A Multicenter Phase 2/3 Trial of the Efficacy and Safety of Intracerebroventricular Radioimmunotherapy Using 131I-omburtamab for Neuroblastoma Central Nervous System/Leptomeningeal Metastases
Phase: PHASE2
Conditions: Neuroblastoma, CNS Metastases, Leptomeningeal Metastases
Sponsor: Y-mAbs Therapeutics

 
 
 
 
CLINICAL TRIAL 
PROTOCOL 
 
A Multicenter Phase 2/3 Trial of the Efficacy 
and Safety of Intracerebroventricular 
Radioimmunotherapy using 131I-omburtamab 
for Neuroblastoma Central Nervous 
System/Leptomeningeal Metastases. 
 
A Phase 2/3, International Clinical Trial 
 
Clinical Trial ID: 101 
EudraCT No.: 2017-001828-22 
IND No.: 9351 
ClinicalTrials.gov Identifier: NCT03275402 
 
 
Version 10.0; 01 May 2020 
 
This Trial Protocol is the property of Y-mAbs Therapeutics and is a 
confidential document. It is not to be copied or distributed to other 
parties without written approval from Y-mAbs Therapeutic 

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SIGNATURE PAGE 
 
 Sponsor Medical Monitor/Expert 
 
 
Y-mAbs Therapeutics A/S 
 
Associate Medical Director 
 Please see e-signature page 
  
 
 Print Name: 
 
 
Signature: 
 Date: 
 
 
 Sponsor 
 
 
Y-mAbs Therapeutics A/S 
 
Project Manager  
 Please see e-signature page 
  
 
 Print Name: 
 Signature: 
 Date: 
 
 

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TABLE OF CONTENTS 
 
1 
PROTOCOL SYNOPSIS ....................................................................................... 7 
2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................... 11 
3 
FLOW CHARTS .................................................................................................. 13 
4 
INTRODUCTION ................................................................................................ 16 
4.1 
Medical background ............................................................................................... 16 
4.2 
Drug profile ............................................................................................................ 17 
4.2.1 
131I-omburtamab ..................................................................................................... 17 
4.2.2 
Radiolabeling .......................................................................................................... 20 
5 
RATIONALE, OBJECTIVE AND BENEFIT-RISK ASSESSMENT ............ 21 
5.1 
Rationale for performing the trial ........................................................................... 21 
5.2 
Rationale for dose selection ................................................................................... 21 
5.2.1 
131I-omburtamab ..................................................................................................... 21 
5.3 
Benefit-risk assessment .......................................................................................... 21 
5.3.1 
Trial objectives ....................................................................................................... 22 
5.3.2 
Primary objective ................................................................................................... 22 
5.3.3 
Secondary objectives .............................................................................................. 22 
6 
DESCRIPTION OF DESIGN AND TRIAL POPULATION .......................... 23 
6.1 
Overall trial design and plan................................................................................... 23 
6.1.1 
Screening ................................................................................................................ 23 
6.1.2 
Treatment ................................................................................................................ 23 
6.1.3 
Safety considerations .............................................................................................. 24 
6.1.4 
Duration of treatment ............................................................................................. 25 
6.1.5 
Screening/pretreatment evaluation ......................................................................... 26 
6.2 
Data Monitoring Committee and Adjudication Committee ................................... 27 
6.3 
Follow-up ............................................................................................................... 27 
6.4 
Discussion of trial design ....................................................................................... 28 
6.5 
Selection of trial population ................................................................................... 28 
6.6 
Recruitment period ................................................................................................. 28 
6.7 
End of trial .............................................................................................................. 28 
6.8 
Number of participants ........................................................................................... 29 
6.9 
Participant selection and withdrawal ...................................................................... 29 
6.9.1 
Inclusion criteria ..................................................................................................... 29 
6.9.2 
Exclusion criteria .................................................................................................... 30 
6.9.3 
Treatment discontinuation criteria .......................................................................... 30 
7 
TREATMENTS .................................................................................................... 32 
7.1 
Investigational Medicinal Product .......................................................................... 32 
7.1.1 
Treatment ................................................................................................................ 32 
 
Bleyer et al. 1977. ................................................................................................... 32 
7.2 
Packaging and labelling of omburtamab ................................................................ 32 
7.2.1 
Storage and handling .............................................................................................. 32 
7.2.2 
Radiolabeling of omburtamab ................................................................................ 33 
7.2.3 
Administration of 131I-omburtamab ........................................................................ 33 

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7.2.4 
Radiation safety ...................................................................................................... 33 
7.2.5 
Protection of thyroid function ................................................................................ 34 
7.2.6 
Participant compliance ........................................................................................... 35 
7.3 
Concomitant therapy .............................................................................................. 35 
7.3.1 
Therapy allowed during the trial ............................................................................ 35 
7.4 
Treatment after discontinuation of IMP ................................................................. 35 
8 
ENDPOINTS ......................................................................................................... 36 
8.1 
Efficacy .................................................................................................................. 36 
8.1.1 
Primary endpoint .................................................................................................... 36 
8.1.2 
Secondary endpoints ............................................................................................... 36 
8.2 
Safety ...................................................................................................................... 36 
8.2.1 
Safety endpoints ..................................................................................................... 36 
9 
PROCEDURES AND ASSESSMENTS ............................................................. 37 
9.1 
Efficacy assessments .............................................................................................. 37 
9.1.1 
Primary endpoint .................................................................................................... 37 
9.1.2 
Secondary endpoints ............................................................................................... 37 
9.2 
Other assessments ................................................................................................... 38 
9.2.1 
Hematology and clinical chemistry ........................................................................ 38 
9.2.2 
CSF for cytology, total protein, glucose and cell count ......................................... 39 
9.2.3 
Blood and CSF for culture ...................................................................................... 39 
9.2.4 
Demographics ......................................................................................................... 39 
9.2.5 
Height and body weight ......................................................................................... 39 
9.2.6 
Medical and surgical history .................................................................................. 39 
9.2.7 
Concomitant medication ......................................................................................... 40 
9.2.8 
Physical examination .............................................................................................. 40 
9.2.9 
Vital signs ............................................................................................................... 40 
9.2.10 
Neurotoxicity .......................................................................................................... 40 
9.2.11 
Non-childbearing potential ..................................................................................... 41 
9.2.12 
Unscheduled visits .................................................................................................. 41 
10 
ADVERSE EVENTS ............................................................................................ 42 
10.1 
Definitions .............................................................................................................. 42 
10.1.1 
Definition of adverse events ................................................................................... 42 
10.2 
Definition of Serious Adverse Events .................................................................... 42 
10.3 
Definition of non-serious AE ................................................................................. 43 
10.4 
Pre-defined AEs of Special Interest ....................................................................... 43 
10.5 
Adverse Event Recording ....................................................................................... 43 
10.6 
Pre-existing conditions ........................................................................................... 43 
10.6.1 
Procedures .............................................................................................................. 43 
10.6.2 
Overdose, medication errors and misuse ................................................................ 43 
10.6.3 
Pregnancy ............................................................................................................... 44 
10.6.4 
Severity ................................................................................................................... 45 
10.6.5 
Relationship to IMP ................................................................................................ 45 
10.6.6 
Outcome ................................................................................................................. 46 
10.7 
Expected side-effects related to 131I-omburtamab and dexamethasone ................. 46 
10.8 
Reporting of Adverse Events ................................................................................. 46 
10.9 
Follow-Up on AEs .................................................................................................. 48 
11 
LABORATORIES ................................................................................................ 50 
11.1 
Clinical chemistry and hematology ........................................................................ 50 

