria for IT 
A patient should be discontinued from IT treatment if any of the following situations occur: 
1. If the patient experiences neutropenia that causes a delay ≥ 14 days after the first dose 
reduction by 20% of irinotecan and the second dose reduction by 20% of 
temozolomide 
2. If the patient experiences thrombocytopenia that causes a delay ≥ 14 days after the 
first dose reduction by 20% of irinotecan and the second dose reduction by 20% of 
temozolomide 
3. If the patient does not meet the criteria to start the next cycle within 21 days after the 
planned subsequent cycle start date 
4. Recurrence of ≥ Grade 3 diarrhea despite maximal use of anti-diarrheals, prophylactic 
antibiotics, and a dose reductions of irinotecan of 20%  
5. Recurrence of ≥ Grade 3 regimen-related nausea and/or vomiting despite optimization 
of anti-emetic drugs and a dose reduction of IT by 20% 
6. If ≥ Grade 3 regimen-related dehydration recurs and persists for >3 days despite a 
dose reduction of IT by 20% 
 
Discontinuation criteria for GM-CSF 
A patient should be discontinued from GM-CSF treatment if any of the following situations 
occur: 
1. Injection site reactions ≥ CTCAE Grade 3 
2. Allergic reactions (including anaphylactic reactions) ≥ CTCAE Grade 3 


 
 
 
 
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For patients discontinuing all IMP treatments due to PD or toxicity as described above, the 
patient should attend the EOT visit (see Section 3) and subsequent enter long-term follow-up 
(see Section 7.8). 
7.13 Withdrawal 
A patient should be withdrawn from the trial at any time if: 
• Patient/legal guardian withdraw consent 
If the patient withdraws from the trial, the patient should be asked to attend an EOT visit as 
soon as possible. Furthermore, if possible the patient should be followed for safety for 6 
weeks after last dose of naxitamab for safety reasons. 


 
 
 
 
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8 
TREATMENTS 
8.1 
Investigational Medicinal Products (IMPs) 
For this trial, Y-mAbs will provide naxitamab, GM-CSF, irinotecan  and temozolomide. All 4 
products are classified as IMPs. The IMPs provided must be used solely for this trial as 
described in this protocol and for no other purpose. For further information on naxitamab, 
GM-CSF and IT refer to the IB and current summary of product characteristics (SmPCs). A 
summary of the IMPs is provided in Table 3. 
No other medicinal products or auxiliary supplies will be provided by Y-mAbs. 
Table 3 IMPs provided by Y-mAbs 
IMP: 
Irinotecan 
Temozolomide Sargramostim 
(GM-CSF) 
 
Naxitamab  
Route: 
IV infusion  
Orally 
Sc 
IV infusion 
Dosing 
instruction: 
Days 1-5            
50 mg/m2/day 
Days 1-5         
100 mg/m2/day  
Days 6-101       
250 µg/m2/day1 
Days 2, 4, 8 
and 101           
2.25 
mg/kg/day1 
Pharmaceutical 
form: 
Solution for 
infusion 
 
Capsules 
Lyophilized 250 
μg single use 
vial 
Solution for 
infusion 
Unit strength 
20 mg/mL 
5, 20 and 100 
mg 
250 μg/vial 
4 mg/mL 
1 Please refer to Appendix 2 for dosing days and dose for treatment of patients who discontinue IT treatment  
8.1.1 
Administration of IMP for Each Patient 
The patient must have a well-functioning intravenous catheter before initiating any treatments 
for IV administration; a central line is recommended. For naxitamab treatment, site should 
have emergency equipment readily available, and the patient should have 2 well-functioning 
IV accesses before any naxitamab treatment is initiated. 
Please refer to the IMP manual for more details on preparation and administration of 
temozolomide, irinotecan, GM-CSF and naxitamab.  
Before administration of IMPs, patients must meet hematologic, renal and hepatic eligibility 
criteria for trial entry at the start of each treatment cycle (see Section 7.11.2). 
8.1.2 
Treatment schedule 
Please refer to Appendix 2 if the patient has discontinued IT treatment due to toxicity. 


 
 
 
 
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Table 4 Treatment schedule 
Treatment days in cycles of 21 
days 
-3 to 0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11-12 13-21 
Premedication (8.4.1, 8.4.3) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Irinotecan 50 mg /m2/day (IV) + 
temozolomide 100 mg/m2/day 
(orally) (8.1.2.1, 8.1.2.2) 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Naxitamab 2.25 mg/kg/day IV 
(9mg/kg/cycle)1 (8.1.2.3)1 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
GM-CSF 250 ug/m2/day s.c 
(8.1.2.4)1 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
1) Patients achieving a CR or PR should receive 8 naxitamab cycles or 5 additional naxitamab cycles following the OR, 
whichever provides the longest treatment with naxitamab. Patients who have achieved a MR or SD at completion of the 8 
cycles may receive naxitamab + GM-CSF consolidation treatment for 5 cycles administered at every 6 weeks 
 
8.1.2.1 
Temozolomide 
Temozolomide will be administered orally at 100 mg/m2/day on Days 1-5. For patients, 
whose body surface area (BSA) is ≥ 0.5m2, the temozolomide dose should be rounded off to 
the nearest 5 mg (Appendix 3). Administration should preferable be on an empty stomach (at 
least 1 hour before or 2 hours after food intake) to decrease nausea and vomiting and improve 
absorption. For patients who are unable to swallow capsules, the capsule content may be 
mixed with apple sauce or apple juice or be prepared for suspension, please refer to Appendix 
6 and Appendix 7. If emesis occurs within 20 min of taking a dose of temozolomide, the dose 
may be repeated once. If emesis occurs after 20 min, the dose should not be repeated.  
8.1.2.2 
Irinotecan 
Irinotecan will be infused IV at 50 mg/m2/day over 90 min on Days 1-5. Antiemetics should 
be administered as necessary according to local SoC. Irinotecan should be administered at 
least 1 hour after temozolomide has been given.  
8.1.2.3 
Naxitamab 
On days when co-administered with GM-CSF, naxitamab infusion is started ≥ 60 min after 
GM-CSF. 
On days when co-administered with IT (i.e., Days 2 and 4), it is recommended to start 
naxitamab infusion at least 1 hour after irinotecan administration to allow for preparations 
and administration of pre-medications. 
Naxitamab should be infused IV at 2.25 mg/kg/day on Days 2, 4, 8 and 10 for a total dose of 
9 mg/kg per cycle (Please refer to Appendix 2 for details on naxitamab treatment if the 
patient has discontinued IT treatment due to toxicity). Administration of naxitamab should be 
adjusted according to Section 8.4.5, if selected naxitamab adverse reactions are observed. If 
any events occur fulfilling a general discontinuation criterion the patient must be withdrawn 
from all treatments immediately and enter long-term FU, see Section 7.12. 
 
At Cycle 1 Day 2 (C1D2): 


 
 
 
 
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Naxitamab should be infused over approximately 60 min. 
All subsequent naxitamab infusions: 
Naxitamab should be infused over approximately 30 min. 
Special circumstances 
The infusion may be given over approximately 60 min. at Day 2 of any cycle at the 
investigator’s discretion if: 
• The patient during C1D2 experienced naxitamab related hypotension: 
o Grade 4 or 
o Grade 3 not adequately responding to intervention 
• At the investigator’s discretion due to severe infusion related adverse drug reactions 
not adequately responding to interventions 
 
The 60/30 min infusion time is a minimum infusion time. If infusion pause or infusion rate 
reduction is required due to infusion related AE (see Section 8.4.5) the infusion time will 
become longer.  
Naxitamab treatment in an out-patient setting is defined as a naxitamab infusion performed in 
the ambulatory setting. 
In-patient treatment (i.e. requiring hospitalization) includes both short term admissions and 
admissions requiring overnight stay. 
8.1.2.4 
GM-CSF 
GM-CSF will be administered sc at 250 μg/m2/day on Day 6 to Day 10. (Please refer to 
Appendix 2 for details on GM-CSF treatment if the patient has discontinued IT treatment due 
to toxicity). The first dose of GM-CSF should be administered at the trial site. GM-CSF and 
auxiliary supplies will be provided to the patient/parents for administration at home after the 
patient/parents has received appropriate training on how to administer the drug. Thorough 
instructions should be given orally and in writing including instructions on how to store and 
administer the reconstituted GM-CSF at home. The patient/parents will be asked to fill in 
records of administration (patient diary). Auxiliary supplies include e.g., syringe, needles, 
sharps disposal container, gloves, alcohol wipes. 
GM-CSF must not be administered simultaneously with, within 24 hours preceding or 24 
hours following receipt of chemotherapy or radiotherapy. 
8.1.3 
Treatment delays and missed dosing 
Minor adjustment of the treatment schedule due to medical circumstances (e.g., infection) at 
the discretion of the investigator or non-medical circumstances (e.g., public holidays) is 
allowed. 
It is allowed to postpone the start of a new cycle due to IT toxicity for up to 21 days after the 
planned subsequent cycle start date (i.e., < 3-weeks delay in start of next cycle) (please see 
treatment discontinuation criteria Section 7.12).  


 
 
 
 
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If a naxitamab dose is missed, administer the missed dose on Day 12. In that case, treatment 
with GM-CSF at 250 μg/m2/day should be continued until Day 12 (i.e., treatment from Day 6 
to Day 12). Please refer to Appendix 2 if the patient has discontinued IT treatment due to 
toxicity. 
8.1.4 
Treatment after Discontinuation of IMP 
If the patient prematurely discontinues all IMPs and after End of Trial, any treatment deemed 
safe and justified by the Investigator can be administered according to clinical practice and at 
the discretion of the Investigator. 
8.1.5 
Drug Accountability and Compliance Check 
Each trial site will be supplied with sufficient IMPs for the trial on an ongoing basis. IMPs 
will be distributed to the trial sites according to enrollment.  
Drug accountability must be documented by the trial staff on the dedicated forms. The 
investigator or designee is responsible for drug accountability and record maintenance (i.e., 
receipt, accountability, and final disposition records). The patient/parents will be provided 
with a diary to record the administration of GM-CSF at home. The patient/parents should 
bring these records to the hospital visits together with all used, partly used and unused GM-
CSF, as instructed by the investigator. All returned, expired, or damaged IMP must be stored 
separately from non-allocated trial products. Non-allocated IMP including expired or 
damaged IMP must be accounted as un-used, at the latest at closure of the trial site. For more 
information on accountability procedures, please refer to IMP manual. 
Clinical personnel at the site will record in the source notes the timing (i.e., date and time) 
and the way of administration of all administrations of irinotecan, temozolomide and 
naxitamab, including changes to infusion rate and dose reductions. Furthermore, the clinical 
personnel will assess the GM-CSF treatment compliance by reviewing the patient diaries. 
Any reasons for non-compliance should be documented in the hospital records and be 
discussed with the patient/parent(s) as applicable. 
8.1.6 
Packaging and Labelling 
Packaging and labelling of naxitamab, GM-CSF and IT will be outsourced to a clinical 
packaging contract manufacturing organization. All products are labelled according to Annex 
13, EudraLex, volume 4 and local requirements. Each unit of product are uniquely numbered. 
Further detailed information on labelling and packaging is described in the IMP manual. 
8.1.7 
Storage and Handling 
The IMPs provided by Y-mAbs must be stored according to the IMP label in a secure 
location with controlled access separately from normal clinical stock. The storage conditions 
must be monitored for adherence to label claims. Temperature monitoring data must be 
reviewed by the Clinical Research Associate (CRA) during monitoring visits. Any deviations 
in storage temperature must be reported immediately and the IMP must not be used until 
acceptance is received. Monitoring must be done using a calibrated, stationary, and 
continuously recording system. As a minimum a calibrated min/max thermometer is required.  
Further detailed information on storage and handling of the IMP is described in the IMP 
Manual. 


 
 
 
 
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8.2 
Medication Errors, Misuse and Abuse 
Medication errors, misuse and abuse must be reported in the medication error eCRF 
Medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the IMPs may include: 
• Administration of wrong drug  
• Wrong route of administration, such as intramuscular (IM) instead of IV  
• 
Accidental administration of a lower or higher dose than intended. An overdose is 
defined as a patient receiving a dose of the IMP exceeding 10% as compared to the 
protocol-specified dose.  An underdose is defined as a patient receiving a dose of the 
IMP less than 10% as compared to the protocol-specified dose. 
• Misuse: Inappropriately use of a medicinal product outside the terms of the protocol 
• Abuse: Intentional excessive use of the IMP which is accompanied by harmful 
physical or psychological effects (e.g., suicide attempt) 
If a medication error results in an AE, the AE must also be reported in the electronic case 
report form (eCRF). If the event qualifies as a SAE it must be reported using the paper 
Clinical AE Report form in addition to the AE form in the eCRF (see also Section 10 for 
reporting of AEs). 
8.3 
Technical complaint 
A technical complaint is any written or oral communication that states any dissatisfaction 
regarding the IMP characteristics and alleges a product defect. A technical complaint can be 
related to e.g., the product appearance (discoloration, presence of particles or sediments), 
product container (damaged or missing seal), product label (damaged, missing, misleading), 
or consignment (wrong amount of vials in the package). A complaint should also be initiated 
if the product is suspected to be falsified.  
Complaints should be immediately (within 24 hours) reported to Y-mAbs Quality Assurance. 
Please refer to the IMP manual for information regarding reporting of a technical complaint. 
8.4 
Concomitant Therapy 
A concomitant medication is any medication other than the IMPs. All concomitant 
medications (including over the counter) that the patient is receiving at the time of screening 
or receives during the trial must be entered in the eCRF with the following information: 
• Generic name (preferred) or trade name 
• Start date 
• Stop date of administration or ongoing at trial termination 
• Time of administration if administered as naxitamab pre-medication (see Section 
8.4.1) 
• Indication/ reason for use 


 
 
 
 
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• Dose 
• Frequency 
• Outcome (for anti-cancer treatments during long-term FU). 
Any changes to concomitant during the trial should be recorded in the eCRF. If a change is 
due to an AE/SAE, then the AE/SAE must be recorded according to Section 10. During long-
term FU, only new anti-cancer therapy should be collected. 
8.4.1 
Pre-medications Prior to Naxitamab Infusions 
Pre-medication is needed to mitigate expected AEs with naxitamab. These include pain, 
infusion-related reactions, hypotension, allergic reactions, nausea/vomiting and potentially 
anxiety.  
Infusion with naxitamab is associated with pain that may be severe. The pain may involve the 
abdomen, lower back, chest, legs and arms. The duration may vary but, for most patients, the 
pain lasts for a couple of hours, and tends to be worst during the naxitamab infusion, 
subsiding approximately 15 min after end of infusion . Due to the pain, patients may “hold 
their breath”. A marked variation in the naxitamab-associated pain may be observed from 
infusion to infusion, and hence the recommended opiod dosages below are applicable only to 
the first infusion. Opiod pre-medications for mitigation of pain during subsequent infusions 
of naxitamab and pain medications after completion of the naxitamab infusion should be 
adjusted at the discretion of the investigator.  
All medications (including opioid usage) should be captured on the concomitant medication 
eCRF. 
At home 
To reduce the risk of pain, gabapentin should be administered from Day -3 to Day 12 of each 
cycle according to local SoC (e.g., dose of 5 to 10 mg/kg with a max dose of 600 mg).  
It is recommended to titrate to the final effective dose during the first 3 days of treatment: 
Day -3: Once daily; Day -2: Twice daily; Day -1 and until Day 10: 3 daily doses (please refer 
to Appendix 2 if the patient has discontinued IT treatment due to toxicity).  
After completion of the naxitamab treatment (i.e. Day 10), it is recommended to tapper off 
the gabapentin treatment: Day 11: Twice daily; Day 12: Once daily. If nerve pain lingers, the 
patient may continue gabapentin on twice daily dosing for up to a week post naxitamab 
treatment before further weaning. 
 