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12 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 51 
12.1 
General Overview ................................................................................................... 51 
12.2 
Populations of Interest ............................................................................................ 51 
12.3 
Efficacy Analysis ................................................................................................... 52 
12.4 
Safety Analysis ....................................................................................................... 52 
12.5 
Dosimetry Analysis ................................................................................................ 53 
12.6 
Pharmacokinetic Analysis ...................................................................................... 53 
12.7 
Interim Analysis ..................................................................................................... 53 
12.8 
Sample Size ............................................................................................................ 53 
12.9 
Handling of missing data ........................................................................................ 54 
13 
ETHICS ................................................................................................................. 55 
13.1 
Independent ethics committee or institutional review board (IRB) ....................... 55 
13.2 
Ethical conduct of the trial ..................................................................................... 55 
13.3 
Participant information and informed consent ....................................................... 55 
13.4 
Special considerations for patients having the Ommaya reservoir implanted at the 
referring hospital or locally but before entering the screening period. .................. 56 
14 
MONITORING AND QUALITY ASSURANCE .............................................. 57 
14.1 
Compliance with Good Clinical Practice ............................................................... 57 
14.1.1 
Protocol compliance ............................................................................................... 57 
14.1.2 
Training of personnel ............................................................................................. 57 
14.2 
Monitoring .............................................................................................................. 57 
14.3 
Source data verification .......................................................................................... 58 
14.3.1 
Source data ............................................................................................................. 58 
14.3.2 
Direct access to source data/documents ................................................................. 58 
14.3.3 
Access to information for monitoring .................................................................... 59 
14.3.4 
Access to information for auditing or inspections .................................................. 59 
14.4 
Quality assurance ................................................................................................... 59 
15 
DATA HANDLING AND RECORD KEEPING .............................................. 60 
15.1 
Electronic case report forms ................................................................................... 60 
15.1.1 
eCRF ....................................................................................................................... 60 
15.2 
Trial documents at site and record retention .......................................................... 60 
15.3 
Data management ................................................................................................... 61 
16 
REPORTING AND COMMUNICATION OF RESULTS .............................. 62 
16.1 
Publication .............................................................................................................. 62 
16.2 
Use of information .................................................................................................. 62 
17 
INSURANCE ........................................................................................................ 63 
18 
CHANGES AND DEVIATIONS TO THE PROTOCOL ................................ 64 
19 
PREMATURE TERMINATION OF THE TRIAL .......................................... 65 
19.1 
Criteria for halting participant enrollment .............................................................. 65 
19.2 
Criteria for termination of the trial ......................................................................... 65 
20 
REFERENCES ..................................................................................................... 66 
 
 
 
 

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TABLE OF TABLES 
Table 1 Schedule of time and events .................................................................................... 13 
Table 2 Normal organ radiation dosimetry (Reference Child anatomic model) for 
intracerebroventricular 131I-omburtamab................................................................................. 19 
Table 3 Treatment dose reduction for patients less than 3 years of age .................................. 32 
Table 4 Accepted activity ranges for treatment doses ............................................................. 33 
Table 5 Assumed power for 3 years OS rates ......................................................................... 53 
 
 
TABLE OF FIGURES 
Figure 1 One 131I-omburtamab treatment cycle after the interim analysis .............................. 25 
Figure 2 Overall design ........................................................................................................... 26 
 
 
TABLE OF APPENDICES 
Appendix 1 Contact details of clinical trial team .................................................................... 70 
Appendix 2 Salvage Treatments Recommended Prior to Trial 101 Entry* ............................ 71 
Appendix 3 Creatinine-based 2009 revised Bedside Schwartz Equation ............................... 72 
Appendix 4 Ommaya patency/CSF flow study ....................................................................... 73 
Appendix 5 Ethical Considerations for Clinical Trials on Medicinal Products Conducted with 
the Paediatric Population ......................................................................................................... 75 
Appendix 6 Template letter to referring oncologist ................................................................ 76 
 
 
 

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1 
PROTOCOL SYNOPSIS 
Title 
A Multicenter Phase 2/3 Trial of the Efficacy and Safety of Intracerebroventricular 
Radioimmunotherapy using 131I-omburtamab for Neuroblastoma Central Nervous 
System/Leptomeningeal Metastases 
EudraCT number 
2017-001828-22 
Investigational New 
Drug (IND) 
9351 
Investigational 
site(s) 
Several sites in Europe and US  
Investigator 
Trial Coordinating Investigator:  
Kim Kramer, M.D. 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. 
New York, NY 10065 
USA 
Sponsor 
Y-mAbs Therapeutics 
Agern Allé 11 
2970 Hørsholm  
Denmark 
Trial ID 
101 
Trial design 
Single-arm, open-label Phase 2/3 trial 
Patient population 
Pediatric neuroblastoma (NB) patients with central nervous system (CNS) relapse as 
evidenced by CNS/leptomeningeal (LM) metastases 
Objectives 
Primary Objective 
1. To evaluate the overall survival (OS) rate at 3 years. 
 
Secondary objectives: 
1. To evaluate CNS/LM progression-free survival (CNS/LM PFS) at 6 and 12 months  
2. To evaluate Overall Survival (OS) at 12 months 
3. To evaluate the objective response rate (ORR) at 6 months. 
4. To evaluate dosimetry of 131I-omburtamab.  
5. To evaluate the pharmacokinetics of 131I-omburtamab. 
6. To evaluate safety of 131I-omburtamab. 
7. To evaluate the immunogenicity of 131I-omburtamab. 
 
Endpoints 
Primary Endpoint: 
1. OS rate at 3 years after the first treatment dose of 131I-omburtamab. 
 
Secondary Endpoints 
1. CNS/LM PFS at 6 and 12 months  
2. OS at 12 months  
3. ORR assessed as a combination of partial response and complete response as defined by 
the Response assessment in Neuro-Oncology (RANO) group criteria for brain 
metastasis (Lin et al, 2015) or leptomeningeal metastases as defined by EANO-ESMO 
criteria (Le Rhun et al, 2017). ORR will be assessed at 6 months after the first treatment 
dose of 131I-omburtamab 
4. ORR according to CSF cytology. Response is defined as a complete response when 
CSF converts from positive at baseline to negative after treatment with 131I-omburtamab 
5. Whole-body, organ, blood, and CSF radiation dosimetry. 
6. Pharmacokinetic analysis of activity in blood and CSF including derivation of best-fit 
uptake and/or clearance parameters (half-times, maximum value) of time-activity 
concentration curves and of I-131 residence times (i.e., cumulated activity) 
concentrations (in Ci-h/g). 
7. The frequency, type, and duration of treatment-emergent severe adverse events and 
serious adverse events, including clinically significant laboratory abnormalities. All 

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adverse events will be graded according to Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.0.  
8. Performance assessment to monitor gross changes in neurological function is performed 
at week 26 and subsequently every 6 months during trial period. 
9. The rate of ADA occurrence assessed three weeks after the first and second treatment 
dose of 131I-omburtamab  
Patient selection 
criteria 
Inclusion criteria: 
1. Patients must have a histologically confirmed diagnosis of NB with relapse in the CNS 
or LM.  
2. Patients need to have progressed in CNS/LM through induction therapy or have 
relapsed in CNS/LM following induction. CNS/LM progression/relapse is defined as 
LM disease or metastatic deposits in the CNS parenchyma, (excluding skull bone-based 
metastases). 
3. Stable systemic disease not requiring chemo/immunotherapy as judged by the 
investigator. 
4. Ventriculoperitoneal (VP) shunts (only shunts with programmable valves can be 
accepted) are allowed however should be closed (or adjusted to highest pressure setting) 
during Investigational Medicinal Product (IMP) infusion. It is recommended that the VP 
shunt remains closed for approximately 5 hours after treatment and then re-adjusted. 
The shunt readjustment times are at the discretion of the treating physician. Closure of 
VP shunt is done at the discretion of the treating physician and the VP shunt should at 
any time based on patient safety evaluation be re-opened at the assessment of the 
treating physician. Patients with ventriculo-atrial or ventriculo-pleural shunts are not 
eligible. 
5. Patients must be between birth and 18 years of age at the time of screening. 
6. Patients must have a life expectancy of at least 3 months as judged by the investigator 
7. Acceptable hematological status defined as:  
• 
Hemoglobin ≥8 g/dL  
• 
White blood cell (WBC) count ≥1000/µL 
• 
Absolute neutrophil count ≥500/µL  
• 
Platelet count ≥50,000/µL 
8. Acceptable liver function defined as: 
• 
ALT and/or AST ≤ 5 times UNL 
• 
Bilirubin ≤ 3 x UNL 
• 
In case either AST or ALT ≥3 x ULN, bilirubin must be ≤ 2 UNL 
9. Acceptable kidney function defined as: 
• 
Estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2 
calculated by the 2009 revised Bedside Schwartz Equation (Appendix 3) 
10. Written informed consent from legal guardian(s) and/or child must be obtained in 
accordance with local regulations. Pediatric patients must provide assent as required by 
local regulations. 
Exclusion criteria: 
1. Patients with primary NB in CNS. 
2. Patients must not have obstructive or symptomatic communicating hydrocephalus. 
3. Patients must not have worsening of neurologic function, according to the assessment 
by investigator, within 3 weeks prior to first dose of 131I-omburtamab.  
4. Patients must not have an uncontrolled life-threatening infection. 
5. Patients must not have received cranial or spinal irradiation less than 3 weeks prior to 
first dose of 131I-omburtamab in this trial.  
6. Patients must not have received systemic chemo/immunotherapy (corticosteroids not 
included) less than 3 weeks prior to enrollment in this trial. 
7. Patients must not have received any anti-B7-H3 treatment prior to enrollment in this 
trial. 
8. Patients must not have severe major non-hematologic organ toxicity; specifically, any 
renal, cardiac, hepatic, pulmonary, and gastrointestinal system toxicity must fall below 

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Grade 3 prior to enrollment in this trial. Patients with stable neurological deficits (due to 
brain tumor) are not excluded. Patients with Grade 3 or lower hearing loss are not 
excluded. 
9. Patients must not be pregnant or breast-feeding.  
10. Female patients of child-bearing potential (i.e. having experienced menarche) and male 
partners to female patients who do not agree to the use of effective contraception during 
treatment and for a period of 12 months after the last 131I-omburtamab dose. Effective 
contraception for women is defined as intrauterine devices or hormonal contraceptives 
(contraceptive pills, implants, transdermal patches, hormonal vaginal devices, or 
injections with prolonged release). Effective contraception for male partners is defined 
as use of condoms. To be exempt from the requirement to use contraception after 131I-
omburtamab treatment, one of the criteria described in section 9.2.11 of this protocol 
must be met.  
11. Fertile male patients who do not agree to the use of condoms during treatment and for a 
period of 12 months after the last 131I-omburtamab dose. For a sterilized male patient to 
be exempt from the requirement to use contraception after 131I-omburtamab treatment, 
he must have undergone surgical sterilization (vasectomy).  
Methodology 
This Phase 2/3 trial is a single-arm, open-label, non-randomized, multi-center efficacy, 
safety, and dosimetry trial of intracerebroventricular (intracerebroventricular meaning 
administration of a medicinal product into the cerebral ventricles (cerebral ventricular 
system) of the brain) 131I-omburtamab in pediatric NB patients with CNS/LM metastases. 
Patients will receive up to two cycles of 131I-omburtamab. In case the patient has a 
subsequent relapse in the CNS/LM after 131I-omburtamab therapy during the follow-up 
period, re-treatment to target minimal residual disease can be considered and allowed. 
Safety and efficacy will be investigated with short-term follow-up at 26 weeks after 
treatment and with long-term follow-up for up to 3 years following treatment. 
Number of patients 
(planned) 
Trial 101 plans to enroll at least 32 patients 
Trial outline 
Screening evaluations including medical history, physical and neurologic examination, 
hematology and clinical chemistry will be completed within 30 days of the first 131I-
omburtamab dose. MRI and CSF cytology will be completed within 3 weeks of the first 131I-
omburtamab dose and baseline performance testing is completed any time after diagnosis of 
CNS/LM metastases. 131I-omburtamab is infused via an indwelling intracerebroventricular 
access device (e.g. Ommaya) and an Ommaya patency/CSR flow study is conducted prior to 
the first 131I-omburtamab infusion. One 131I-omburtamab cycle takes 4 weeks and includes a 
treatment dose, an observation period and post-treatment evaluations. An interim analysis, 
evaluating the dosimetry and pharmacokinetic endpoints as well as available safety and 
efficacy data, will be conducted on data from patients having received at least treatment 
cycle 1 (dosimetry and treatment dose) prior to January 1st, 2020.  Starting January 1st, 2020, 
no further patients will be administered dosimetry doses.  
 
Patients can be treated in an outpatient setting or may be admitted as inpatients for the 
treatment infusions. 
 
Patients without Grade 4 toxicity, as described in section 6.1.4, and without objective 
disease progression (as determined by neurologic and/or radiographic examination) by MRI 
at week 4 in cycle 1 will be eligible to receive a second 131I-omburtamab dosing cycle. 
Patients with Grade 3 toxicity will receive a second dosing cycle at the discretion of the 
investigator.  
 