At hospital 
• Saline solution 0.9% (to reduce risk of severe hypotension) 
o Patients should be preloaded with saline 0.9%  infusion 10mL/kg over 1 hour 
just prior to the start of all naxitamab infusions 
• Opioids 
Per os (PO) opioids are preferred over IV to diminish IV related side effect such as 
hypotension, respiratory depression, and/or decreased responsiveness 
o Oxycodone 0.1 – 0.2 mg/kg with a max dose of 5 mg PO (45 – 60 min before 
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o In cases where PO administration is not feasible (15 min before naxitamab 
infusion):  
▪ Hydromorphone 0.00375 – 0.015 mg/kg IV administration over 2 - 10 
min 
or 
▪ Morphine Sulfate/ Morphine Sodium Chloride 0.025-0.1 mg/kg given 
IV over 2-10 min 
• Corticosteroids (30 min – 2 h prior to naxitamab infusion) 
o All patients at the first infusion in the first cycle must receive: 
▪ IV methylprednisolone 2 mg/kg with a max dose of 80 mg or 
equivalent corticosteroid dose 
o The same corticosteroid premedication should be given in the following 
circumstances: 
▪ At the first infusion in the following cycle if the patients had a CTCAE 
Grade 3 bronchospasm/anaphylaxis at the last cycle’s first infusion 
▪ At the following infusion if the patient had a Grade 3 
bronchospasm/anaphylaxis at the last infusion 
▪ When infusion related reactions are not sufficiently controlled by the 
other premedications at the investigator´s discretion. 
• Antipyretics (30 min before naxitamab infusion)  
o Paracetamol (acetaminophen) 10 mg/kg to maximum 15 mg/kg (max 750 mg 
total dose) PO or IV 
• Antihistamine (30 min before naxitamab infusion) 
o Hydroxyzine 0.5 – 1 mg/kg (max 50 mg) PO/IV, or 
o Diphenhydramine 0.5 – 1 mg/kg (max 50 mg) IV or  
o Cetirizine <20 kg: 2.5 mg; >20 kg: 5 mg; If > 12y AND > 30 kg: 10 mg PO or 
o Loratadine 5 mg for patients 2 – 5 years of age; 10 mg for patient > 5 years of 
age PO or 
o Equivalent according to local SoC 
• H2 antagonist according to local SoC 
• Antiemetics (30 min before naxitamab infusion) 
o Ondansetron 5 mg/m2 or 
o Equivalent according to local SoC 
If a patient receives antiemetics prior to IT treatment on Days 2 and 4, additional 
administration of antiemetics prior to naxitamab infusion will be at the discretion 
of the investigator 
• Anxiolytics, if applicable 
o Lorazepam 0.01 – 0.02 mg/kg (max 1mg) IV pro re nata (PRN) or  
o Equivalent according to local SoC 
 
In case of inadequate pain control or hypersensitivity to the above-mentioned pain 
medications, an alternative strategy to mitigate treatment-induced pain can be introduced at 
the discretion of the investigator. Ketamine can be a useful alternative to mitigate naxitamab-
induced pain40. In case of inadequate pain control with opioids, ketamine can be used 
according to local SoC. 


 
 
 
 
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8.4.2 
Supportive therapy to be readily available during naxitamab  
The following supportive therapies should be readily available at the bedside as pre-prepared 
treatments when the naxitamab infusion is initiated 
• For use at the onset of pain (pre-charged syringes): 
o Hydromorphone 0.00375 – 0.015 mg/kg given IV over 1 – 5 min, or 
o Morphine sulfate/ Morphine Sodium Chloride 0.025 – 0.1 mg/kg given IV 
over 1 –5 min. 
o Opiate doses may be repeated every 5 min for a total of 4 doses. The low, but 
frequent intermittent doses are preferred to mitigate the risk of opioid 
associated hypotention. 
o Additional doses may be ordered and given PRN at the discretion of the 
treating physician 
• PRN:  
o Lorazepam 0.01-0.02 mg/kg PO or IV (max 1 mg) or equivalent according to 
local SoC 
o H1 receptor blocker according to local SoC (e.g., dexclorfeniramine at 0.15 
mg/kg IV (max 5 mg) or diphenhydramine for IV administration)  
o NSAID according to local SoC 
o Methylprednisolone 2 mg/kg IV with a max dose of 80 mg (in case 
corticosteroid was not given as pre-medication) or equivalent corticosteroid 
dose. If corticosteroid was administered as pre-medication, a dose reduction 
should be considered at the investigator’s discretion 
o Adrenalin (epinephrine) 0.01 mg/kg IV or IM (max 0.5 mg) 
o Selective beta2-adrenergic receptor agonist nebulized administered PRN 
according to local SoC (e.g., salbutamol  < 20 kg: 2.5 mg; >20 kg: 5 mg) for 
bronchospasm  
o Epinephrine for inhalation PRN for stridor 
o Naloxone IV 1 mcg/kg/doses (to be repeated every 2-3 min until response) for 
management of potential acute cases of respiratory depression: 
o Saline 0.9% for bolus infusion: 10-20 mL/kg IV according to Section 8.4.5.2  
o Cold and hot pads to be applied locally in any body area ad libitum as part of 
pain management 
o Oxygen (oxygen mask and humidified oxygen inhalation equipment must be 
available) 
8.4.3 
Pre-medication prior to administration of irinotecan   
Prevention and management of irinotecan associated diarrhea 
Irinotecan associated early and late diarrhea and the risk hereof should be handled according 
to local SoC. This includes but is not limited to: 
• Advise on diet (e.g., to eliminate substances that may contribute to diarrhea)  
• Instructions on the use of loperamide  
• Instructions on how to prevent diarrhea-induced dehydration   
• Instructions on what situations the patient/parent should contact the investigator 
• Cephalosporin 


 
 
 
 
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o For prevention of irinotecan-associated diarrhea, it is recommended to 
administer cephalosporin according to SoC (e.g., cefixime 8 mg/kg/day PO 
once daily or cefpodoxime 10mg/kg/day PO divided into 2 daily doses, 
maximum dose 400mg/day). Treatment should be started 2 days prior to the 
first dose of irinotecan and continued until 3 days after the last dose of 
irinotecan (i.e., a total of 10 days in each cycle)  
Pneumocystis prophylaxis 
• Patients should receive pneumocystis prophylaxis according to local SoC while on IT 
treatment 
 
8.4.4 
Management of selected IT adverse reactions  
8.4.4.1 
Management of hematologic toxicities 
Patients who experienced hematologic toxicity should receive dose-reduction of IT treatment 
as described in the following sections at the discretion of the investigator. 
 
Dose-limiting neutropenia 
Patients who experience neutropenia (absolute count <750/µL) that causes a delay of ≥ 14 
days between treatment cycles in the absence of other toxicity requiring dose modification, 
should have the temozolomide dose reduced by 20% for subsequent cycles (i.e., 80 
mg/m2/day see dose reduction nomogram in Appendix 4). If despite this 20% dose reduction 
neutropenia (absolute count <750/µL) recurs, causing a delay of ≥ 14 days between treatment 
cycles, reduce the irinotecan dose by 20% (i.e., irinotecan dose 40.0 mg/m2/day) and 
temozolomide dose by additional 20% (i.e., 60 mg/m2/day see dose reduction nomogram in 
Appendix 5) for subsequent cycles. For neutropenia requiring discontinuation of IT (please 
refer to Section 7.12). 
Dose-limiting thrombocytopenia 
For patients who experience thrombocytopenia (<75,000/µL) that causes a delay of ≥ 14 days 
between treatment cycles with or without other hematologic toxicities, the dose of 
temozolomide should be reduced by 20% for subsequent cycles (i.e., 80 mg/m2/day see dose 
reduction nomogram in Appendix 4). If despite this 20% dose reduction, thrombocytopenia 
(<75,000/µL) recurs causing a delay of ≥ 14 days between treatment cycles, reduce the 
irinotecan dose by 20% (i.e., irinotecan dose 40.0 mg/m2/day) and temozolomide dose by 
additional 20% (i.e., 60 mg/m2/day see dose reduction nomogram in Appendix 5) for 
subsequent cycles. For thrombocytopenia requiring discontinuation of IT (please refer to 
Section 7.12). 
Delayed recovery of platelets, neutrophils, hepatic and/or renal laboratory parameters 
Patients who do not meet laboratory criteria to start the next treatment cycle (see eligibility 
criteria Section 7.11.2) within 21 days after the planned subsequent cycle start date (i.e., there 
is a ≥ 3-week delay in start of next cycle) must be discontinued from IT. 


 
 
 
 
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8.4.4.2 
Management of non-hematologic toxicities 
Patients who have experienced non-hematologic toxicity should receive dose-reduction of IT 
treatment as described in the following sections at the discretion of the investigator. 
Dose modification for diarrhea 
See Section 8.4.3  for patient/family instructions for supportive care measures for patients 
who develop therapy-associated diarrhea.  
• If ≥ CTCAE Grade 3 therapy-associated diarrhea is experienced by a patient despite 
maximal use of anti-diarrheal medications and appropriate use of prophylactic 
antibiotics, the dose of irinotecan should be reduced by 20% for subsequent cycles 
(i.e., irinotecan dose 40.0 mg/m2/day) 
• For treatment related diarrhea requiring discontinuation of IT (please refer to Section 
7.12) 
An IT cycle should not be initiated until treatment-related diarrhea is recovered to ≤ CTCAE 
grade 1.  
 
Dose modifications for nausea and vomiting 
• For patients with ≥ CTCAE Grade 3 regimen-related nausea and/or vomiting 
adjustments in the anti-emetic regimen should be made during the next cycle of 
therapy 
• If ≥ CTCAE Grade 3 regimen-related nausea and/or vomiting recurs despite 
optimized anti-emetic usage, doses of IT should be reduced by 20% for subsequent 
cycles (ie, irinotecan dose 40 mg/m2/day; for temozolomide see dose reduction 
nomogram in Appendix 4)  
• For ≥ CTCAE Grade 3 regimen related nausea and/or vomiting requiring 
discontinuation of IT (please refer to Section 7.12) 
Dose modifications for dehydration 
• If dehydration is related to diarrhea or nausea/vomiting, the guidance in the preceding 
section should be followed 
• If regimen-related ≥ CTCAE Grade 3 dehydration persists for > 3 days in the absence 
of significant diarrhea or nausea/vomiting, doses of IT should be reduced by 20% for 
subsequent cycles (i.e., irinotecan dose 40 mg/m2/day; for temozolomide see dose 
reduction nomogram in Appendix 4)  
• For recurrent ≥ CTCAE Grade 3 regimen-related dehydration requiring 
discontinuation of IT, please refer to Section 7.12) 


 
 
 
 
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8.4.5 
Management of selected naxitamab adverse reactions 
8.4.5.1 
Management of bronchospasm and hypoxia 
Bronchospasm Grade 2 
• Reduce naxitamab infusion rate to approximately 50% of previous infusion rate 
• Give nebulized beta2-adrenegic receptor agonist 
• If the patient stabilizes and recovers (i.e., bronchospasm CTCAE Grade ≤ 1), the 
infusion rate can be increased to previous rate based on clinical judgement 
 
Bronchospasm with hypoxia CTCAE ≥ 3 
• Pause naxitamab infusion 
• Give nebulized beta2-adrenergic receptor agonist  
• If the response is not satisfactory treat according to local SoC 
o Consider epinephrine inhalation  
o Consider additional IV antihistamine  
o Consider IV corticosteroids 
• If the patient stabilizes and recovers from hypoxia (meaning bronchospasm CTCAE 
Grade ≤ 2), resume infusion at approximately 50% of previous infusion rate. If the 
patient continues to be stabilized, infusion rate can gradually be increased to infusion 
rate prior to the event based on clinical judgement 
• Please refer to Section 7.12 for treatment discontinuation criteria 
8.4.5.2 
Management of hypotension  
Hypotension Grade 2 
• Administer 0.9% saline bolus 10-20 mL/kg IV over 5-15 min 
 
Hypotension Grade 3 without other signs or symptoms 
• Decrease naxitamab infusion rate to approximately 50% 
• Administer IV 0.9% saline bolus 10-20 mL/kg over 5-15 min. Monitor blood pressure 
(BP) closely (at least after completion of the bolus and again 15 min later)  
o If the patient remains hypotensive, repeat bolus as described above (maximum 
a total of 60 mL/kg) and consider additional treatments as described below 
o If the patient stabilizes, consider increasing to the infusion rate prior to the 
event  
 
Hypotension Grade 3 with other signs or symptoms such as bradycardia, hypoxia, not 
adequately responding to treatment or Grade 4 hypotension 
• Pause naxitamab infusion 
• Initiate aggressive fluid resuscitation according to local standard of care (e.g., 
American College of Critical Care Medicine (ACCC)41  
• Monitor vital signs closely 
• If the patient remains hypotensive, repeat IV 0.9% saline bolus as described above  
o If resolution to CTCAE ≤ Grade 2: resume naxitamab infusion at 
approximately 50% of the previous infusion rate. If the patient has stabilized 
and the naxitamab infusion is well tolerated increase to the infusion rate prior 
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o If the patient remains hypotensive, consider additional treatments as described 
below 
• If the patient is NOT warm and well-perfused or do not respond satisfactorily to IV 
0.9% saline bolus treatments or does respond to IV 0.9% saline bolus but only 
temporarily, the following should be considered:  
o Give naloxone if the patient is difficult to arouse 
o If naloxone has no effect or based on clinical judgement, consider 
administration of an inotrope/pressor according to local SoC (e.g., epinephrine 
IV/intramuscular (IM)) 
▪ If desired effect is achieved and the hypotension is CTCAE ≤ Grade 2, 
consider resuming naxitamab infusion at 50% of the previous infusion 
rate. If hypotension CTCAE Grade 3 occurs again consider halting 
naxitamab infusion  
▪ If the patient continues to be hypotensive and difficult to arouse, stop 
the current naxitamab infusion permanently and initiate appropriate 
treatment and observations at the discretion of the investigator (e.g., 
hospitalization in the intensive care unit) 
• Next naxitamab infusion is to be initiated at 50% of the initial infusion rate prior to 
the event at the discretion of the investigator. Adjustment of the premedication’s 
should be considered 
8.4.5.3 
Management of hypertension  
• Treat all possible causes including pain, urinary retention, allergic reaction, anxiety, 
and agitation 
• Treat hypertension according to local SoC 
 
If hypertension persists at the 90th percentile or higher of BP for age, height, and sex 
according to National Institutes of Health (NIH)42 guideline  
• Before naxitamab infusion: The investigator should be informed. 
• During naxitamab infusion: Follow the patient closely with additional BP 
measurements 
• After naxitamab infusion: The patient should be followed closely with additional BP 
measurements and physical examination: 
o During the naxitamab treatment cycle: Additional BP measurements between 
treatment days i.e., on Days 3, 5, 7 and 9 (on Days 2 and 4 for patients treated 
with naxitamab+GM-CSF alone (see Appendix 2) 
o After the last dose of naxitamab in a cycle, i.e., on Day 10 (on Day 5 for 
patients treated with naxitamab + GM-CSF alone, see Appendix 2):  
▪ additional BP measurements the following 3 days on Days 11, 12 and 
13 (on Days 6, 7 and 8 for patients treated with naxitamab + GM-CSF 
alone, see Appendix 2) 
▪ physical examination on Day 13 (Day 8 for patients treated with 
naxitamab + GM-CSF alone, see Appendix 2) 
If hypertension persists at the 99th percentile or higher of BP for age, height, and sex 
according to NIH42 guideline 
• Before naxitamab infusion: 


 
 
 
 
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o The BP should be treated before infusion can be initiated (see below for 
details on hypertension algorithm) 
• During naxitamab infusion: 
o Treat any pain, anxiety, and/or fluid retention as applicable follow the patient 
closely with additional BP measurements 
o Consider medical interventions at the discretion of the investigator 
• After naxitamab infusion: 
o Start therapy for acute hypertension according to local SoC (e.g., a calcium 
channel blocker as needed)  
o Admit to inpatient services for monitoring  
o If the patient does respond to anti-hypertensive therapy, an angiotensin-
converting enzyme (ACE) inhibitor (e.g., enalapril at starting dose 0.08 
mg/kg/dose once daily; max dose 5mg daily) or a calcium antagonist (e.g., 
amlodipine according to local SoC) may be prescribed prior to future cycles of 
naxitamab at the discretion of the investigator 
o If the patient has a history of hypertension with naxitamab requiring 
antihypertensive treatment (e.g., enalapril/amlodipine) on treatment days, 
consider holding the antihypertensive therapy on Day 2 to avoid potential 
hypotension 
o If the patient does not respond to anti-hypertensive therapy, consider 
permanent discontinuation from naxitamab treatment 
 
Posterior reversible encephalopathy syndrome (PRES) 
In case of increased risk of PRES (including high BP, headache, seizures, altered 
consciousness and visual disturbance): 
• Admit patient for observation and consider anti-hypertensive therapy 
• When BPs are stable < 99th percentile for height according to NIH42 the patient can be 
discharged but should return the next day for follow-up and further treatment of 
hypertension at the discretion of the investigator 
• Please also refer to Section 7.12 for treatment discontinuation criteria 
8.4.5.4 
Management of infusion-related reactions ≥ CTCAE Grade 2, other 
than hypoxia, bronchospasm, hypotension, and hypertension 
• Pause naxitamab infusion 
• If resolution to CTCAE Grade ≤ 1: 
o Resume naxitamab infusion at 50% of the previous infusion rate and monitor 
closely at bedside 
o When signs and symptoms resolve, gradually increase infusion rate up to the 
rate before the event at the investigator´s discretion 
o If reaction occurs again, reduce naxitamab to the tolerated infusion rate 
throughout the remaining time of the infusion 
o At the next naxitamab infusion, the infusion rate should be initiated at the 
reduced rate. If well tolerated the infusion rate can be gradually increased at 
the investigator’s clinical judgement 
• If no resolution of the reaction: 


 
 
 
 
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o Consider appropriate treatment at the discretion of the investigator (see 
Section 8.4)  
o If resolution to ≤ CTCAE Grade 1, consider resuming naxitamab infusion at 
50% of the previous infusion rate as described above 
o If no resolution, consider additional treatments and observations, and whether 
to stop current infusion at the investigator’s clinical judgement. 
• Please refer to Section 7.12  for discontinuation criteria 
8.4.6 
Management of GM-CSF (sargramostim) Adverse Reactions 
• Hold GM-CSF if total white blood cell (WBC) count is > 50 x109/L and/or absolute 
neutrophil count (ANC) > 20 x109/L; resume at 50% dose when the WBC count 
and/or ANC is < 20 x109/L. Administer full dose with subsequent cycles and modify 
again if the WBC count exceeds 50 x109/L and/or ANC exceeds 20 x109/L 
• Localized skin reactions to GM-CSF are common, and GM-CSF can be continued 
when reactions are mild. Rotation of sites of injections is recommended when skin 
reactions occur. Consider use of antihistamines. If ≥ CTCAE Grade 3 injection site 
reactions occur, stop GM-CSF for the current cycle and discontinue GM-CSF for 
subsequent cycles of therapy 
• Serious allergic reactions (including anaphylactic reactions) have been reported with 
GM-CSF. If ≥ CTCAE Grade 3 allergic reaction occurs discontinue GM-CSF 
 
8.4.7 
Therapy and Procedures Allowed During Trial 
Any treatment needed for patient wellbeing (including supportive care) that will not interfere 
with IMP administration may be given at the discretion of the Investigator.  
Radiotherapy: 
Radiotherapy may be administered for local control of primary site in patients who have 
achieved a response at metastatic sites but with residual primary tumor after 8 cycles. 
Furthermore, radiotherapy to localized painful lesions is allowed, provided at least one 
measurable/MIBG evaluable lesion is not irradiated.  
Lesions irradiated during protocol therapy cannot be used to assess tumor response. Patients 
should be evaluated prior to radiotherapy with appropriate tumor imaging.  
For discontinuation criteria due to PD, see Section 7.12. 
Surgery: 
Surgery to primary site is allowed for patients who have achieved a response at metastatic 
sites but with residual primary tumor after 8 cycles. If a patient is to undergo surgery due to 
residual primary tumor, a pause in treatment with IMPs will be allowed. This should be as 
short as possible with a delay of next cycle of maximum 3 weeks. 
8.4.8 
Prohibited Therapy/Procedures During the Trial 
The following are prohibited during the trial: 


 
 
 
 
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• Systemic anti-cancer treatment, other than naxitamab and IT.  
• St John's wort 
• CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital, carbamazepine 
• Aprepitant as an anti-emetic 
• Radiotherapy to metastatic site(s) other than mentioned in Section 8.4.7 
• Surgery to metastatis site(s) other than mentioned in Section 8.4.7 
• Any live-attenuated vaccines 
• IV Immunoglobulin 
• Any IMP not defined in this protocol  
Except for IV methylprednisolone or equivalent corticosteroid for pre-medication prior to 
naxitamab infusion (see Section 8.4.1), pharmacologic doses of systemic corticosteroids 
should be used ONLY for life-threatening conditions (i.e., life-threatening allergic reactions 
or anaphylaxis such as bronchospasm or stridor) unresponsive to other measures. The use of 
dexamethasone as an anti-emetic is not permitted. Corticosteroid therapy can be used as a 
premedication for transfusion in patients known to have a history of transfusion reactions or 
for treatment of an unexpected transfusion reaction (hydrocortisone 2 mg/kg or less or an 
equivalent dose of an alternative corticosteroid).  
 
The use of corticosteroid during protocol therapy beyond pre-medication (as mentioned 
above) must be clear from the indication in the eCRF. 
 


 
 
 
 
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9 
PROCEDURES AND ASSESSMENTS 
9.1 
Efficacy Assessments 
9.1.1 
Response Assessments 
The primary endpoint is ORR. This will be based on BM biopsies and aspirates (histology, 
cytology) and imaging and assessed according to INRC37 (see Table 5, Table 6, Table 7 and 
Table 8). The imaging should be done either as: 
• CT/MRI and 123I-MIBG + single-photon emission computed tomography 
(SPECT)/CT or 
• CT/MRI and 123I-MIBG whole body planar scan if no hybrid gamma camera is 
available or 
• CT/MRI and FDG-PET/CT if MIBG-nonavid tumor  
The same imaging modality should preferably be used throughout the trial (please refer to the 
imaging acquisition guideline). 
BM examinations should comprise bilateral BM trephine biopsies and BM aspirates (i.e., 2+2 
samples) as per INRC43 (please refer to laboratory manual). 
BM trephine biopsies should be evaluated by histology and immunohistochemistry (IHC). 
Two highly specific target antigens should be used for IHC, such as synaptophysin, tyrosine 
hydroxylase, chromogranin A, or paired-like homeobox 2b (PHOX2B). The target antigens 
used for IHC should remain the same throughout the trial. BM aspirates should be evaluated 
by cytology and MRD (please see Section 9.1.1.1). If volume of aspirates is not sufficient, 
BM response assessment should be prioritized over MRD assessment by RTqPCR.  
Images and BM biopsies/aspirates (excluding results from RTqPCR, see Section 9.1.1.1) will 
be assessed locally at site but will also be reviewed centrally by independent external experts. 
The local response assessment will be used throughout the trial for the decision to continue or 
discontinue IMPs. Imaging and BM biopsies/aspirates must be done within 7 days (+ 3 days) 
of the same response assessment (except at screening).The centralized review will be done 
retrospectively.  
Table 5 Primary (soft tissue) Tumor response 
Response 
Anatomic + MIBG (FDG-PET†) Imaging 
CR 
< 10 mm residual soft tissue at primary site AND 
Complete resolution of MIBG or FDG-PET uptake (for MIBG-nonavid tumors) at primary site 
PR 
≥ 30% decrease in longest diameter of primary site AND 
MIBG or FDG-PET uptake at primary site stable, improved, or resolved 
PD 
> 20% increase in longest diameter taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study) AND 
Minimum absolute increase of 5 mm in longest dimension‡ 
SD 
Neither sufficient shrinkage for PR nor sufficient increase for PD at the primary site 
Abbreviations: 
                            
CR, complete response 
CT, computed tomography 
FDG, [18F] fluorodeoxyglucose 
MIBG, metaiodobenzylguanidine 
PD, progressive disease 
PET, positron emission tomography 
PR, partial response 


 
 
 
 
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Response 
Anatomic + MIBG (FDG-PET†) Imaging 
 
SD, stable disease 
*Not for use in assessment of metastatic sites. 
†Used for MIBG-nonavid tumors. 
‡Mass that does not meet PD measurement criteria but has fluctuating MIBG avidity will not be considered PD. 
 
Table 6 Tumor response at metastatic soft tissue and bone sites 
Response 
Anatomic + MIBG (FDG-PET*) Imaging 
CR 
Resolution of all sites of disease, defined as: 
• 
Nonprimary target and nontarget lesions measure < 10 mm AND 
• 
Lymph nodes identified as target lesions decrease to a short axis< 10 mm AND 
• 
MIBG uptake or FDG-PET uptake (for MIBG-nonavid tumors) of nonprimary lesions 
resolves completely 
PR 
• 
≥ 30% decrease in sum of diameters† of nonprimary target lesions compared with 
baseline AND all of the following: 
• 
Nontarget lesions may be stable or smaller in size AND 
• 
No new lesions AND 
• 
≥50% reduction in MIBG absolute bone score (relative MIBG bone score ≥0.1 to ≤0.5) 
OR ≥50% reduction in number of FDG-PET–avid bone lesions§ 
PD 
Any of the following: 
• 
Any new soft tissue lesion detected by CT/MRI that is also MIBG avid or FDG-PET 
avid 
• 
Any new soft tissue lesion seen on anatomic imaging that is biopsied and confirmed to 
be NB or ganglioneuroblastoma 
• 
Any new bone site that is MIBG avid 
• 
A new bone site that is FDG-PET avid (for MIBG-nonavid tumors) AND has CT/MRI 
findings consistent with tumor OR has been confirmed histologically to be NB or 
ganglioneuroblastoma 
• 
>20% increase in longest diameter taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study) AND minimum absolute 
increase of 5mm in sum of diameters of target soft tissue lesions 
• 
Relative MIBG score ≥1.2§ 
SD 
Neither sufficient shrinkage for PR nor sufficient increase for PD of nonprimary lesions 
Abbreviations: 
                            
CR, complete response 
CT, computed tomography 
FDG, [18F] fluorodeoxyglucose 
MIBG, metaiodobenzylguanidine 
MRI, magnetic resonance imaging 
PD, progressive disease 
PET, positron emission tomography 
PR, partial response 
SD, stable disease 
* Used for MIBG-nonavid tumors 
†Sum of diameters is defined as the sum of the short axis of discrete lymph nodes (ie, cervical, axillary nodes) 
added to the sum of the longest diameters of non–lymph node soft tissue metastases. Masses of conglomerate 
nondiscrete lymph nodes will be measured using longest diameter. 
§ Relative MIBG score (based on Curie) is the absolute score for bone lesions at time of response assessment  
divided by the absolute score for bone lesions at baseline before therapeutic interventions 
‡For patients with soft tissue metastatic disease, resolution of MIBG and/or FDG-PET uptake at the soft tissue 
sites is not required; all size reduction criteria must be fulfilled. 
 
Table 7 BM metastasis response 
Response 
Cytology/Histology   
CR 
BM with no tumor infiltration on reassessment, independent of baseline tumor 
involvement 
PD 
Any of the following: 
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-BM with tumor infiltration that increases by > twofold and has >20% tumor infiltration on 
reassessment 
MD 
Any of the following: 
-BM with ≤5% tumor infiltration and remains >0 to ≤5% tumor infiltration on 
reassessment or 
-BM with no tumor infiltration that has ≤5% tumor infiltration on reassessment or 
-BM with >20% tumor infiltration that has >0 to ≤5% tumor infiltration on reassessment 
SD 
BM with tumor infiltration that remains positive with >5% tumor infiltration on 
reassessment but does not meet CR, MD, or PD criteria 
NOTE. In the case of discrepant results between aspirations or core biopsies from two or more sites taken at 
the same time, the highest infiltration result should be reported using the criteria in this table 
Abbreviations: 
BM, bone marrow 
CR, complete 
response 
MD, minimal disease 
PD, progressive disease 
SD, stable disease 
 
Overall response 
Overall response will be defined by combining response of the individual components (i.e., 
primary (soft tissue) tumor, metastatic soft tissue, bone sites, and BM metastasis). 
Table 8 Determination of overall response 
Response 
Criterion   
CR 
All components meet criteria for CR 
PR 
PR in at least one component and all other components are either CR, MD* (BM), PR 
(bone), or NI†; no component with PD  
MR 
PR or CR in at least one component but at least one other component with SD; no 
component with PD 
SD 
SD in one component with no better than SD or NI† in any other 
component; no component with PD 
PD 
Any component with PD 
Abbreviations: 
BM, bone marrow 
CR, complete response 
MD, minimal disease 
MR, minor response 
NI, not involved 
PD, progressive disease 
PR, partial response 
SD, stable disease (a minimum duration of 6 weeks is 
required#)44 
* For BM assessment only. 
† Site not involved at trial entry and remains uninvolved. 
# Time window of – 5 days is acceptable  
9.1.1.1 
Response assessment of BM MRD43: 
BM aspirate samples for RTqPCR should be taken at baseline, after C2 and after C4. RTq-
PCR analyses will be performed centrally. 
The results of RTqPCR will reported as the cycle threshold (Ct) value in which the 
expression of the NB mRNA for tyrosine hydroxylase and PHOX2B is normalized to the 
internal control (the reference housekeeping gene; β2-microglobulin)43. The lower Ct for 
reporting RTqPCR for the neuroblastoma mRNAs is a Ct value of 40. A tumor negative BM 
has a Ct value ≥ 40 for all of the neuroblastoma mRNAs examined, when amplification of the 
reference housekeeping gene generates a Ct value of <25. Further details on BM sampling for  
RTqPCR analysis  will be provided in the laboratory manual. 
 


 
 
 
 
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9.1.2 
Timing of response assessment 
For timing of response assessment for patients who have discontinued IT treatment due to 
toxicity, please refer to Appendix 2.  
The response assessments will be performed after C2, C4, C8, C13, and EOT. All response 
assessments (except EOT) should be performed before D1 of next cycle. 
In addition, for patients who achieve:  
• a first CR or PR after C4 OR 
• a first CR or PR after C8 
a confirmatory response assessment should be performed within 4-6 weeks after detection of 
the overall response. 
If the patient discontinue treatment due to PD, response assessment at EOT is not required 
provided that PD is documented by scan and/or biopsy.  
For patients who have not experienced PD or started new anti-cancer treatment, response 
assessment should be performed at approximately every 4 months after EOT during long-
term FU (see Section 3).  
9.2 
Safety Assessment 
9.2.1 
Physical Examination 
The physical examination should include an assessment of general appearance and a review 
of systems (dermatologic, head, eyes (incl examination for mydriasis, signs/symptoms of 
blurred/altered vision), ears, nose, mouth/throat/neck, thyroid, lymph nodes, and respiratory, 
cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic systems). A 
physical examination should be performed at screening, prior to first treatment with IMP in 
each cycle, at EOT and otherwise as clinically indicated. 
9.2.2 
Vital Signs 
Vital sign measurements must include heart rate, respiratory rate, body temperature and BP. 
Additionally, peripheral oxygen saturation (SpO2) must be measured when clinically 
indicated. Temperature must be measured by using the same method (e.g., ear thermometer) 
each time. Vital signs must be assessed at screening and in connection with each treatment 
cycle as outlined below: 
On Days 1, 3 and 5 prior to administration of temozolomide. 
On naxitamab in fusion days (Days 2, 4, 8 and 10) 
• Prior to administration of temozolomide (Days 2 and 4) 
• 
Prior to pre-medication (e.g.,hydromorphone or morphine) 
• 
Prior to start of naxitamab infusion 
• 
~15 min after start of naxitamab infusion 
• 
~30 min after start of naxitamab infusion 
• 
Prior to each hydromorphone or morphine IV therapy as feasible (no temperature) 
• 
At completion of naxitamab infusion including flush (no temperature) 


 
 
 
 
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• 
~15 min after completion of the flush (no temperature) 
• 
Every hour while patient is recovering in the outpatient clinic 
Furthermore, vital signs must be assessed at EOT and as clinically indicated. The latter 
includes when a vital sign parameter is part of an AE on an infusion day. 
Please refer to Appendix 2 for patients who have discontinued IT treatment due to toxicity.  
9.2.3 
Naxitamab Discharge Criteria 
Vital signs should be stable and satisfactory at the discretion of the investigator 
A minimum of 2 hours after completion of naxitamab treatment, or 2 hours after the last dose 
of any IV opioid must have elapsed. 
9.2.4 
Echocardiography 
An echocardiography should be performed at screening (refer to Section 3). The investigator 
should make an overall interpretation and assess for trial eligibility. 
9.2.5 
Pulmonary Function Test and Oxygen Saturation 
A pulmonary function test and oxygen saturation should be performed at screening, if 
clinically indicated. The investigator should make an overall interpretation of the pulmonary 
function test(s) and oxygen saturation and assess for trial eligibility. 
9.2.6 
ECG 
12-lead ECG should be obtained as outlined in the flow chart (see Section 3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  
ECG is a local assessment at screening, and at EOT. If the patient needs sedation before 
ECG, the ECG can be performed in connection with imaging. The investigator should make 
an overall interpretation of the ECG and at screening assess for trial eligibility. 
9.2.7 
Pain Assessment 
Pain scores should be assessed for all naxitamab infusions and at the following time points: 
• Prior to start of naxitamab 
• Worst pain during infusion; to be assessed at the end of infusion 
• ~ 15 min after end of infusion 
• ~ 30 min after end of infusion 
• Prior to discharge  
 
The same scale must be used during all naxitamab infusions, also if the patient turns 6 years 
during the trial. The Face, Legs, Arms, Cry, Consolability (FLACC) scale for patients ≤ 5 
years old at screening and Wong-Baker FACES® pain scale for patients 6 years or older at 
screening. 
If patients of at least 6 years of age cannot comply with the Wrong-Baker faces pain scale it 
is permitted to use the FLACC scale at the investigators discretion as long as it is used 
consistently throughout all naxitamab infusions. Please refer to Appendix 8 and Appendix 9.  