Patients who finish both treatment cycles and complete week-8 assessments will enter the 
short-term follow up phase. Patients who finish only one treatment cycle will be registered 
as early treatment discontinuation and continue to the short-term follow-up visit at week 26. 
If week-8 assessments are not or cannot be completed, the next visit will be the short-term 
follow up visit at week 26.  
 
Patients will be monitored for adverse events during and after 131I-omburtamab infusion. 
Patients will have pre- and post-treatment clinical assessments including neurologic 
examination, hematology and serum chemistry, blood and CSF cultures, endocrinology 

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assessments, CSF analysis, and pre- and post 131I-omburtamab performance testing. 
Performance testing will be performed at trial baseline, 3 months after the last 131I-
omburtamab infusion, and twice yearly thereafter at the discretion of the investigator.  
IMP 
Monoclonal antibody omburtamab is a murine immunoglobulin G1 (IgG1) antibody raised 
in BALB/c mice. Omburtamab recognizes tumor-associated antigen B7-H3. The purified 
antibody is stored in glass vials between -25 to -15ºC. The patients will receive omburtamab 
antibody radiolabelled with radioactivity calibrated to 50 mCi per treatment cycle. There 
will be a treatment dose reduction for patients younger than 3 years of age. 
Trial period and 
duration 
Trial duration will be up to 3 years for each patient. Safety and efficacy assessments will be 
performed for 26 weeks after the first 131I-omburtamab cycle, with long-term follow up for 
up to 3 years after start of treatment. 
Statistical 
considerations 
An interim analysis to evaluate the dosimetry endpoint as well as available safety and 
efficacy data, will be performed on data from patients having received at least treatment 
cycle 1 (both dosimetry and treatment dose) prior to January 1st, 2020.  Starting January 1st, 
2020, no further patients will be administered dosimetry doses. 
Final analysis will be performed when at least 32 treated patients have completed long-term 
follow-up (3 years or until death). OS rate at 3 years and its 95% confidence interval will be 
estimated using Kaplan-Meier methods. 
 
 PFS will also be analyzed using 
Kaplan-Meier methods. Dosimetry will be summarized with descriptive statistics (n, mean, 
median, standard deviation (SD), minimum, maximum). 
 
Safety summaries will be provided for treatment exposure, patient disposition, adverse 
events, adverse events leading to discontinuation and serious adverse events, laboratory 
safety data (serum chemistry and hematology), vital signs, and physical examination. The 
incidence of adverse events will be tabulated and reviewed for potential significance and 
clinical importance. 
 
 
 
 

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2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event  
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BALB/c 
BALB/c Mouse Sarcoma Virus 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CGCCR 
Central German Childhood Cancer Registry 
CNS 
Central Nervous System 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSF 
Cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DSRCT 
Desmoplastic Small-Round-Cell Tumor 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EAC 
Event Adjudication Committee 
EOT 
End of Trial 
FAS 
Full Analysis Set 
h 
Hour 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IgG 
Immunoglobulin G 
I.v. 
Intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
MBq 
Megabecquerel 
LDH 
Lactate Dehydrogenase 
LM 
Leptomeningeal 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mCi 
Millicurie 
mg 
Milligram 
mGy 
Milligray 
mL 
Milliliter 
MRI 
Magnetic Resonance Imaging 
mSv 
Millisievert 
MSK 
Memorial Sloan Kettering Cancer Center 
MYCN 
V-Myc Myelocytomatosis Viral Related Oncogene 
NB 
Neuroblastoma 
NCI 
National Cancer Institute 
ORR 
Objective response rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PET 
Positron emission tomography 

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PI 
Principal Investigator 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic 
PO 
Per Os (by mouth) 
PPS 
Per Protocol Analysis Set 
RANO 
Revised Assessment in Neuro-Oncology 
RBC 
Red Blood Cells 
ROI 
Regions-of-interest 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
sc 
Subcutaneous 
SD 
Standard deviation 
SPECT 
Single-Photon Emission Computed Tomography 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TSH 
Thyroid Stimulating Hormone 
UNL 
Upper Normal Limit 
VP 
Ventriculoperitoneal 
WBC 
White Blood Cells 
WHO 
World Health Organization 

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3 
FLOW CHARTS 
Table 1 Schedule of time and events 
Dosing/Measurements/Evaluations 
Trial Periods 
 
Screening 
131I-omburtamab Treatment Period1 
Follow-up21 
Long Term 
Follow-up21 
Day –29 to 0 
Week 1 & 5 
Week 2 & 6 
Week 3 & 7 
Week 4 & 8 
Week 26 
Weeks 52, 78, 
104, 130 & 156 
Informed consent 
X2 
 
 
 
 
 
 
Eligibility check 
X 
 
 
 
 
 
 
Demographics, height, and body weight 
X 
 
 
 
 
 
 
Medical, surgical and disease history 
X 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X19 
X19 
TSH/free and total T43 
X 
X 
 
 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
 
 
Vital signs4 
X 
X 
X 
X 
X 
 
 
Clinical chemistry & Hematology 
X 
X 
X 
X 
X 
 
 
Performance test6 
X5 
 
 
 
 
X 
X 
MRI of the brain and spine7 
X5 
 
 
 
X 
X22 
 
Neurotoxicity8 
X 
X 
 
 
X 
X 
 
Placement of an indwelling 
intracerebroventricular access device (e.g. 
Ommaya)9 
X 
 
 
 
 
 
 
Ommaya patency/CSF flow study  
X 
 
 
 
 
 
 
CSF for cytology, total protein, glucose, and 
cell count10 
X5 
 
 
 
X 
X 
 
Blocking of thyroid 131I uptake11 
X12 
X 
X 
 
(X)13 
 
 
Premedication (oral dexamethasone or an i.v. 
equivalent)14 
 
X 
 
 
 
 
 
Premedication with an anti-pyretic15 
 
X 
 
 
 
 
 
Conditional blood and CSF for culture16  
 
X16 
 
 
 
 
 
Intracerebroventricular 131I-omburtamab 
treatment dose 17 
 
X 
 
 
 
 
 
Adverse events18 
X 
X 
X 
X 
X 
X 
X 

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Dosing/Measurements/Evaluations 
Trial Periods 
 
Screening 
131I-omburtamab Treatment Period1 
Follow-up21 
Long Term 
Follow-up21 
Day –29 to 0 
Week 1 & 5 
Week 2 & 6 
Week 3 & 7 
Week 4 & 8 
Week 26 
Weeks 52, 78, 
104, 130 & 156 
Pregnancy testing 
X20 
 
 
 
X20 
X20 
 
Clinical response assessment for CNS/LM 
metastasis23 
X 
 
 
 
X 
X 
 
Collection of information on systemic disease 
progression24 
 
X 
X 
X 
X 
X 
X 
Collection of information on CNS/LM 
disease progression25 
 
 
 
 
 
 
X 
ADA blood and CSF 26 
X 
 
 
 
X 
 
  
PK blood and CSF 27 
 
X 
X 
 
 
 
 
1 The 131I-omburtamab treatment periods is divided in 4-week cycles (if a patient will receive 1 or 2 cycles is at the discretion of the investigator). A cycle consists of a 
treatment dose in the first week, followed by observation, and samples are taken during week 2 and 3 where after post-treatment evaluations will take place during week 4. 
For more details about the 131I-omburtamab cycles see section 6.1.4. 
2  Informed Consent must be obtained before any trial related procedures. Procedures or tests that are performed as a part of standard clinical care prior to informed consent, 
and therefore, not for the purpose of the trial, do not need to be repeated at screening if they have been performed within the allowed screening timelines. In these cases, 
source documents must show that these procedures or tests were performed as standard clinical practice and not for the purpose of the present trial. In case the indwelling 
intracerebroventricular access device (e.g. Ommaya) is placed in connection with the tumor resection, the informed consent must be obtained prior to the surgery and can 
be done before the start of the screening period if necessary. The investigator is responsible for documenting this properly. 
3 Thyroid stimulating hormone (TSH)/ free and total T4 to be assessed at screening, pre-dose week 1 and 4, pre-dose week 5 and 8, week 26 if applicable and weeks 52, 78, 
104 130 and 156. 
4 Measurements of pulse oximetry, heart rate, respiratory rate, temperature, and blood pressure. 
5 To be performed within 3 weeks prior first IMP infusion.  
6 Lansky Scale  16 years, Karnofsky Scale ≥16 years. Post week 26 every 6 months. 
7 (Magnetic resonance imaging of the brain and spine  to be completed before first IMP administration), at week 4 (± 4 days), 8 (± 4 days) and 26 (± 24-29 weeks ) 
8 Gross investigation of cranial nerves by physical examination and radiographical investigation as described in section 6.1.3. Evaluating neurological Adverse Events 
(AEs), the National Cancer Institute clinical neurotoxicity criteria will be used. Any patient that develops a Grade 4 neurotoxicity must be discontinued from treatment. 
The clinical neurotoxicity evaluation is to be conducted at screening and weeks 1, 4, 5, 8 and 26. The radiographic assessment of neurotoxicity and disease progression (by 
MRI) is to be conducted at screening, weeks 4 and 8 and week 26.  
9 Only for patients who do not have an intracerebroventricular device already placed. The procedure must be conducted prior to first dose and after the patient has been 
assessed to be eligible to enter the trial. 
10 If CSF sample is positive for abnormal cells or outside reference ranges for any of the following: 1. total protein 2. glucose 3. cell count, it must be repeated within 4 
weeks of the sample at screening. If abnormal CSF glucose (CTCAE ≥ Grade 2) is obtained, a fasting serum glucose is to be obtained at next patient visit. At week 26, the 
CSF analysis should include cytology only.  

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11 Treatment with potassium iodide and Cytomel should be initiated 1 week prior to each 131I- omburtamab infusion in a cycle and continue until 2 weeks after 131I-
omburtamab infusion in the same cycle. . 
12 Thyroid protection should be initiated 1 week prior to IMP administration. See section 7.2.5 for further details. 
13 Thyroid protection should be initiated 1 week prior to next IMP administration – this is only applicable for week 4 and not week 8. See section 7.2.5 for further details. 
14 Beginning 24 hours before 131I-omburtamab administration please see section 6.1.2. 
15 Given 1-2 hours prior to 131I-omburtamab administration, including oral acetaminophen/paracetamol and antihistamine (e.g., diphenhydramine), please see section 6.1.216 
Drawn and held for culture if elevated body temperature after dosing suggests infection rather than expected response to intracerebroventricular dosing. 
17 Dose reduction: 50% (25 mCi) for patients < 1 of age and 33% (33.5 mCi) for patients age 1 year to < 3 years of age, respectively.  
18 Non-SAE’s captured from signing the informed consent form (ICF) to dosing should be recorded as medical history. AEs should be reported until 3 weeks after the last 
IMP administration. SAE’s should be captured from signing the ICF. Starting at week 4 (for patients receiving only one cycle) and starting at week 8 (for patients 
receiving both cycles) only SAEs considered related to 131I-omburtamab or new onset of cancers regardless of causality should be reported.  
19 Limit to therapy related to cancer.  
20 In case fertile women (experienced menarche prior to screening or during treatment, until week 8) are enrolled; pregnancy testing should take place at screening, at week 
4 and week 8, and at follow-up at week 26. 
21 Follow-up at week 26 (24-29 weeks after first treatment) and Long-term follow-up visits at Weeks 52, 78, 104, 130 & 156 (± 4 weeks) can be done at referral site.  
22 If done at referral site imaging parameters as required in the Imaging Manual should be followed to the extent possible.  
23 If this is the screening visit record any significant findings on the medical history page. For other visits evaluate the clinical status according to the following comparison 
to the previous assessment: Improved, Stable or Worse. See section 9.2.10.  
24 If systemic disease progression has occurred, this information is to be collected in the eCRF 
25 If CNS/LM disease progression has occurred, this information is to be collected in the eCRF 
26 Blood and CSF sampling for ADA will be done at baseline, 3 weeks after the 1st treatment (wk 4) and 3 weeks after the 2nd treatment dose (wk 8). 2 mL of blood and 0.5 
mL of CSF will be collected per timepoint and sampling will be conducted conservatively given the age of the patients 
27 Blood and CSF PK sample collection will be done 1h after treatment, 6h after treatment, 24h after treatment and 7 days after treatment (wk 2 & wk 6) for both cycles. 2 
mL of blood and 0.5 mL of CSF will be collected per timepoint and sampling will be conducted conservatively given the age of the patients, See section 9.1.2.7 

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4 
INTRODUCTION 
4.1 
Medical background 
NB is a rare cancer of neural crest origin. The neuroectodermal cells that comprise neuroblastic 
tumors originate from the neural crest during fetal development and are destined for the adrenal 
medulla and sympathetic nervous system. Neuroblasts can transform into NB, a term that may be 
used to describe a spectrum of neuroblastic tumors, including ganglioneurinoma (benign), NB 
(malignant), and ganglioneuroblastoma (borderline aggressive). In this text, NB refers to the 
malignant form if not specified otherwise. NB is a disease of childhood. About 37% of patients 
are diagnosed as infants, and 90% are younger than 5 years, with a median age of 19 months, at 
diagnosis (London et al. 2005). The highest incidence is seen in the first months of life 
(Howlader et al. 2012; Gurney et al.1997; London et al. 2005). 
 