 
 
 
 
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9.2.8 
Non-child-bearing Potential/Pregnancy Test 
Pregnancy testing and contraceptive requirements do not apply for female patients of non-
child-bearing potential. Non-child-bearing potential in female patients will be confirmed by 
one of the following: 
• Females who have not reached menarche or 
• Females who have not had menses within the past 12 months and have a follicle-
stimulating hormone (FSH) ≥40 IU/L or 
• Females who have not had menses within the past 24 consecutive months if a FSH 
measurement is not available or 
• Females who have undergone surgical sterilization (e.g., hysterectomy, or bilateral 
oophorectomy, or bilateral salpingectomy).  
Pregnancy and contraceptive requirements for female patients of child-bearing potential 
Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test at 
screening and are excluded from the trial if they do not agree to use highly effective 
contraception for a period of 6 months after the last treatment with IT or 42 days after last 
treatment with naxitamab whichever comes last.  Highly effective contraceptive methods can 
achieve a failure rate of less than 1% per year when used consistently and correctly. Such 
methods include: 
• 
combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
progestogen-only hormonal contraception associated with inhibition of ovulation: 
• 
oral 
• 
injectable 
• 
implantable 
• 
intrauterine device (IUD) 
• 
intrauterine hormone-releasing system (IUS) 
• 
bilateral tubal occlusion 
• 
vasectomised partner1 
• 
sexual abstinence2 
1 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner 
of the female patient and that the vasectomised partner has received medical assessment of the surgical success. 
2 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 patient. 


 
 
 
 
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If a patient is assessed to be of child-bearing potential, either at screening or become so 
during the course of the trial, a serum pregnancy test must be performed prior to each 
treatment cycle and at EOT.  
Contraceptive requirements for male patients 
Male patients must use contraception (condom) for a period of 6 months after last treatment 
with IT or 42 days after last treatment with naxitamab whichever comes last. Male partners 
for female patients are advised to use condom while the female partner is being treated with 
IT and for 2 weeks after last treatment. 
9.2.9 
Clinical Laboratory Assessments 
All protocol clinical laboratory assessments, as defined in Section 11.1, must be conducted in 
accordance with the flowchart and the laboratory manual.  
9.3 
Other Assessments 
9.3.1 
Demographics and Other Baseline Characteristics 
Information on the patient’s demographics will be collected during screening in the eCRF. 
The following demographic information will be entered: 
• Age or date of birth if allowed by local legislation 
• Gender 
• Ethnic origin if allowed by local legislation 
• Race if allowed by local legislation 
• Current average alcohol consumption per week, if applicable  
• Smoking status, if applicable  
9.3.2 
Height and Body Weight 
Height (without shoes) must be measured at screening and before each cycle and entered in 
the eCRF (centimeter or inches, one decimal). Body weight (without overcoat and shoes) will 
be measured at screening and before the first administration of IMP in each cycle and entered 
in the eCRF (kilogram (kg) or pounds, one decimal). The BSA should be calculated using the 
Mosteller formula before each treatment cycle for calculation of the IMP doses. 
9.3.3 
Medical and Surgical History 
Information on the patient’s medical history, past and all current diseases (including surgical 
procedures) and general health, will be collected if available during screening and includes, 
but is not limited to: 
• General medical history 
• Information on NB diagnosis including tumor characteristics, prior treatment for NB 
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A concomitant illness is any illness, other than the disease being investigated, which is 
present at trial start or found as a result of the screening procedure.  
The information collected for medical history and concomitant illnesses includes: 
• Diagnosis 
• Date of onset 
• Date of resolution 
Any clinically significant worsening of a concomitant illness that occurs after a patient 
provided consent must be reported as an AE (Section 10.5). 
9.3.4 
Performance Test 
A performance test will be performed at screening, prior to each cycle and EOT. The scales 
to be used are Lansky for children < 16 years of age and Karnovsky for adolescents and 
adults ≥ 16 years of age. Please refer to Appendix 10. The same scale must be used during 
the trial, also if the patient turns 16 years during the trial. 
 
9.3.5 
Unscheduled Visits 
If any assessments need re-evaluation, an additional response assessment is needed, or follow 
up on an (S)AE is required, the patient can be called for an unscheduled visit at the discretion 
of the Investigator. Data obtained during unscheduled visits pertaining to the clinical trial will 
be collected as unscheduled visits in the eCRF. 


 
 
 
 
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10 ADVERSE EVENTS 
10.1 Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical 
product which does not necessarily have a causal relationship with the treatment. 
An AE can, therefore, be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a product, 
whether or not considered related to the product. 
An AE includes:  
• A clinically significant worsening of a concomitant illness.  
• A laboratory abnormality which is clinically significant, i.e., an abnormality that 
suggests a disease and/or organ toxicity and is of a severity that requires active 
management. Active management includes interventional treatment or further 
investigations, for example change of medicine dose or more frequent follow-up due 
to the abnormality. 
Pre-existing condition, (i.e., a disorder present before the AE reporting period started and 
noted on the medical history/physical examination form) should not be reported as an AE 
unless the condition worsens, or episodes increase in frequency during the AE reporting 
period. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs. A medical condition for which an unscheduled procedure was performed 
should, however, be reported if it meets the definition of an AE. For example, an acute 
appendicitis should be reported as the AE and not the appendectomy. 
10.2 Definition of Serious Adverse Events 
Each AE is to be classified by the Investigator as either serious or non-serious. This 
classification of the seriousness of the AE determines the reporting procedures to be 
followed. An AE that meets one or more of the following criteria/outcomes is classified as 
serious: 
• Is fatal or life-threatening1 
• Requires inpatient hospitalization or prolongation of existing hospitalization2 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Medically important event3 
1: The term "life-threatening" in the definition of "serious" refers to an event in which the patient, in view of 
either the Investigator or Sponsor, was at risk of death at the time of the event; it does not refer to an event, that 
hypothetically might have caused death if it was more severe. Death alone is not considered an AE; it is an 
outcome of an AE. 


 
 
 
 
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Reports of death should be accompanied by the corresponding AE term for the event that led to death. However, 
sudden death or death due to unexplainable cause should be reported as an SAE, while follow-up is pursued to 
determine the cause.  
2: Hospitalization is defined as admission to a hospital/inpatient (irrespective of the duration of physical stay) or 
is not admitted to a hospital/not an inpatient but stays at the hospital for treatment or observation for more than 
24 hours. Events leading to hospitalizations for the following reasons should not be reported as SAEs: 
• 
Trial-related purposes, not associated with any deterioration in condition  
• 
Social reasons in the absence of any deterioration in the patient’s general condition 
• 
Elective surgery or other scheduled hospitalization periods that were planned before the patient was 
included in this trial. 
3: Medical and scientific judgment must be exercised in deciding whether an AE is believed to be “medically 
important”. Medically important events may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above. 
10.3 Definition of Non-Serious Adverse Events 
A non-serious AE is any AE which does not fulfil the definition of an SAE.  
10.4 Definition of Predefined Adverse Events of Special Interest 
The following AEs (serious and non-serious) are selected as AEs of Special Interest (AESIs): 
• Hypertension: 
o Requiring antihypertensive therapy or 
o Which persists at the 90th percentile or higher for age, height and sex and 
requires additional monitoring after naxitamab infusion according to Section 
8.4.5.3 
• Hypotension CTCAE Grade 3 
• AEs leading to incomplete dosing of naxitamab during a cycle (i.e., the total planned 
dose of naxitamab was not given in a cycle)  
10.5 Adverse Event Reporting 
10.5.1 
Non-Serious Events 
Non-serious AEs should be reported from the day of first IMP administration until 42 days 
after the last IMP administration. Non-serious AEs occurring between signing the ICF and 
the first IMP administration must be recorded as medical history. 
10.5.2 
Serious Adverse Events 
Serious AEs should be reported from signing the ICF until 42 days after the last IMP 
administration. 
10.5.3 
Adverse Events during Follow-up 
From 42 days after the last IMP dose and until the end of the trial, only SAEs at least 
possibly related to naxitamab, new onset of secondary malignancies and autoimmune 
diseases (irrespective of seriousness) regardless of causality should be reported (within 24 
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10.5.4 
Adverse Events with Onset after End of Trial 
If the Investigator becomes aware of an SAE after End of Trial with a suspected causal 
relationship to the IMPs, it should immediately be reported to Sponsor (see contact details in 
Section 10.7.1)  
10.5.5 
Recording of Adverse Events 
All events meeting the definition of an AE must be collected and reported in the eCRF. 
SAEs, and AESIs (whether serious or non-serious) should be reported both in the eCRF and 
on the Clinical AE Report form.  
During each contact with the trial site staff, the patient must be asked about AEs, for example 
by asking: “Have you experienced any problems since the last contact?” All AEs, observed 
by the Investigator or patient, must be reported by the Investigator. 
10.5.6 
Diagnosis of Adverse Events 
The Investigator should report the diagnosis, if available. If no diagnosis is available, the 
Investigator should record each sign and symptom as individual AEs using separate AE 
forms. If a diagnosis becomes available, the signs and/or symptoms reported should be 
replaced by the diagnosis. 
10.5.7 
Onset Date and Time 
Start date for an (S)AE is the date of occurrence of the first symptom. The time should be 
entered if  
• the event starts on an IMP dosing day or the day after a naxitamab dosing day 
• if the duration of the event is less than 24 hours.  
10.5.8 
End Date and Time 
The end date should be filled in if the outcome of an AE is fatal, recovered/resolved or 
recovered/resolved with sequelae. The end time should be entered for all AEs for which start 
time should be entered (see section 10.5.7), and/or if the duration of the event is less than 24 
hours or if deemed relevant. 
10.5.9 
Severity 
The Investigator will use the CTCAE version 5.0 to describe the severity of the AE. If the 
severity changes over the course of the event, the grade assigned by the Investigator should 
be the most severe, that occurred during the AE period.  
10.5.10 
Outcome 
Investigator must judge outcome of the AE by the following terms: 
• Recovered 
• Recovered with sequelae (description of the sequelae should be provided) 
• Not recovered 
• Fatal 


 
 
 
 
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• Unknown* 
*Should only be used if patient is lost to follow-up. 
10.5.11 
Relationship to Investigational Medicinal Product 
The Investigator must assess whether the event is related to the IMPs. A suspected adverse 
drug reaction is defined as one in which there is a reasonable possibility that one of the IMPs 
caused the AE. Relatedness must be assessed and reported from the first time the AE is being 
reported. When assessing the causal relationship of an AE to the IMPs, the following should 
be taken into consideration: 
Not related (unlikely) 
The AE is not related to any of the IMPs, which means the AE: 
• Does not follow a reasonable temporal sequence from IMP administration 
• Is readily explained by the patient’s clinical state or by other modes of therapy 
administered to the patient  
• Is clearly not related to the IMP 
Possibly Related 
The AE follows a reasonable temporal sequence from IMP administration but could have 
been produced by the patient’s clinical state, medical history, or the trial 
procedures/conditions. 
Alternative etiology should be provided for all AEs assessed as possibly related to IMPs. 
Probably Related 
The AE is probably related to one or more of the IMPs, which means the AE: 
• Follows a reasonable temporal sequence from IMP administration 
• Abates spontaneously upon discontinuation of the relevant IMP(s) (de-challenge) 
without any curative treatment 
• Is confirmed by reappearance of the same reaction on repeat exposure (re-challenge) 
(if applicable) 
• Cannot be reasonably explained by the known characteristics of the patient’s clinical 
state or medical history 
10.5.12 
Action Taken with Investigational Medicinal Product 
The action taken with the IMPs should be noted as: 
• Dose decreased 
• Dose administration rate decreased 
• Drug interrupted 
• Drug postponed 


 
 
 
 
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• Drug discontinued 
• None 
• Not Applicable** 
• Unknown. 
**: should be used if the AE occurs before first treatment or after end of treatment. 
10.6 Events Requiring Immediate Reporting  
The following events require reporting within 24 hours of knowledge (for details see Section 
10.5): 
• SAE 
• AESI 
• Pregnancy 
10.6.1 
Pregnancy  
Any pregnancy, including partner pregnancy, that occurs during trial participation must be 
reported to Sponsor within 24 hours of knowledge using the pregnancy form. Pregnant trial 
patients must be discontinued from IMP treatment immediately (see Section 7.12). The 
pregnancy must be followed up to determine outcome and status of mother and child. The 
child must be followed at least to the age of one month. Pregnancy complications and 
elective terminations for medical reasons must be reported as an AE or SAE. Spontaneous 
abortions must be reported as an SAE. 
10.7 Timelines for Initial Reporting of AEs 
SAEs/AESIs 
• The paper Clinical AE Report form must be reported from site to Sponsor within 24 
hours of the Investigator’s first knowledge of the event. The paper Clinical AE Report 
form is to be sent to the designated drug safety provider (see Section 10.7.1). New 
follow-up information available at site must be reported within 24 hours of knowledge 
All AEs 
• The eCRF AE form should be updated in accordance with agreed data entry timelines 
(see Section 15.2.2). 
Please follow the eCRF completion instructions for reporting of AEs. 
10.7.1 
Contact details for reporting: 
Completed paper Clinical AE Report forms and paper pregnancy forms must immediately be 
reported to: 
safetymailbox@ymabs.com 


 
 
 
 
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10.8 Follow-up on Adverse Events 
SAE/AESIs: 
• New follow-up information available at site must be reported within 24 hours of 
knowledge. 
• Follow-up information requested from Sponsor must be replied to within three working 
days. The eCRF AE form should be updated in accordance to agreed data entry timelines 
(see Section 15.2.2 ). 
• If an ongoing SAE/AESI changes in intensity, relationship to IMP or as new information 
becomes available for the event, the paper Clinical AE Report Form should be completed 
and sent to the designated drug safety provider within 24 hours of the change in 
assessment (see Section 10.6).  
• Grade 3 or higher non-serious AEs that are considered treatment related and all SAEs 
(including AESIs) should be followed on a regular basis, according to the Investigator’s 
clinical judgment, until the event has been resolved or until the Investigator can assess it 
as chronic or stable. This includes follow-up after EOT 
Non-SAEs 
Non-serious AEs should be followed until they are either resolved, returned to baseline, or 
until 42 days after last dose of IMPs, whichever comes first 
10.9 Reporting of SUSARs  
Sponsor will ensure that all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSARs) is reported to regulatory authorities in accordance with 
regulatory requirements. 
The Contract Research Organization (CRO) appointed by Sponsor will notify Investigators of 
SUSARs in accordance with local requirements. Furthermore, Investigators will be informed 
of any trial-related SAEs that may warrant a change in any trial procedure. The CRO 
appointed by Sponsor will inform the Institutional Review Boards (IRBs)/Independent Ethics 
Committees (IECs) of SUSARs in accordance with local requirement, unless locally this is an 
obligation of the Investigator.  
The Sponsor assessment of expectedness for naxitamab will be performed according to the 
current version of the IB. For IT and GM-CSF the applicable reference documents will be 
used. 
10.10 Communication of Significant Safety Issues 
In the event of any significant safety related issues, the Sponsor will decide upon immediate 
action to be taken including prompt notification of the DMC and will communicate to 
regulatory authorities, Investigators, IECs/IRB, and patients as needed within regulatory 
timelines. 