NB is a life-threatening disease that is associated with poor long-term survival. Generally, 
survival rates depend highly on whether the tumor is low risk, intermediate risk, or high risk: 
• For patients with low-risk tumors, five-year OS was 97% in a large COG trial (Strother et 
al. 2012). 
• For patients with intermediate-risk tumors, three-year OS rate was about 96% in a large 
COG trial (Baker et al. 2010). 
• For high-risk patients, survival rates of 40-50% have not changed significantly during the 
last two decades (Pinto et al. 2015). 
Conventional systemic treatment for newly diagnosed patients does not adequately treat the 
central nervous system and leptomeningeal (LM) space, , which may serve as a sanctuary site 
leading to relapse (Matthay et al. 2003; Kramer, Gerald, et al. 2001). In large series, the 
incidence of CNS/LM disease in relapsed patients is between 6-10% and the incidence of 
CNS/LM tumor will likely increase as better treatment options induce longer systemic 
remissions and increased frequency of CNS relapse. CNS relapses are almost uniformly lethal 
(Matthay et al. 2003; Choi et al. 2005; Zhu et al. 2015; Kellie et al. 1991; Shaw and Eden 1992; 
Wiens and Hattab 2014; Watts 1992; Sakata et al. 1993; Astigarraga et al. 1996; Kramer, 
Kushner, et al. 2001). Specific factors that can predict CNS/LM metastasis have not been 
identified.  
Furthermore, general management guidelines for recurrent NB in CNS are lacking consensus  in 
Europe and the US, and specific treatment for metastatic CNS NB has yet to be approved. 
Leptomeningeal cancer remains a challenging problem and the long-term outcome for children 
with leptomeningeal disease due to solid tumors remains poor with rapid progression over a 
period of weeks to months (Neville KA, Blaney SM. Leptomeningeal cancer in the pediatric 
patient. Cancer Treat Res. 2005; 125:87–106 
). In addition, there are significant toxicities associated with therapy in those children who are 
ultimately cured. Various treatment combinations, comprising one or more of the following 
treatments, are currently used in the clinic: 
• Surgery of bulky tumor prior to irradiation and chemotherapy to reduce symptoms, 
edema and hemorrhage or to correct CSF flow. 
• Craniospinal or focal irradiation to alleviate symptoms and to obtain disease control and 
to correct CSF flow in case of obstruction.  

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• Standard systemic combination chemotherapy (e.g., irinotecan plus temozolomide) may 
improve outcome, but significant toxicity and complications typically limit this form of 
treatment to patients with high likelihood of benefit. 
Memorial Sloan Kettering Cancer Center (MSK) has developed 131I-omburtamab for the 
treatment of pediatric recurrent NB with CNS/LM metastases and 131I-omburtamab has been 
studied in  clinical trials at MSK with more than 
 treated patients over 15 years. 131I-
omburtamab has been used as monotherapy for the treatment of NB patients with CNS)/LM 
metastases (trial 03-133) and patients with Desmoplastic Small Round Cell Tumor (DSRCT) 
(trial 09-090). In addition, 131I-omburtamab has been used in a tumor detection trial (trial 00-
066). 
 
The development of 131I-omburtamab for the treatment of NB with CNS/LM metastases has 
entered phase 1/2, and an interim analysis (data reported through Aug-2017) based on 
 
 from the on-going trial 03-133 is available. The results hold promise for a potential 
breakthrough as evidenced by low toxicity, high rate of radiographic improvements, and long-
term survival.  
 
The median survival for the patients included in the interim analysis was 47 months versus 6 
months in various historical cohorts (Kramer, Kushner, and Modak 2017; Berthold, Hömberg, 
and Baadsgaard 2017). Survival past 3 years historically is rare, less than 10% (Kramer et al. 
2017), which is aligned with findings by (Berthold, Hömberg, and Baadsgaard 2017), 
demonstrating a 3-year survival rate of 8.2% (Berthold et al. 2017). In contrast, for NB patients 
in study 03-133, the estimated 3-year survival of 56% and an estimated 5-year survival of 43% is 
reported. Survivors have been followed for up to 11.1 years, with a current mean duration of 
follow up of 2.6 years. Fifty-one (54.8%) of the
 patients treated with 131I-omburtamab 
remained alive at their last follow up.  
 
Late effects from 131I-omburtamab are rare except for hypothyroidism related to 131I-uptake and 
irradiation, which is easily treated with thyroid replacement therapy. Based on the information 
above, 131I-omburtamab will be further investigated in the proposed phase 2/3 trial for treatment 
of pediatric NB patients with CNS/ LM metastases. 
4.2 
Drug profile 
4.2.1 
131I-omburtamab 
131I-omburtamab is a radiolabeled monoclonal antibody that targets cluster of differentiation 276 
(CD276) (also known as B7-H3, (Modak, 2001 #471)(Xu et al. 2009). CD276 is a member of 
the B7/CD28 immunoglobulin superfamily which regulates T-cell functions in tumor 
surveillance, infections, and autoimmune diseases. CD276 is a tumor-associated antigen highly 
overexpressed on a wide range of human solid tumors, but minimally in normal tissues. CD276 
is distributed on the cell membrane of solid tumors of neuroectodermal, mesenchymal, and 
epithelial origin in adult and pediatric patients and its presence is often correlated with negative 
prognosis and poor clinical outcome. Upon administration, 131I-omburtamab binds selectively to 
the B7-H3 antigen (CD276/B7-H3) expressed on tumor cell membranes. The iodine-131 emits 
beta radiation that causes deoxyribonucleic acid (DNA) damage and tumor cell death. Iodine-
131 has a half-life of 8 days and the beta radiation penetrates up to 3 millimeters, with effects 

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not only on the antibody binding cell, but also on neighboring tumor cells (Larson et al. 2015). 
For further information, please see the current 131I-omburtamab Investigator’s Brochure (IB). 
4.2.1.1 
Non-clinical pharmacology and toxicology 
Pharmacology 
 
 
 
 
 
 
 
Toxicology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
An overview of the studies is presented in the IB. 
 
Non-clinical summary 
 
 
 
 
 
 
 
 
 
 
4.2.1.2 
Effects on Humans 
Normal Organ Dosimetry 
 
 
 
 
 
 

 
 
 
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from an interim analysis of dosimetry show that absorbed dose estimates exhibit high inter-
patient variability across all organs, consistent with previous results from previous trials with 
131I-omburtamab (Table 2). For more detailed information, please see the current 131I-
omburtamab investigator’s brochure. 
 
 
Previous clinical experience 
To date the MSK-produced 131I-omburtamab has been used in 
 clinical trials at MSK, U.S. 
 
 
 
• 
 
 
• 
 
 
 
 

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4.2.2 
Radiolabeling 
Omburtamab will be radiolabeled with iodine-131 by a radiopharmacy connected to the treating 
institution or at a designated central radiopharmacy (section 7.1) according to a qualified 
procedure described in a manufacturing agreement.  
 

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5 
RATIONALE, OBJECTIVE AND BENEFIT-RISK ASSESSMENT 
5.1 
Rationale for performing the trial 
The proposed phase 2/3 international multi-center trial evaluates the efficacy and safety of 
intracerebroventricular (intracerebroventricular meaning administration of a medicinal product 
into the cerebral ventricles (cerebral ventricular system) of the brain) 131I-omburtamab as well as 
the dosimetry in pediatric NB patients with CNS/LM metastases. The findings of the proposed 
trial will expand and be compared with the findings of the single center trial of 
intracerebroventricular 131I-omburtamab in pediatric patients with NB CNS/LM metastases 
treated in the MSK Trial 03-133. The aggregate findings from the two trials evaluating patients 
from several centers in the US as well as Europe seek to provide a basis for establishing 131I-
omburtamab as the next generation treatment of NB patients with CNS/LM metastases. 
5.2 
Rationale for dose selection 
5.2.1 
131I-omburtamab 
 
 
 
 
 
 
 
 
 
 
A second treatment cycle of 131I-omburtamab was administered 5 weeks after the first dose 
under the condition that the first treatment cycle was tolerable and without objective disease 
progression. The administered dose was adjusted in children under 3 years of age, as is standard 
for intracerebroventricularly administered therapies (section 7.1). 
5.3 
Benefit-risk assessment 
There are sufficient data to support an assessment of benefit and risk for the treatment of NB 
with CNS/LM metastases with 131I-omburtamab. 
 