 
 
 
 
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10.11 Data Monitoring Committee 
The DMC is an external committee composed of members whose expertise covers relevant 
specialties. The DMC is established to review and evaluate accumulated data from the trial 
with an interval between meetings of approximately 3 months and ad hoc. The DMC is 
established to assure patient safety and to evaluate benefit-risk balance during conduct of the 
trial. The DMC will provide recommendations on trial continuation, modification, or 
termination. Responsibilities, procedures, and workflow of the DMC are specified in the 
DMC charter. 
Recommendation from the DMC will be discussed by the Sponsors Safety Committee.  The 
outcome will be communicated to the regulatory authorities/IRBs/IECs/investigators if there 
are a significant change to trial conduct e.g., urgent safety measure, amendment to trial 
protocol and/or ICF. 


 
 
 
 
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11 LABORATORIES 
11.1 Clinical Laboratory Assessments 
The laboratory samples specified in Table 9 will be measured by a local laboratory. 
Laboratory tests should be performed as described in Table 9 and as clinically indicated. 
Please refer Appendix 2 if the patient has discontinued IT treatment due to toxicity. 
Table 9 Protocol required laboratory assessments 
Timing of Laboratory assessments 
Parameters 
Screening 
Cycle 1*: Prior to dosing D1, D5, 
and D8. In addition on D15 
Subsequent cycles*: Prior to dosing 
D1, D5 and D8  
EOT 
 
*D10 all cycles: If modified naxitamab 
dosing due to missed dose (ie naxitamab to 
be administered on Day 12 and GM-CSF 
continued until Day 12)  
Hematology 
• Hemoglobin  
• Hematocrit 
• White blood cells (WBC) Lymphocytes 
(absolute and %) 
• Neutrophils (absolute and %) 
• Eosinophils (absolute and %) 
• Basophils (absolute and %) 
• Monocytes (absolute and %) 
• Platelet count 
Screening 
Cycle 1: prior to dosing D1, D3, D5, 
D8 and D15 
Subsequent cycles: prior to each 
cycle and D8 
EOT 
 
 
Liver and kidney function blood tests  
• ALT 
• AST 
• Alkaline phosphatase 
• Total bilirubin 
• Lactate dehydrogenase (LDH) 
• Blood urea nitrogen (BUN) 
• Creatinine 
• eGRF 
• Albumin (only prior to each cycle) 
Screening 
Cycle 1:prior to dosing  D1, D3, D5, 
and D8  
Subsequent cycles: prior to each 
cycle 
EOT 
Serum electrolytes 
• Sodium 
• Potassium 
• PO4 
• Mg++ 
Prior to each cycle 
Urine analysis (dipstick) 
• Protein 
• Glucose 
• Leucocytes 
Screening 
Prior to each cycle 
EOT 
Pregnancy test, if applicable 
• Serum pregnancy test for WOCBP see 9.2.8 for 
further information 
 


 
 
 
 
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The WBC and differential counts should be repeated on sequential days during all treatment 
cycles if ANC is > 20 x109/L or WBC > 50 x109/L on the day prior to GM-CSF treatment. 
11.2 Immunogenicity 
Samples for assessment of anti-drug antibodies (ADA) should be sent to a special laboratory 
for analysis. Please refer to the laboratory manual for more information.  
Table 10 ADA samples 
ADA assessment: 
Prior to dosing in each cycle 
EOT 
• Anti-naxitamab antibodies* 
 
*Analyses will be performed in batches. Therefore, results will not be available during the 
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12 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE  
12.1 General Overview 
The data will be summarized in tables, as appropriate, showing the number of patients with 
non-missing data (n), mean, standard deviation, median, minimum, and maximum for 
continuous data and showing counts and percentage for categorical data. Data will also be 
listed as deemed appropriate.  
12.2 Sample Size 
With the statistical methodology for the primary endpoint (Section 12.4.1) in mind, 52 
patients are needed to, with 82% power, demonstrate that the response rate is statistically 
significantly higher than 20%. This sample size incorporates a drop-out (here: patients either 
not having evaluable disease at baseline based on central review vs. local assessment, or 
treated patient dropping out of the trial before the first post-baseline assessment) rate of 20%, 
based on results from the ongoing 201 trial.  
Table 11 Sample sizes, assumptions and power 
Null 
response 
rate 
Response 
rate 
Unadjusted number 
of patients 
Drop-out (20%) 
adjusted number of 
patients 
Statistical 
Power 
40% 
20% 
41 
52 
82% 
40% 
20% 
56 
70 
91% 
40% 
25% 
78 
98 
80% 
40% 
25% 
102 
128 
90% 
 
12.3 Populations of Interest 
• Full Analysis Set 
The full analysis set (FAS) will include all patients enrolled in the trial who had 
evaluable disease as per central review and received at least one dose of IMP. 
• Per Protocol Analysis Set (PPS) 
The PPS will include all FAS patients who have no major protocol violations with impact 
on the primary endpoint. Additional patients with other protocol violations may be 
uniformly excluded on the basis of data review. The precise reasons for excluding 
patients from the PPS will be fully defined and documented before data lock. 
• Safety Analysis Set (SAF) 
The SAF will include all enrolled patients who receive at least one dose of IMP. 
12.4 Efficacy Analysis 
Patients will be evaluated for response according to the INRC37 and assigned one of the 
following response categories: CR, PR, MR, SD, PD or NE (Not Evaluable). In the 
calculations of any response rates, NE patients will be included in the denominator: not 
evaluable patients count as non-responders.  


 
 
 
 
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Overall response and DoR will be evaluated both centrally, and locally by the investigators: 
the central evaluation is the primary and the local evaluations are used as sensitivity analysis.  
12.4.1 
Primary endpoint: ORR at or before completion of four cycles 
The null hypothesis: 𝐻0: 𝑝𝑂𝑅= 20% will be tested, using the two-sided exact binomial test, 
against the alternative  𝐻𝑎𝑙𝑡: 𝑝𝑂𝑅≠20% on the overall 5% significance level, where 𝑝𝑂𝑅 
denotes the ORR at or before completion of four cycles. This 20% threshold is based on the 
results from the phase 2 study by Bagatell et al.18 in patients with primary refractory or first 
relapsed NB, where the ORRs to IT treatment ranged from 11% to 19%18 (see Section 4.3.3).  
  
The ORR and rates of the response categories will be summarized in tables for the FAS and 
PPS. The rates will be presented with their corresponding exact binomial two-sided 95% 
confidence intervals.  
The results will be presented for both central and local evaluation; the former is the basis for 
the primary endpoint and the latter is an exploratory endpoint. 
OR information for individual patients will be presented in listings. 
12.4.2 
ORR after 2 cycles, CR rate after 2 and 4 cycles, MR rate and “MR or 
better” rate  
The ORR after 2 cycles, CR rate at or before completion of four cycles, CR rate after 2 
cycles, MR rate at or before completion of four cycles as well as the “MR or better” rate at or 
before completion of four cycles will be calculated and presented in the same way as the 
primary endpoint, see Section 12.4.1 above. 
12.4.3 
Duration of response 
The DoR, in patients with OR, will be estimated and summarized using Kaplan-Meier 
methodology. If no progression or death event is observed, DoR will be censored at the time 
of the last response assessment. The DoR will be censored if: 
• more than one assessment visit in a row is missed, or 
• an anti-cancer therapy other than naxitmab and IT is administered (ignoring allowed 
therapies and procedures such as radiotherapy or surgery of the primary site, cf. 
Section 8.4.7 for details). 
 
The distribution of the DoR will be summarized by estimates and two-sided 95% confidence 
intervals of the first, second and third quartiles. The number of patients with events and the 
number of censored patients will be presented. The reasons for censorings will be 
summarized.  
Summary tables will be presented for the FAS and PPS. The DoR will be presented in patient 
data listings including the onset of response date, observed event date, censoring flag, 
censoring date and censoring reason. The results will be presented for both central and local 
evaluation. The latter will be considered exploratory. 
12.4.4 
Rate of patients who obtain CR in BM and convert to MRD negative 
The proportion of patients with disease in BM at enrollment who obtain CR in BM and 
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presented in the same way the primary endpoint for the sub-population of patients who are 
BM MRD positive at baseline, for the FAS and PPS.  
12.4.5 
Time to First Subsequent Therapy 
Time to First Subsequent Therapy (TFST) will be estimated and summarized using Kaplan-
Meier methodology. If no new subsequent anti-cancer treatment is observed, the TFST will 
be censored at the last visit in the trial. The TFST-results will be presented in the same way 
as for DoR. 
12.4.6 
PFS and OS 
PFS will be censored in the same way as DoR. If no death event is observed, OS will be 
censored at the date of the last assessment. PFS and OS will be estimated using Kaplan-Meier 
methods and presented in same way as DoR. In addition, the Kaplan-Meier estimates of the 
proportions, together with the corresponding CIs, of patients without progression or death 
(PFS) and alive (OS) at 1 and 2 years will be presented for the two endpoints respectively. 
The PFS results will be presented for both central and local evaluation. The latter will be 
considered exploratory. 
12.4.7 
Exploratory Endpoints 
The analyses of the exploratory endpoint will be described in the SAP. 
12.5 Safety Analysis 
The SAF will be used for the safety analyses. The overall observation period will be divided 
into 3 parts: 
1. 
pre-treatment period: from day of patient’s informed consent to the day before 
first dose of IMP 
2. 
on-treatment period: from day of first dose of IMP to 42 days after last dose of 
IMP 
3. 
post-treatment period: starting at day 43 after last dose of IMP. 
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period 
cannot be made, then the respective data will be assigned to the on-treatment period. 
Additional analyses and presentations will be included in the SAP. 
12.5.1 
Adverse events 
AE data will be presented descriptively in summary tables and listings. AEs will be regarded 
as Treatment-Emergent AEs (TEAEs) if they occur after start of first IMP administration.  
An infusion/administration related TEAE is an AE that occurs on a day of IMP 
administration (after start of IMP administration) and is considered related to the IMP 
treatment. 
An infusion related hypersensitivity TEAE is an AE that match a selected list of 
hypersensitivity terms based on reported preferred terms (including the MedDRA SMQ 
narrow scopes of anaphylactic reaction, angioedema, hypersensitivity and severe cutaneous 
reaction), that occurs on a day of naxitamab infusion (after the infusion start) or the day after 
a naxitamab infusion irrespectively of relatedness to naxitamab. 


 
 
 
 
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AEs with onset during the pre- and post-treatment period will be listed. AEs with onset 
during the on-treatment period will be summarized as follows: summaries of AEs will be 
presented for all TEAEs, IMP-related TEAEs, CTCAE Grade 3 or higher TEAEs, IMP-
related CTCAE Grade 3 or higher TEAEs, infusion/administration-related TEAEs, infusion 
related hypersensitivity TEAEs, SAEs, IMP-related SAEs, CTCAE Grade 3 or higher SAEs, 
IMP-related CTCAE Grade 3 or higher SAEs, TEAEs leading to treatment discontinuation, 
AEs leading to death.   
12.5.2 
Safety laboratory data 
Descriptive statistics will be presented for baseline values, absolute values, and changes from 
baseline in safety laboratory parameters. Laboratory data will be summarized in tables and 
presented in figures by type of laboratory test. 
12.5.3 
Vital signs 
Changes from baseline in vital signs will be presented in summary tables. 
12.6 Pain assessments during naxitamab infusions 
Pain scores will be presented in summaries and listings. 
12.7 Analysis of ADA Formation 
ADA data will be presented in summary tables and listings. For subjects who develop ADA 
during the trial, time to first positive ADA assessment from first day of naxitamab 
administration will be presented in a figure.  
12.8 Hospitalization days 
The number of hospitalization days will be presented in summary tables and listings. 
12.9 Naxitamab infusions in out-patient setting 
The number of naxitamab infusions in out-patient setting will be presented in summary tables 
and listings. 
12.10 Interim Analysis 
Ad-hoc interim analyses may be performed in relation to health authority interactions. 
12.10.1 
Multiplicity adjustments 
No multiplicity adjustments will be made. 
12.11 Subgroup Analyses 
The primary endpoint will be analyzed and presented for the following subgroups: 
• primary refractory vs. first relapse vs first PD during frontline therapy 
• soft tissue lesions present at baseline (yes / no) 
• tumor MYCN amplification status (yes / no) 
• prior exposure to anti-GD2 antibody therapy (yes / no) 
• ADA status (negative at all times / positive at any time) 
• disease compartment (bone, BM, bone and BM combined (i.e., OR excl. soft tissue 
lesions) as well soft tissue) 
• geographical region  


 
 
 
 
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• site 
• age group (0 - <2, 2 - <6, 6 - <12, 12 - <18 and >=18 years) 
• body weight group (<20 kg; 20-<50 kg; >=50 kg)  
• sex (male/female) 
• race 
Overviews of AEs will be presented for the following subgroups: 
• primary refractory vs. first relapse vs first PD during frontline therapy 
• ADA status (negative at all times / positive at any time) 
• geographical region  
• age group (0 - <2, 2 - <6, 6 - <12, 12 - <18 and >=18 years) 
• body weight group (<20 kg; 20-<50 kg; >=50 kg) 
• sex (male/female) 
• race 
12.12 Handling of Missing Data 
Handling of patients not evaluable for the efficacy endpoints is described in Section 12.4.1. 
Handling of AEs with unknown onset dates is described in Section 12.5 and handling of AEs 
with onset outside reporting periods is described in Section 12.5.1. 
12.13 Statistical Analysis Plan 
The Statistical Analysis Plan (SAP) will in further detail describe the analyses presented 
above. 
Handling and presentation of data such as prior cancer therapies, demographics, baseline 
disease status, trial drug exposure, other trial assessments and protocol deviations (incl. 
COVID-related ones) will be described in the SAP. In addition, analyses of the proportion of 
patients who discontinue IT due to unacceptable toxicity and subsequently receive naxitamab 
+ GM-CSF alone, and the time to such a discontinuation, will be described in the SAP. 
12.14 Reporting of trial results 
The results from this trial will be presented in a Clinical Study Report (CSR).   
13 ETHICS 
13.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
This protocol and any accompanying material to be provided to the patient (such as patient 
information sheets and/or descriptions of the trial used to obtain informed consent) will be 
submitted by the Investigator to an IRB/IEC. Approval from the IRB/IEC must be obtained 
before starting the trial and should be documented in a letter to the Investigator.  
It is the responsibility of the Investigator or his/her representative to obtain approval from the 
IRB/IEC before enrolment of any patient into the trial for the trial protocol/protocol 
amendments, advertisements, the patient information and the Informed Consent, including 
any written material to be given to the patient. 