 
 
 
 
 
 
 
 
 
 
 

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5.3.1 
Trial objectives 
5.3.2 
Primary objective 
1. To evaluate the overall survival (OS) rate at 3 years. 
5.3.3 
Secondary objectives 
1. To evaluate CNS/LM progression-free survival (CNS/LM PFS) at 6 &12  months  
2. To evaluate Overall Survival (OS) at 12 months 
3. To evaluate the objective response rate (ORR) at 6 months. 
 
4. To evaluate dosimetry of 131I-omburtamab.  
5. To evaluate the pharmacokinetics of 131I-omburtamab. 
6. To evaluate safety of 131I-omburtamab. 
7. To evaluate the immunogenicity of 131I-omburtamab. 

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6 
DESCRIPTION OF DESIGN AND TRIAL POPULATION 
6.1 
Overall trial design and plan 
This single-arm, open-label, non-randomized trial includes a screening period followed by 
treatment and observation periods. At least 32 patients are expected to be enrolled. Before 
entering the screening period, patients are recommended to have received salvage therapy 
including surgery, irradiation (preferable craniospinal) and high dose chemotherapy 
(recommended modalities listed in Appendix 2).  
 
Patients without an objective disease progression (as determined by radiographic examination) 4 
weeks after the first infusion and without clinically significant Grade 4 toxicity, are eligible for a 
second dosing cycle. 131I-omburtamab will be administered via an indwelling 
intracerebroventricular access device (e.g. Ommaya). In order to avoid an additional procedure 
and burden to the patient, it can be considered to place the intracerebroventricular access device 
in connection with the recommended tumor resection procedure (see section 13.4).   
 
After 131I-omburtamab treatment, safety and efficacy will be assessed as described in the flow 
charts in Table 1 Schedule of time and events with follow-up at week 26 followed by long-term 
follow up for up to 3 years with regards to survival. An interim analysis, evaluating the 
dosimetry and pharmacokinetic endpoints as well as available safety and efficacy data, has been 
conducted on data from patients having received at least treatment cycle 1 (both dosimetry and 
treatment dose) prior to January 1st, 2020.  Starting January 1st, 2020, no further patients will be 
administered dosimetry doses. After completion of the interim analysis, the dosimetry doses 
have been removed from treatment cycles. After this, a treatment cycle will take 4 weeks, 
compared to the previous 5 weeks cycle and will include a treatment dose only followed by an 
observation period and post-treatment evaluations. 
6.1.1 
Screening 
Screening evaluations (including medical history, physical and neurologic examination, 
hematology, clinical chemistry) must be completed within 30 days before the first 131I-
omburtamab dose at week 1. In case the indwelling intracerebroventricular access device (e.g. 
Ommaya) is placed in connection with the tumor resection, the informed consent must be 
obtained prior to the surgery, and before the start of the screening period MRI, CSF cytology and 
baseline performance testing are to be completed within 3 weeks before the first 131I-
omburtamab dose. Adequate CSF flow for 131I-omburtamab intrathecal therapy is determined by 
Ommaya patency/CSF flow study as outlined in Appendix 4.  Patients with obstructive or 
symptomatic communicating hydrocephalus will be excluded.  
6.1.2 
Treatment 
Patients can be treated in an outpatient setting or may be admitted as inpatients for the treatment 
infusions. Local safety instructions for storage and handling of radioactive drug products must 
be strictly followed. Radiation safety precautions may include patient isolation and the use of 
lead shielding, or designated rooms to ensure that the dose rate in the surrounding areas meets 
regulatory requirements. 
 
 

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Thyroid protection must be ensured by adequate stable iodide saturation by use of e.g. oral 
potassium iodide and Cytomel (liothyronine sodium or equivalent). Thyroid protection should be 
initiated 1 week prior to first 131I-omburtamab infusion in a cycle and continue until 2 weeks 
after last 131I-omburtamab infusion in the same cycle. Thyroid protection is administered in 
relation to each treatment cycle. Please refer to section 7.2.5 for details.  
 
 
 
 
 
  
 
 
 
 
 
A treatment dose of 131I-omburtamab is administered during week 1. The treatment dose is 
followed by a 3-week observation period followed by MRI, CSF cytology, and safety 
monitoring. 
 
6.1.3 
Safety considerations 
Patients will be monitored for AEs following signing of the informed consent form (ICF). 
 
National Cancer Institute clinical neurotoxicity criteria will be used. All neurologic 
abnormalities (regardless CTCAE grade) present prior to intrathecal 131I-omburtamab infusions 
will be recorded as Medical History. In the absence of clear evidence of tumor progression, it 
may be assumed that new neurological signs and symptoms are treatment related. 
 
Neurotoxicity will also be assessed clinically and radiographically. Assessment of cranial 
nerves, gross motor function and sensory function will be performed by physical examination. 
Assessment and grading of radiographically cortical atrophy, cerebral ventricular size, white 
matter changes or other abnormalities will be made by a neuro-radiologist. Altered CSF flow 
will be interpreted by the trial nuclear medicine physicians. 
 
Lansky (Karnovsky for children ≥ 16 years) performance score will be analyzed to evaluate 
gross neurologic function and a measure of a patient’s overall function.  
 
Expected risks are described in current 131I-omburtamab IB and section 10.7.  
 
Patients and guardians will be informed of the risk of uncommon or unexpected new side effects. 
 
Expected toxicities will be treated at the discretion of the investigator and could include the 
following: 
• Urticaria will be treated with antihistamines.  

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• During administration of 131I-omburtamab, emergency support for anaphylaxis must be 
readily available, including epinephrine, diphenhydramine, hydrocortisone, and/or 
dexamethasone at the bedside. 
• Patients with myelosuppression may be supported with blood products or granulocyte-
colony stimulating factor according to local standard of care. If indicated, patients also 
may have banked stem cells reinfused. There is to be a minimum of one week between 
support for myelosuppression as a stated above and IMP administration.  
 
 
6.1.4 Duration of treatment  
A single treatment cycle will last 4 weeks and includes premedication, intracerebroventricular 
131I-omburtamab administration 
, an observation period, and 
post-treatment evaluations (see Figure 1 One 131I-omburtamab treatment cycle after the interim 
analysis).  
 