 
 
 
 
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13.2 Ethical Conduct of the Trial 
The trial will be conducted in accordance with the protocol, applicable regulatory 
requirements, ICH Good Clinical Practice45 (GCP and the ethical principles of the 
Declaration of Helsink46 as adopted by the 18th World Medical Assembly in Helsinki, 
Finland, in 1964 and sub-sequent versions. 
The trial will be conducted according to Ethical Considerations for Clinical Trials on 
Medicinal Products Conducted with the Pediatric Population47 (recommendations of the ad 
hoc group for the development of implementing guidelines for Directive 2001/20/EC relating 
to GCP in the conduct of clinical trials on medicinal products for human use).  
13.3 Patient Information and Informed Consent 
The Investigator or his/her designee must obtain the written informed consent from each 
patient, and/or the patients acceptable authorized representative, before any trial related 
procedures are performed as applicable to local regulations. The written patient information 
must not be changed without prior discussion with the Sponsor and approval by the IRB/IEC. 
Patient and legal representative (e.g., parent(s) or guardian(s)) must receive full trial 
information, both verbally and written, before consent is given. A child or adolescent patient 
will be informed and included in the conversations with the parents, to the extent that he/she 
can understand given his/her age. A patient information sheet will be prepared addressing 
legal representative(s) and a version especially addressing the adolescent population will also 
be prepared, if applicable according to local regulations.  
The patient information will contain full and adequate verbal and written information 
regarding the objective and procedures of the trial and the possible benefits and risks 
involved. This will include any information of possible transfer of biological materials, 
imaging and other needed for central analysis. Regardless of legal representative(s) written 
consent, the participation shall not take place if the patient objects. Objection can also be 
non-verbal and expressed by the child’s attitude, body language or resistance. Informed 
Consent (parents), and if applicable informed assent (child/adolescent), must be signed in 
accordance with local regulations. 
If applicable to local regulations: if the child turns 18 during his/her participation in the trial, 
a written consent must be obtained from him/her before the trial can continue. 
Before signing the ICF, the patient/parents must be given sufficient time to consider the 
possible participation. Further, each patient must be informed about their right to with-draw 
from the trial at any time. Parents and patients will also be informed that research 
participation is voluntary but if they withdraw from the trial, their data will still be used. 
When the informed consent form has been signed, the patient/parent(s) receives a copy of the 
signed form and the original is retained in the Investigator site file. A second copy may be 
kept in the patient’s medical notes. The informed consent forms must be signed and dated 
both by the signee and by the person providing the information to the patient/parents. It is 
recommended to notify the patient’s family doctor of the patient’s consent to participate in 
the trial. 


 
 
 
 
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13.4 Confidentiality 
The Investigator must assure that patients’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties according to local requirements. The 
Investigator must keep a screening log showing codes, names, and addresses for all patients 
screened and for all patients enrolled in the trial.  
The Investigator agrees that the IMPs and all information received from Sponsor including 
but not limited to the IB, this protocol, data, eCRFs, and other trial information, remain the 
sole and exclusive property of Sponsor during the conduct of the trial and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the trial or as required by law) without prior written consent from 
Sponsor. The Investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the trial site to any third party or otherwise into the 
public domain. 


 
 
 
 
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14 MONITORING AND QUALITY ASSURANCE 
14.1 Compliance with Good Clinical Practice 
The Investigator will ensure that this trial is conducted in accordance with the principles of 
the “Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, 
Washington, Seoul, and South Africa)46, International Council on Harmonisation (ICH) 
guidelines45, or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the trial patient.  
14.2 Protocol Compliance 
The Investigator is responsible for ensuring the trial is conducted in accordance with the 
procedures and evaluations described in this protocol. Deviations from the protocol should 
not occur. If deviations do occur, the Investigator must inform the CRA for discussion and 
decision on required action(s). Deviations should be documented in writing including an 
explanation. Documentation of deviations will be filed in the Investigator’s site file and a 
copy in the Sponsor’s file. Depending on the nature of the deviation, this may be reported to 
the appropriate regulatory authority. 
14.2.1 
COVID related protocol deviations 
Protocol deviations related to the COVID pandemic should be documented in the source data 
and in the eCRF. 
14.3 Changes to the Protocol 
Protocol modifications, except those intended to reduce immediate risk to trial patients, may 
only be made by Sponsor. Protocol modifications will follow local requirements for 
submission to the competent authorities and IRB/IECs. Approval must be obtained before 
changes can be implemented. 
14.3.1 
Training of Personnel 
Training of personnel will be conducted during the site initiation visit. If change of personnel 
occurs, it is the responsibility of the Principal Investigator (PI) to train new personnel and it 
should be documented by e.g., completion of training log form. If the protocol or any trial 
specific procedures are updated, it is the responsibility of the CRA and PI to ensure 
documented training of all personnel. 
Prior to the first dosing with naxitamab, sites with no earlier experience with naxitamab 
treatment must have watched a video with personnel from sites with naxitamab experience.  
Before administration of naxitamab, the personal should be trained in resuscitation and 
treatment of severe hypotension according to local standard41. 
14.4 Monitoring 
In accordance with the principles of ICH GCP and the Sponsor or its designee’s SOPs, 
monitoring of the trial will be arranged. During the trial, the CRA will have regular contacts 
with the trial site, including visits to ensure that the trial is conducted and documented 
properly in compliance with the protocol, ICH GCP, and applicable local regulations. The 


 
 
 
 
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extent of monitoring will be based on a risk assessment and will be described in a monitoring 
plan. 
The CRA will ensure that accountability of IMPs is performed and will review source 
documents for verification of consistency with the data entered in the eCRFs (source data 
verification). The CRA will also provide information and support to the investigational sites.  
The Investigator should provide a curriculum vitae or equivalent documentation of suitability 
to be responsible for the trial including valid GCP training (i.e., within the previous two (2) 
years), a copy of current licensure, and should sign a financial disclosure on conflict of 
interests. All Investigators and other responsible personnel should be listed together with 
their function in the trial on the signature and delegation list to be filed in the Investigator site 
file. 
During these contacts, the monitoring activities will include: 
• Drug accountability 
• AE identification/review 
• Checking and assessing the progress of the trial  
• Reviewing trial data collected to date for completeness and accuracy 
• Conducting source document verification by reviewing each patient’s eCRF against 
source documents (e.g., medical records, ICF, laboratory result reports, raw data 
collection forms)  
• Identifying any issues and addressing resolutions 
These activities will be done in order to verify that the: 
• Data are attributable, legible, contemporaneous, original and accurate 
• Safety and rights of the patients are being protected  
• Trial is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements 
The Investigator will allow the CRA direct access to all relevant documents and allocate 
ample time and the time of the personnel to the CRA to discuss findings and any relevant 
issues.  
In addition to contacts during the trial, the CRA will contact the site prior to the start of the 
trial to discuss the protocol and data collection procedures with the site personnel. 
14.4.1 
Monitoring of Pharmacies 
If a pharmacy is needed to be involved at the site, then monitoring of the records kept here 
will be described in the Monitoring Plan. 


 
 
 
 
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14.5 Source Data Verification 
14.5.1 
Source Data 
All digital or paper hospital records regarding the treatment of the patient included in the 
trial are considered source data. The following minimum amount of information should be 
reported in the hospital records: 
• Clinical trial identification 
• Patient identification 
• Date when patient information was given and when signed Informed Consent was 
obtained 
• Diagnosis 
• Fulfilment of inclusion criteria 
• Specification of treatment with IMP 
• Specification of visit dates, concomitant medications, and any (S)AEs 
• Specification of the patient’s cessation in the trial (e.g., premature withdrawal) 
• Specification of the patient’s outcome in the trial 
14.5.2 
Direct Access to Source Data/Documents 
The Investigator(s)/institution(s) will permit trial-related monitoring, audits, review and 
regulatory inspection(s), access to source data/hospital records. The CRA verifies that each 
patient has consented in writing to direct access to the original source data/hospital records by 
the use of written patient information and signed informed consent. 
14.5.3 
Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the CRA must have direct access to the 
Investigator’s source documentation in order to verify the data entered in the eCRFs for 
consistency. The CRA is responsible for routine review of the eCRFs at regular intervals 
throughout the trial to verify adherence to the protocol and the completeness, consistency, 
and accuracy of the data being entered into the eCRF. The CRA should have access to any 
patient records needed to verify the entries on the eCRFs. The Investigator agrees to 
cooperate with the CRA to ensure that any problems detected in the course of these 
monitoring visits are resolved. 
14.5.4 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of Sponsor may conduct inspections or audits of 
the clinical trial. If the Investigator is notified of an inspection by a regulatory authority, the 
Investigator agrees to notify the CRA immediately. The Investigator agrees to provide to 
representatives of a regulatory agency or Sponsor access to source documentation, facilities, 
and personnel for the effective conduct of any inspection or audit. 


 
 
 
 
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14.5.5 
Quality Assurance 
At its discretion, the Sponsor (or designee) may conduct a quality assurance audit of this trial. 
Auditing procedures of the Sponsor (or designee) will be followed in order to comply with 
GCP guidelines and ensure acceptability of the trial data for registration purposes. If such an 
audit occurs, the Investigator will give the auditor direct access to all source documents, will 
provide a guided tour of the facilities and will allocate ample time and the time of the 
personnel to the auditor as may be required to have interviews and discuss findings and 
potential issues. 


 
 
 
 
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15 DATA HANDLING AND RECORD KEEPING 
15.1 Electronic Case Report Forms 
For each patient screened, an eCRF must be completed and signed by the Investigator. This 
also applies to records for those patients who fail to complete the trial. If a patient withdraws 
from the trial, the reason must be noted in the eCRF. If a patient is withdrawn from the trial 
because of a treatment-limiting AE, thorough efforts should be made to clearly document the 
outcome. For screening failure patients, the date of informed consent, reason for failure, 
demographic data and any SAE must be captured in the eCRF. 
15.2 eCRF 
An eCRF will be established to collect data in a validated and effective way and in 
compliance with ICH guidelines including audit trail and a query module. The patient’s 
identity must always remain confidential. All information in the eCRFs should be in English.  
The completed eCRF data should not be made available in any form to third parties (except 
for authorized representatives of appropriate regulatory authorities) without written 
permission from the Sponsor. 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data entered in the eCRFs. 
15.2.1 
Corrections to Data 
Corrections to the eCRF data can be made by the Investigator or the Investigator’s delegated 
staff. The eCRF will contain an audit trail capturing as a minimum: the original and 
corrected/changed data, identification of the person correcting/changing the data, date and 
time of the correction/change and reason for the correction. 
If corrections are made by the Investigator’s delegated staff after the date the Investigator has 
signed the eCRF, the Investigator must re-sign the eCRF. 
15.2.2 
Data Entry Timelines 
The Investigator must ensure that data is entered in the eCRF as soon as possible after the 
trial visit and no later than five (5) working days after the trial visit. Timeliness of data 
entries are monitored in the eCRF system. Data entry later than five (5) days after the trial 
visit does not qualify as protocol non-compliance (Section 14.2) and does not need to be 
documented by the Investigator; however, the CRA will address lateness during monitoring 
visits. 
15.3 Trial Documents at Site and Record Retention 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
trial to be fully documented and the trial data to be subsequently verified. These documents 
should be classified into at least the following two categories: (1) Investigator’s site file, and 
(2) patient clinical source documents. The Investigator’s site file will contain the 
protocol/amendments, and IRB/IEC approval with correspondence, informed consent, drug 
records, personnel curriculum vitae and authorization forms, and other appropriate 
documents and correspondence. The Investigator is required to complete a source data list, 


 
 
 
 
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defining where the specific source data can be found (patient record/trial specific patient 
record). 
During the trial, the Investigator will have full access to the eCRF. After the trial is 
completed, the Investigator will receive a copy of the eCRF on CD-ROM or other appropriate 
electronic storage device. 
All clinical trial documents must be retained by the Investigator until at least 25 years after 
the clinical trial. Investigators may be required to retain documents longer if required by 
applicable regulatory requirements, by local regulations, or by an agreement with Sponsor. 
The Investigator must notify Sponsor before destroying any clinical trial records. Should the 
Investigator wish to assign the trial records to another party or move them to another 
location, Sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the trial site for any or all of 
the documents, special arrangements must be made between the Investigator and Sponsor to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
Investigator in case of a regulatory audit. 
When source documents are required for the continued care of the patient, appropriate copies 
should be made for storage outside of the site.  
Biological samples (for ADA assessment, and BM assessments (histology, 
immunohistochemistry, smears of BM and BM aspirates for RTqPCR) will be discarded after 
the analysis has been completed and no later than at the finalization of the full clinical trial 
report. If requested by the local sites, the BM material may be returned before End of Trial. 
The pathology vendor will store the BM material electronically for up to 20 years after End 
of Trial. 
15.4 Data Management 
All data, except laboratory data, will be collected using an eCRF compliant with 21 CFR Part 
11 regulation. Laboratory data centrally collected will be transferred to data management 
facility for inclusion in the clinical database. Data management will be performed in 
accordance with applicable standards and data cleaning procedures. Only authorized access 
to the eCRF will be possible using encrypted username and password. Roles in the system are 
given according to functions. All tasks performed in the eCRF are logged in an audit trail. 
The eCRF will contain validation checks to maintain an ongoing quality check of data 
entered. The Investigator will approve the data using an electronic signature and thereby 
confirm the accuracy of the data entry. Medical history and AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary. Concomitant medication 
will be coded using the World Health Organization (WHO) Drug dictionary. 


 
 
 
 
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16 PREMATURE TERMINATION OF THE TRIAL 
The Sponsor reserves the right to close a trial site or terminate the trial at any time for the 
reasons below at the sole discretion of the Sponsor. If the trial is suspended or terminated, the 
investigator must inform the patients promptly and ensure that adequate considerations is 
given to the protection of the patient’s interest. The Sponsor must promptly inform the 
regulatory authorities and provide a detailed explanation of the termination. Furthermore, the 
investigator or Sponsor will inform IECs/IRBs. 
Trial sites will be closed upon completion. A trial site is considered closed when it has been 
verified that all required documents are filed as required, that the IMP have been destroyed 
and a trial site closure visit has been performed. 
The investigator may initiate trial site closure at any time, provided there is a reasonable 
cause and sufficient notice in advance of the intended termination. 
16.1 Criteria for Halting Patient Enrolment 
Enrolment will be halted temporarily until DMC feedback on continuation of the trial has 
been received if one of the following criteria is met: 
• If an event, alone or in combination with other safety information, is judged by either 
Sponsor or DMC chairman to warrant an acute DMC meeting One or more patients 
experience unexpected, IMP related sudden death during the treatment period 
If the above-mentioned criteria are met, the DMC will review the safety results and determine 
how to proceed as described in Section 10.11. 
Patients already included at the time of clinical trial halt, will continue in the clinical trial but 
further dosing will be postponed until a decision has been reached by the DMC. 
16.2 Criteria for Termination of the Trial 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended 
number of patients. After such a decision, all delivered unused IMP and other trial-related 
materials must be collected without delay and all eCRFs must be completed as far as 
possible. 
The trial could be prematurely discontinued in the following situations (examples): 
• New findings about the IMPs that is considered significantly to worsen the benefit/risk 
ratio 
• Compliance with the trial protocol proves difficult 
• Recruitment of eligible patients is far too low or slow 
• Level of Investigator, Sponsor or patient compliance becomes unacceptable 
• Critical changes are observed in Sponsor or trial site personnel, administrative or 
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• The DMC recommends discontinuation 


 
 
 
 
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17 REPORTING AND COMMUNICATION OF RESULTS 
17.1 Publication 
The data collected in this trial are the property of the Sponsor. Sponsor commits to 
communicate and make available for public disclosure, the results of the clinical trial 
regardless of outcome, in accordance with applicable regulatory requirements. Public 
disclosure implies publication in scientific journals, abstract submission for scientific 
meetings and other types of disclosure (e.g., via ClinicalTrials.gov). Co-authorship from 
Investigators will be in accordance with International Committee of Medical Journal Editors 
(ICMJE) rules: 
• Substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; AND 
• Drafting the work or revising it critically for important intellectual content; AND 
• Final approval of the version to be published; AND 
• Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
A predefined publication committee will follow the entire process; decide on publication, 
manuscript authorship for the entire clinical trial and authorship of potential additional 
manuscripts based on sub-studies. All manuscripts relating to sub-studies will state that they 
are sub-studies and cite the main publication. The publication committee will also decide on 
which journal(s) to submit to. Positive, negative as well as inconclusive results will be 
published e.g., at www.clinicaltrials.gov or www.clinicaltrialsregister.eu. 
17.2 Use of Information 
Sponsor will make one main publication from the clinical trial and all other publications 
should come afterwards and refer to the main clinical trial publication. 
All information not previously published concerning the IMPs, including patent 
applications, manufacturing processes, basic scientific data, clinical trial data and results, 
etc., is considered confidential and remains the sole property of the Sponsor. The 
Investigator agrees to use this information only in connection with this trial and will not use 
it for other purposes without written permission from the Sponsor. 
No such communication, presentation, or publication will include Sponsor’s confidential 
information. All presentation and publications will be governed by the publication 
committee. Proposed publication(s) or presentation(s) along with the respective scientific 
journal or presentation forum should be provided to the Sponsor at least 30 days prior to 
submission of the publication or presentation. Publication authors will comply with 
Sponsor’s request to delete references to its confidential information (other than the trial 
results) in any paper or presentation and agrees to withhold publication or presentation for an 
additional 60 days in order to obtain patent protection if deemed necessary. 


 
 
 
 
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18 INSURANCE 
Insurance and liability will be in accordance with applicable local laws and regulations and 
GCP. 


 
 
 
 
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antibody and granulocyte-macrophage colony-stimulating factor. J Clin Oncol. 
2012;30(4):426-32. 
30. 
Barker E, Mueller BM, Handgretinger R, Herter M, Yu AL, Reisfeld RA. Effect of a 
chimeric anti-ganglioside GD2 antibody on cell-mediated lysis of human neuroblastoma 
cells. Cancer Res. 1991;51(1):144-9. 
31. 
Friedman GK, Castleberry RP. Changing trends of research and treatment in infant 
neuroblastoma. Pediatr Blood Cancer. 2007;49(7 Suppl):1060-5. 
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Schmidt ML, Lukens JN, Seeger RC, Brodeur GM, Shimada H, Gerbing RB, et al. 
Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective 
Children's Cancer Group study. J Clin Oncol. 2000;18(6):1260-8. 
33. 
Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, et al. The 
International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force 
report. J Clin Oncol. 2009;27(2):289-97. 


 
 
 
 
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34. 
U.S. Department of Health and Human Services Food and Drug Administration. 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics Guidance for 
Industry 2018 [Available from: https://www.fda.gov/media/71195/download. 
35. 
European Medicines Agency, CHMP. Guideline on the evaluation of anticancer 
medicinal products in man. EMA/CHMP/205/95 Rev.5 2017 [09-Jun-2020]. Available from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-evaluation-
anticancer-medicinal-products-man-revision-5_en.pdf. 
36. 
Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, et al. 
Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to 
treatment. J Clin Oncol. 1993;11(8):1466-77. 
37. 
Park JR, Bagatell R, Cohn SL, Pearson AD, Villablanca JG, Berthold F, et al. 
Revisions to the International Neuroblastoma Response Criteria: A Consensus Statement 
From the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol. 
2017;35(22):2580-7. 
38. 
Irwin MS, Park JR. Neuroblastoma: paradigm for precision medicine. Pediatr Clin 
North Am. 2015;62(1):225-56. 
39. 
Yanik GA, Parisi MT, Naranjo A, Nadel H, Gelfand MJ, Park JR, et al. Validation of 
Postinduction Curie Scores in High-Risk Neuroblastoma: A Children's Oncology Group and 
SIOPEN Group Report on SIOPEN/HR-NBL1. J Nucl Med. 2018;59(3):502-8. 
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Tong W, Maira M, Gagnon M, Saragovi HU. Ligands Binding to Cell Surface 
Ganglioside GD2 Cause Src-Dependent Activation of N-Methyl-D-Aspartate Receptor 
Signaling and Changes in Cellular Morphology. PLoS One. 2015;10(8):e0134255. 
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Brierley J, Carcillo JA, Choong K, Cornell T, Decaen A, Deymann A, et al. Clinical 
practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 
update from the American College of Critical Care Medicine. Crit Care Med. 
2009;37(2):666-88. 
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National High Blood Pressure Education Program. The fourth report on the diagnosis, 
evaluation, and treatment of high blood pressure in children and adolescents. Blood Pressure 
Levels for Boys and Girls by Age and Height Percentile: US Department of Health and 
Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute; 
2005 [09-Jun-2020]. Available from: 
https://www.nhlbi.nih.gov/files/docs/guidelines/child_tbl.pdf. 
43. 
Burchill SA, Beiske K, Shimada H, Ambros PF, Seeger R, Tytgat GA, et al. 
Recommendations for the standardization of bone marrow disease assessment and reporting 
in children with neuroblastoma on behalf of the International Neuroblastoma Response 
Criteria Bone Marrow Working Group. Cancer. 2017;123(7):1095-105. 
44. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47. 
45. 
International Council for Harmonisation. Integrated addendum to ICH E6 (R1): 
guideline for good clinical practice E6 (R2). Current Step. 2015;2:1-60. 
46. 
World Medical Association. WMA Declaration of Helsinki-Ethical principles for 
medical research involving human subjects. Fortaleza, Brazil; 2013. 
47. 
European Union. Ethical considerations for clinical trials on medicinal products 
conducted with minors. Recommendations of the expert group on clinical trials for the 
implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for 
human use. Revision 1 2017 [07-May-2021]. Available from: 
https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-
10/2017_09_18_ethical_consid_ct_with_minors.pdf. 


 
 
 
 
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48. 
Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New 
equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3):629-37. 
49. 
Trissel LA, Zhang YB, Koontz SE. Temozolomide stability in extemporaneously 
compounded oral suspensions. Int J Pharm Compd. 2006;10(5):396-9. 
 
 
 
 


 
 
 
 
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20 APPENDICES 
Appendix 1 Creatine-based 2009 revised Bedside Schwartz 
Equation 
 
eGRF = 0.413 x (height/Scr)48  
Height is expressed in centimeters 
Abbreviations/Units: 
• eGRF = mL/min/1.73 m2 
• Scr (Standardized serum creatinine) = mg/dL 
 
 
 


 
 
 
 
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Appendix 2 Flowchart and assessment for patients who 
discontinues IT treatment due to toxicity 
This appendix describes the Treatment/Measurements/Evaluations relevant for patients who 
has discontinued treatment with IT due to toxicity. The below flowchart replaces the one in 
Section 3, if the patient moves from treatment with HITS to treatment with naxitamab + GM-
GSF alone. 
Table 12 Schedule of time and events: screening, treatment and follow-up for patients in 
treatment with naxitamab + GM-CSF alone 
Treatment/Measurements/ 
Evaluation 
Cycle 1 for patients in treatment with 
naxitamab and GM-CSF alone 
 
 
 
 
 
D -4 to 
0 
D1  
D2 
D3 
D4 
D5 
D6 +7 
Next cycles 
EOT2 
Long
-term 
FU3 
Physical examination (9.2.1)  
X 
X 
 
 
 
 
 
X 
X 
 
Height and weight (9.3.2)  
X 
 
 
 
 
 
 
X 
 
 
Serum pregnancy test, if 
applicable (9.2.8) 
X5 
 
 
 
 
 
 
X 
X 
 
Vital signs (Appendix 2) 
 
X 
 
X 
 
X 
 
X 
X 
 
Electrocardiogram1 (9.2.6) 
 
 
 
 
 
 
 
 
X 
 
Clinical laboratory 
assessments (Appendix 2) 
X 
X 
 
X 
 
X 
 
X 
X 
 
Anti-drug antibodies (ADA) 
(11.2) 
X 
 
 
 
 
 
 
X 
X 
 
Bone marrow biopsy/apirates  
(9.1.1, 9.1.1.1, 9.1.2)  
 
 
 
 
 
 
 
X6 
X4 
X8 
Imaging (9.1.1, 9.1.1.1, 9.1.2) 
 
 
 
 
 
 
 
X7 
X4 
X8 
Performance test (9.3.4) 
X 
 
 
 
 
 
 
X 
X 
 
Pain assessment (9.2.7) 
 
X 
 
X 
 
X 
 
X 
 
 
Pre-treatment (8.4.1, 
Appendix 2) 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Treatment (8.1.1, Appendix 
2)  
X 
X 
X 
X 
X 
X 
 
X 
 
 
Drug accountability and 
compliance check (8.1.5) 
 
X 
 
X 
 
X 
 
X 
 
 
Hand out diary (8.1.5 ) 
X 
 
 
 
 
 
 
X 
 
 
Adverse events (10) 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Concomitant medication(s) 
(8.4) 
X 
X 
 
X 
 
X 
 
X 
X 
X 
1 If the patient needs sedation before ECG, the ECG can be performed in connection with imaging. 
2 EOT visit should take place 6 (up to 10) weeks after last treatment. If treatment is discontinued due to PD, planned 
initiation of new anti-NB treatment prohibited as per protoocol, withdrawal from the trial or investigator judges it warranted 
due to medical reasons/non-compliance, the patient should be called for EOT visit as soon as possible and subsequently be 
followed for safety and new anti-cancer therapy for 6 weeks after last treatment. 
3 Long-term FU evaluations should take place approximately every 4 months until 2 years after EOT. During long-term FU, 
information on death, PD, SAEs ongoing at EOT visit, new SAEs at least possibly related to naxitamab, autoimmune 


 
 
 
 
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diseases and new onset of secondary malignancies should be collected. Furthermore, new anti-cancer therapy should be 
collected as concomitant medication.  
4 Not to be performed at EOT if the patient discontinues treatment due to PD, provided that PD is documented by scan 
and/or biopsy (see Section 9.1.2). 
5 Should be performed on D-4 prior to GM-CSF administration 
6 Bilateral aspirates and biopsies (2+2): After C2, C4 C8 and EOT (Cycles in the HITS regimen included) (see Section 
9.1.2). 
• 
For patients with CR or PR after 8 cycles: Assessments will furthermore be performed after C11  
• 
For patients with MR or SD after 8 cycles: Assessments will furthermore be performed after C10, C12  
• 
Samples for RTqPCR should be taken after C2 and C4 
All response assessments (except EOT) should be performed before D1 of next cycle. 
In addition, for patients who achieve:  
• 
a first CR or PR after C4 OR 
• 
a first CR or PR after C8 
a confirmatory response assessment should be performed within 4-6 weeks after detection of the overall response. 
7 Imaging schedule follows timing of BM biopsies (see #6 above). For a FDG PET scan, the patient must be in fasting state 
for at least 4 hrs prior to the scan. If the patient is not fasting serum glucose determination must be performed prior to the 
administration of FDG (PET scan only). Please refer to the imaging charter for more details. 
8 For patients who have not experienced PD, response assessment should be performed at approximately every 4 months 
after EOT during long-term FU (see Section 9.1.2). 
Pre-medication: 
Gabapentin should be administered from Day -4 to Day 7 of each cycle according to local 
SoC (e.g. dose of 5 to 10 mg/kg with a max dose of 600 mg). It is recommended to titrate to 
the final effective dose during the first 3 days of treatment:  
• Day -4:  once daily 
• Day -3:  twice daily 
• Day -2 and onwards until Day 7: 3 times daily 
Treatment 
The treatment regimen/cycles are different for patients who are treated with naxitamab + 
GM-CSF alone compared to patients who are treated with HITS. Please see below: 
Each treatment cycle is 28 days. 
GM-CSF: 
GM-CSF should be administered sc at 250 µg/m2 per day from Day -4 to Day 0 and 500 
µg/m2 per day at Day 1 to Day 5. The patient/parents will be asked to fill in records of 
administration (patient diary).  
If any events occur fulfilling a GM-CSF discontinuation criterion the patient must 
discontinue GM-CSF but will be allowed to continue naxitamab treatment, see Section 7.12 
Naxitamab: 
On days when co-administered with GM-CSF, naxitamab infusion is started ≥ 60 min after 
GM-CSF. 
Naxitamab should be infused IV at 3 mg/kg/day on Days 1, 3, and 5 for a total dose of 9 
mg/kg per cycle. Administration of naxitamab should be adjusted according to Section 8.4.5 
if selected naxitamab adverse reactions are observed. If any events occur fulfilling a general 


 
 
 
 
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discontinuation criterion the patient must be withdrawn from naxitamab and GM-CSF 
treatment immediately and enter long-term follow-up, see Section 7.12.  
Naxitamab should be infused over approx. 30 min.  
Special circumstances: 
The infusion may be given over approximately 60 min. at Day 1 of any cycle at the 
investigator’s discretion if: 
• The patient during the C1D2 infusion (HITS regimen) experienced naxitamab related 
hypotension: 
o CTCAE Grade 4 or  
o Grade 3 not adequately responding 
• At the investigators discretion due to severe infusion related adverse drug reactions 
not adequately responding to interventions 
The 60/30 min infusion time is a minimum infusion time. If infusion pause or infusion rate 
reduction is required due to infusion related AE (see Section 8.4.5) the infusion time will 
become longer.  
Table 13 Treatment with naxitamab + GM-CSF alone 
Treatment days in cycles of 28 days 
-4 to 0 
1 
2 
3 
4 
5 
6+7 
11-28 
Premedication  
(analgesics and/or antihistamines) (8.4.1) 
X 
X 
X 
X 
X 
X 
X 
 
GM-CSF 250 ug/m2/day s.c (8.4.6)1 
X 
 
 
 
 
 
 
 
GM-CSF 500 ug/m2/day s.c (8.4.6)1 
 
X 
X 
X 
X 
X 
 
 
Naxitamab 3 mg/kg/day IV (9mg/kg/cycle)1 
(8.1.2.3)1 
 
X 
 
X 
 
X 
 
 
1 Patients achieving a CR or PR should receive 8 naxitamab cycles or 5 additional naxitamab cycles following the OR, 
whichever provides the longest treatment with naxitamab. Patients who have achieved a MR or SD at completion of the 8 
cycles may receive naxitamab + GM-CSF consolidation treatment for 5 cycles administered at every 8 weeks. The total 
number naxitamab cycles to be administered includes the treatment cycles administered in the HITS regimen 
Missed dosing 
If a naxitamab dose is missed, administer the missed dose the following week, but the 3 
infusions of naxitamab must be administered within a period of maximum 10 days. If a 
patient is treated on a modified schedule, the GM-CSF dosage will be the same as the 
standard on days -4 to 0, but GM-CSF will be administered at 500 μg/m2/day on the day of 
the first infusion of naxitamab, on the day before and on the day of the second infusion of 
naxitamab, and on the day before and on the day of the third infusion of naxitamab. The 
modified schedule ensures that the same total dosage of GM-CSF is administered in the 
standard and in the modified schedules. 
Laboratory assessments: 
Laboratory tests should be performed as described in the table below and as clinically 
indicated. 
 


 
 
 
 
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Table 14 Protocol required laboratory assessments for patient treated with naxitamab + 
GM-CSF alone 
Timing of Laboratory assessments 
Parameters 
All cycles*: Prior to dosing D-4, D1, 
D3, D5  
EOT 
 
* If modified naxitamab dosing due to 
missed dose (ie naxitamab missed dose to be 
administered within the first 10 days of a 
cycle) check hematology parameters on day 
of last naxitamab administration in the cycle 
prior to administration of GM-CSF  
Hematology 
• Hemoglobin  
• Hematocrit 
• White blood cells (WBC) 
• Lymphocytes (absolute) 
• Neutrophils (absolute) 
• Eosinophils (absolute) 
• Basophils (absolute) 
• Monocytes (absolute) 
• Platelet count 
All cycles: prior to dosing D1, D3, 
D5 
EOT 
 
 
Liver and kidney function blood tests  
• ALT 
• AST 
• Alkaline phosphatase 
• Total bilirubin 
• LDH 
• BUN 
• Creatinine 
• Albumin (only prior to each cycle) 
All cycles: prior to dosing D1, D3, 
D5  
EOT 
Serum electrolytes 
• Sodium 
• Potassium 
 
Prior to each cycle 
Urine analysis (dipstick) 
• Protein 
• Glucose 
• Leucocytes 
Prior to each cycle 
EOT 
Pregnancy test, if applicable 
Serum pregnancy test for WOCBP see 9.2.8 for 
further information 
ADA  
Prior dosing in each cycle 
EOT 
• Anti-naxitamab antibodies 
• Naxitamab AB (neutralizing effect) 
The complete blood count (CBC) and differential counts should be repeated on sequential 
days during all treatment cycles if ANC is > 20 x109/L or WBC > 50 x109/L on the previous 
day. 
 
Vital signs 
• 
Prior to pre-medication (e.g., hydromorphone or morphine) 
• 
Prior to start of naxitamab infusion 


 
 
 
 
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• 
~15 min after start of naxitamab infusion 
• 
~30 min after start of naxitamab infusion 
• 
Prior to each hydromorphone or morphine IV therapy as possible/feasible (no 
temperature) 
• 
At completion of naxitamab infusion including flush (no temperature) 
• 
~15 min after completion of the flush (no temperature) 
• 
Every hour while patient is recovering in the outpatient clinic 
Please refer to Section 9.2.7 for pain assessments and Section 9.2.3 for naxitamab discharge 
criteria. Furthermore, vital signs should be measured at EOT and as clinical indicated. 


 
 
 
 
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Appendix 3 Temozolomide dosing (100mg/m2/day) Nomogram 
Temozolomide is dosed based on BSA. The dose should be rounded off to the nearest 5 
mg (round 2.5 mg down). For patients with BSA <0.5 m2, dosing is based on body 
weight (kg). 
For patients with a BSA < 0.5 m2: Use 3.3 mg/kg. 
Examples: 
Patient has a BSA of 0.3 m2 and weighs 5 kg. Patient administered dose = 5 kg x 3.3 mg/kg = 
16.5 mg 
Patient has a BSA of 0.66 m2. Calculated dose is 0.66 m2 x 100 mg/m2 = 66 mg/day; 
Administered dose = 65 mg temozolomide/day. 
 
 
 
 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose (mg) 
< 0.50 
3.3 mg/kg 
3.3 mg/kg 
0.50-0.52 
50-52 
50 
0.53-0.57 
53-57 
55 
0.58-0.62 
58-62 
60 
0.63-0.67 
63-67 
65 
0.68-0.72 
68-72 
70 
0.73-0.77 
73-77 
75 
0.78-0.82 
78-82 
80 
0.83-0.87 
83-87 
85 
0.88-0.92 
88-92 
90 
0.93-0.97 
93-97 
95 
0.98-1.0 
98-100 
100 
1.01-1.05 
100-105 
105 
1.06-1.14 
105-114 
110 
1.15-1.24 
115-124 
120 
1.25-1.34 
125-134 
130 
1.35-1.44 
135-144 
140 
1.45-1.54 
145-154 
150 
1.55-1.64 
155-164 
160 
1.65-1.74 
165-174 
170 
1.75-1.84 
175-184 
180 
1.85-1.94 
185-194 
190 
1.95-2.00 
195-200 
200 
> 2.0 
> 200 
200 


 
 
 
 
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Appendix 4 Nomogram for Reduced Dosing (80 mg/m2/day ) of 
Temozolomide  
Temozolomide is dosed based on BSA for patients whose BSA is at least 0.5 m2. For these 
patients, doses are rounded to the nearest 5 mg. For patients with BSA <0.5 m2, dosing is 
based on body weight (kg). If unacceptable temozolomide associated specific toxicities occur 
(see Section 8.4.4), a 20% dose reduction should be applied (80mg/m2/day). If the toxicity 
recurs despite the dose reduction a second 20% dose reduction (60 mg/m2/day) may be 
applied (see Appendix 5) 
For patients with a BSA < 0.5 m2: Use 2.6 mg/kg. 
 
Examples:  
• For a patient with a BSA of 0.3 m2 and weighs 5 kg, the calculated dose is 5 kg x 2.6 
mg/kg = 13.0 mg 
• For a patient with a BSA of 0.66 m2, the calculated dose = 52.8 mg/dose; 
administered dose = 55 mg temozolomide/dose. 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose 
(mg) 
0.2-0.49 
2.6 mg/kg 
2.6 mg/kg 
0.50 - 0.53  
40 - 42 
40 
0.54 - 0.59 
43 - 47 
45 
0.60 -0.65 
48 - 52 
50 
0.66-0.71 
53 -57 
55 
0.72-0.78 
58 - 62 
60 
0.79-0.84 
63 - 67 
65 
0.85-0.90 
68 - 72 
70 
0.91-0.96 
73 - 77 
75 
0.97-1.03 
78 - 82 
80 
1,04-1.09 
83 - 87 
85 
1.10-1.15 
88 - 92 
90 
1.16-1.21 
93 - 97 
95 
1.22-1.28 
98 - 102 
100 
1.29-1.34 
103 -107 
105 
1.35-1.40 
108 - 112 
110 
1.41-1.46 
113 - 117 
115 
1.47-1.53 
118 - 122 
120 
1.54-1.59 
123 - 127 
125 
1.60-1.65 
128 - 132 
130 
1.66-1.71 
133 - 137 
135 
1.72-1.78 
138 - 142 
140 
1.79-1.84 
143 - 147 
145 
1.85-1.90 
148 - 152 
150 
1.91-1.96 
153 - 157 
155 
>1.96 
>157 
160 


 
 
 
 
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Appendix 5 Nomogram for Reduced Dosing (60 mg/m2/day) of 
Temozolomide  
Temozolomide is dosed based on BSA for patients whose BSA is at least 0.5 m2. For these 
patients, doses are rounded to the nearest 5 mg. For patients with BSA <0.5 m2, dosing is 
based on body weight (kg). If unacceptable temozolomide associated specific toxicities recur 
despite the first dose reduction by 20% (see Section 8.4.4), a second 20% dose reduction (60 
mg/m2/day) should be applied. 
For patients with a BSA < 0.5 m2: Use 2.0 mg/kg. 
 
Examples:  
• For a patient with a BSA of 0.3 m2 and weighs 5 kg, the calculated dose is 5 kg x 2.0 
mg/kg = 10.0 mg 
• For a patient with a BSA of 0.66 m2, the calculated dose = 39.6 mg/dose; 
administered dose = 40 mg temozolomide/dose. 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose 
(mg) 
0.2-0.49 
2.0 mg/kg 
2.0 mg/kg 
0.50 - 0.54  
30 - 32 
30 
0.55 - 0.62 
33 - 37 
35 
0.63 -0.70 
38 - 42 
40 
0.71-0.79 
43 - 47 
45 
0.80-0.87 
48 - 52 
50 
0.88-0.95 
53 -57 
55 
0.96-1.04 
58 - 62 
60 
1.05-1.12 
63 - 67 
65 
1.13-1.20 
68 - 72 
70 
1,21-1.29 
73 - 77 
75 
1.30-1.37 
78 - 82 
80 
1.38-1.45 
83 - 87 
85 
1.46-1.54 
88 - 92 
90 
1.55-1.62 
93 - 97 
95 
1.63-1.70 
98 - 102 
100 
1.71-1.79 
103 -107 
105 
1.80-1.87 
108 - 112 
110 
1.88-1.95 
113 - 117 
115 
>1.95 
>117 
120 
 
 
 


 
 
 
 
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Appendix 6 Temozolomide 10 mg/mL suspension 
Preparation of oral suspension of Temozolomide49: 
Recipe for 100 mL 
 
Temozolomide (from 10 Temodar 100 mg capsules) 
1,000 mg 
Povidone K-30 
500 mg 
Anhydrous citric acid 
25 mg 
Purified water 
1,5 mL 
Ora-Plus 
50 mL 
Ora-Sweet or Ora-Sweet SF qs 
100 mL  
Note: It is necessary to wear suitable protective garb and to perform this procedure in a fume 
hood. The suspension must be administered at the trial site. 
1. Empty the contents of 10 temozolomide 100 – mg capsules in a glass mortar of sufficient 
size 
2. Weigh 500 mg of povidone K-30 powder and add to the mortar 
3. Triturate to assure thorough mixing and that the mixture is reduced to a fine powder 
4. Dissolve 25 mg of anhydrous citric acid and purified water  
5. Add the mixture of anhydrous citric acid and purified water to the mortar to wet the 
powder 
6. Mix thoroughly to form a uniform paste 
7. Add a small amount of Ora-Plus suspension vehicle to the triturated paste with thorough 
mixing to ensure a uniform mixture 
8. Add the balance of the Ora-Plus suspension vehicle with thorough mixing to ensure a 
uniform mixture 
9. Transfer the resulting mixture to a glass graduated cylinder  
10. Rinse the mortar and pestle with small aliquots of the appropriate syrup (Ora-Sweet or 
Ora-Sweet SF); repeat the rinsing three times 
11. Add an additional quantity of the appropriate syrup vehicle to the bottle to bring the final 
volume to 100 mL and shake the resulting suspension well 
12. Package in amber plastic prescription bottles and label the containers with “Shake well” 
and “Refrigerate” and the expiry date which is 60 days after preparation 


 
 
 
 
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Appendix 7 Recommendations for administration of 
Temozolomide 
(Patients who are unable to swallow capsules and cannot obtain a suspension) 
If the patient is unable to swallow capsules, the below instructions or the one in Appendix 5 must be 
followed for safe administration of temozolomide. 
It is necessary to wear suitable protective garb and to perform this procedure in a fume hood. 
• 
Temozolomide can be mixed in apple sauce or apple juice 
• 
Place the apple sauce or apple juice in a disposable container 
• 
Open each capsule required for the daily dose and place the powder in a medicine cup 
• 
Add the whole contents of the medicine cup to either apple sauce or apple juice. The 
medicine will not dissolve completely if mixing in apple juice so have extra apple juice on 
hand so you can add it to any remaining powder in the bottom of the cup 
• 
If you need to have additional juice or apple sauce remove your gloves before touching the 
main container then place new gloves on before adding the additional juice or apple sauce to 
the medicine. (You do not want to contaminate the main container with any powder that may 
be on your gloves.) 
• 
Anything that comes into contact with the medicine must be disposable, such as the spoon 
used for mixing or eating the apple sauce 
 
 


 
 
 
 
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Appendix 8 Wong-Baker FACES® Pain Rating Scale 
 
Instructions 
Prior to the naxitamab infusion, the Wong Baker FACES Pain Rating Scale should be 
presented and explained to the patient, by informing the patient that each face on the scale 
represents a person who has no pain, some pain or a lot of pain. The staff who will be asking 
the patient to rate his/her pain should explain that:   
• Face 0 does not hurt at all. 
• Face 2 hurts just a little bit. 
• Face 4 hurts a little bit more. 
• Face 6 hurts even more. 
• Face 8 hurts a whole lot. 
• Face 10 hurts as much as you can imagine, although you don´t have to be crying to have 
this worst pain. 
The rating should be done by asking the patient to choose the face that best depicts the pain 
they are experiencing. 
For details of pain assessment please see Section 9.2.7.  
 
 
 


 
 
 
 
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Appendix 9 FLACC Behavioral Scale 
FLACC Behavioral Scale 
Categories 
  
Scoring 
  
0 
1 
2 
Face 
No particular 
Occasional grimace or 
Frequent to constant 
expression or smile 
frown, withdrawn, 
frown, clenched jaw, 
disinterested 
quivering chin 
Legs 
Normal position or 
Uneasy, restless, tense 
Kicking, or legs drawn 
relaxed 
up 
Activity 
Lying quietly, normal 
Squirming, shifting 
Arched, rigid, or 
position, moves easily 
back and forth, tense 
jerking 
Cry 
No cry (awake or 
Moans or whimpers, 
Crying steadily, 
asleep) 
occasional complaint 
screams or sobs, 
frequent complaints 
Consolability 
Content, relaxed 
Reassured by 
Difficult to console or 
occasional touching, 
comfort 
hugging, 
or being talked to, 
distractable 
Each of the five categories (F) Face; (L) Legs; (A) Activity; (C) Cry; (C) Consolability is 
scored from 0-2, which results in a total score between zero and ten. 
 
Copyright© 2002, The Regents of the University of Michigan. All Rights Reserved. 
 
FLACC Behavioral Pain Scale 
Patients who are awake: Observe for at least 1-2 min. Observe legs and body uncovered. 
Reposition patient or observe activity, assess body for tenseness and tone. Initiate consoling 
interventions if needed 
Patients who are asleep: Observe for at least 2 min or longer. Observe body and legs 
uncovered. If possible, reposition the patient. Touch the body and assess for tenseness and 
tone. 
 
Face 
Score 0 point if patient has a relaxed face, eye contact and interest in surroundings 
Score 1 point if patient has a worried look to face, with eyebrows lowered, eyes, partially 
closed, cheeks raised, mouth pursed 
Score 2 points if patient has deep furrows in the forehead, with closed eyes, open mouth and 
deep lines around nose/lips 
 
Legs 
Score 0 points if patient has usual tone and motion to limbs (legs and arms) 
Score 1 point if patient has increase tone, rigidity, tense, intermittent flexion/extension of 
limbs 
Score 2 points if patient has hyper tonicity, legs pulled tight, exaggerated flexion/extension of 
limbs, tremors 


 
 
 
 
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Activity 
Score 0 points if patient moves easily and freely, normal activity/restrictions 
Score 1 point if patient shifts positions, hesitant to move, guarding, tense torso, pressure on 
body part 
Score 2 points if patient is in fixed position, rocking, side-to-side head movement, rubbing 
body part 
 
Cry 
Score 0 points if patient has no cry/moan awake or asleep 
Score 1 point if patient has occasional moans, cries, whimpers, sighs 
Score 2 points if patient has frequent/continuous moans, cries, grunts 
 
Consolability 
Score 0 points if patient is calm and does not require consoling 
Score 1 point if patient responds to comfort by touch or talk in - 1 min 
Score 2 points if patient require constant consoling or is unconsoled after an extended time 
Whenever feasible, behavioral measurement of pain should be used in conjunction with self-
report. When self-report is not possible, interpretation of pain behaviors and decision-making 
regarding treatment of pain requires careful consideration of the context in which the pain 
behaviors were observed. 
Each category is scored on the 0-2 scale which results in a total score of 0-10Assessment of 
Behavioral Score: 
0 = Relaxed and comfortable 
1-3 = Mild discomfort 
4-6 = Moderate pain 
7-10 = Severe discomfort/pain 
 
Copyright© 2002, The Regents of the University of Michigan. All Rights Reserved. 
 
 
 


 
 
 
 
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Appendix 10 Performance tests 
Lansky Scale  
(recipient age < 16 years) 
Karnofsky Scale 
(recipient age ≥ 16 Years) 
Able to carry on normal activity; no special care 
is needed 
Able to carry on normal activity; no special care 
is needed 
100 
Fully active 
100 
Normal, no complaints, no evidence of 
disease 
90 
Minor restriction in physically strenuous 
play 
90 
Able to carry on normal activity 
80 
Restricted in strenuous play, tires more 
easily, otherwise active 
80 
Normal activity with effort 
Mild to moderate restrictions 
Unable to work, able to live at home cares for 
most personal needs, a varying amount of 
assistance needed 
70 
Both greater restrictions of, and less time 
spent in active play 
70 
Cares for self, unable to carry on normal 
activity or to do active work 
60 
Ambulatory up to 50% of time, limited 
active play with assistance/supervision 
60 
Requires occasional assistance but is able 
to care for most needs 
50 
Considerable assistance required for any 
active play, fully able to engage in quiet 
play 
50 
Requires considerable assistance and 
frequent medical care 
Moderate to severe restrictions 
Unable to care for self, requires equivalent of 
institutional or hospital care, disease may be 
progressing rapidly 
40 
Able to initiate quiet activities 
40 
Disabled, requires special care and 
assistance 
30 
Needs considerable assistance for quiet 
activity 
30 
Severely 
disabled, 
hospitalization 
indicated, although death not imminent  
20 
Limited to very passive activity initiated 
by others (e.g., TV) 
20 
Very sick, hospitalization necessary 
10 
Completely disabled, not even passive 
play 
10 
Moribund, fatal process progressing 
rapidly 
 
 


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