Figure 1 One 131I-omburtamab treatment cycle after the interim analysis 
 
 
Patients without Grade 4 toxicity and without objective disease progression (as determined by 
neurologic and/or radiographic examination) by MRI at week 4 in cycle 1 will be eligible to 
receive a second 131I-omburtamab dosing cycle. Patients with Grade 3 toxicity will receive a 
second dosing cycle at the discretion of the investigator. For patients presenting with ongoing 
Grade 3 or 4 myelosuppression at week 4, a delay of dosing cycle 2 for up to 8 weeks can be 
introduced. Dose delay may be enforced at the discretion of the treating physician.  
 
In case of a subsequent relapse in the CNS/LM during the follow-up period, re-treatment to 
target minimal residual disease can be considered and allowed in case the patient/parents provide 
written consent to this. In these cases, it is recommended that patients undergo the salvage 
treatment as specified in Appendix 2 before subsequent administration of 131I-omburtamab. The 
administration of 131I-omburtamab in these cases must follow the scheme of the treatment cycle 
as illustrated in Figure 2. 
Patients who complete at least one treatment cycle will be evaluable. All patients who complete 
at least one treatment cycle (one dose of 131I-omburtamab) will form part of the dataset. 
However, patients who do not continue to the second treatment cycle (for whatever reason) will 
be registered as “early treatment discontinuation” in the eCRF. Patients receiving both treatment 

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cycles of 131I-omburtamab will be registered as “completed treatment” in the eCRF. All 
evaluable patients will first enter a follow-up period through week 26 (Figure 2) and thereafter 
the long-term follow-up where patients will be evaluated every half year for up to 3 years post-
131I-omburtamab treatment where after the trial is ended. 
 
) 
6.1.5 
Screening/pretreatment evaluation 
Pre-treatment evaluations should be completed within 30 days of start of treatment, unless 
otherwise specified, with regards to:  
• Informed consent by the patient/patient’s legal guardian(s) and assent by the patient as 
required by local EC/Institutional Review Board (IRB).  Informed Consent must be 
obtained before any trial related procedures.  Procedures or tests that are performed as a 
part of standard clinical care prior to informed consent, and therefore, not for the purpose 
of the trial do not need to be repeated at screening if they have been performed within the 
allowed screening timelines. In these cases, source documents must show that these 
procedures or tests were performed as standard clinical practice and not for the purpose 
of the present trial. In case the indwelling intracerebroventricular access device (e.g. 
Ommaya) is placed in connection with the tumor resection, the informed consent must be 
obtained prior to the surgery and can be done before the start of the screening period if 
necessary and up to three months before the start of the screening period.  
 
• Eligibility assessment 
• Collection of patient demographic information 
• Collection of disease history, including initial diagnosis, dates of initial diagnosis and 
recurrence, date of CNS/LM metastases diagnosis, prior treatments, and prior surgical 
interventions as well as outcome of such treatments/ interventions 
• Physical examination (including height and weight) 
• Vital signs 
• Neurologic examination 
• Performance testing 

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• Concomitant medications 
• Complete medical and surgical history  
• Hematology including complete blood count (CBC) with differential count (including 
eosinophils) and platelet count  
• Clinical chemistry including serum electrolytes (K+, Na+, Cl-), creatinine, blood urea 
nitrogen (BUN), AST, ALT, lactate dehydrogenase (LDH), total bilirubin, albumin, total 
protein, glucose, T4 and TSH 
• CSF cytology, total protein, glucose cell count 
• Baseline MRI of the brain and spine  
• Placement of an indwelling intracerebroventricular access device (i.e.  if not already in 
place) 
• Ommaya patency/CSF flow study prior to the first infusion 
• Pregnancy testing (only fertile women, experienced menarche prior to screening or 
during treatment, until week 8) 
6.2 
Data Monitoring Committee and Adjudication Committee 
The data monitoring committee (DMC) is an external committee composed of members whose 
expertise covers relevant specialties including statistics. The DMC is established to review and 
evaluate accumulated data from the trial both ad hoc and when 25, 50 and 100% of patients have 
been enrolled with a maximum interval between meetings of 3 months. 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.  
 
 
 
 
 
 
 We keep the IB as 
source document for reference safety information and refer to this in the protocol. In addition to 
listing expected side-effects in protocol section 10.7, to further ensure patient safety, we have 
included AEs of special interest in protocol section 10.4. 
 
Based on above, no stopping rule is introduced; however, single patient withdrawal criteria’s are 
described in protocol section 6.9.3 in order to ensure patient safety.  
 
Any significant finding/ significant recommendation from the DMC and endorsed by the 
Sponsors Safety Committee will be communicated to the regulatory authorities. 
 
6.3 
Follow-up 
Short-term (26 weeks): will include SAE’s considered related to 131I-omburtamab or new onset 
of cancers regardless of causality, physical examinations, concomitant medications, neurological 
and performance test results and MRI of the brain and spine as described in details in flow charts 

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in Table 1 Schedule of time and events. Pregnancy testing at week 4 and 8 and 26 (only fertile 
women who have experienced menarche prior to screening or during treatment, until week 8. 
 
Long term (3 years): clinical sites will provide status reports for each patient at 6-month 
intervals. Details of data collection procedures can be found in the trial flow chart (Table 1 
Schedule of time and events).  
 
For patients who have relocated back to their home country after the treatment period, the data 
that would normally be collected at the follow-up visits at the trial hospital can be collected at 
the referral hospital. The referral hospital is not an investigational site and will not be trained in 
the protocol. The trial investigator must coordinate the collection of the requested follow-up data 
every 6 months for up to 3 years following treatment. The safety, survival and relapse status 
including MRI assessments must be collected to be able to comply with the obligations while 
ensuring the best possible treatment and safety for the patient. In case the referral site evaluates 
MRI as to signify CNS/LM progression, this will supersede any other assessment. Ideally the 
referring oncologist should share the imaging report with the investigator but at the least, the 
investigator will add notes from the communication with the referring oncologist in the patient 
files, and the monitor will check consistency between eCRF entry and investigators notes in the 
patient files (see appendix 6).  
 
 
 
6.4 
Discussion of trial design 
Available clinical data from a single-site trial indicates that treatment with 131I-omburtamab may 
provide a robust and durable improvement in median survival of NB patients with CNS 
metastases from 6 to 47 months, providing a reasonable basis for undertaking the present trial 
when compared to survival for external controls receiving existing therapies. Consequently, an 
open, single-arm design has been chosen since any controlled design would be considered 
unethical.  
6.5 
Selection of trial population 
Iodine-131 omburtamab is primarily developed for treatment of NB patients with CNS/LM 
metastases, a population whose median survival does not exceed 6 months with current 
treatment options. Patients need to have progressed through induction therapy or have relapsed 
in CNS/LM following induction. 
6.6 
Recruitment period 
At least 12 months of recruitment time is estimated to be needed to enroll the planned number of 
patients. 
6.7 
End of trial 
End of trial (EOT) will occur when all patients have been followed until the visit at 3 years, or 
death whichever comes first. 

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6.8 
Number of participants 
At least 32 and a maximum of 50 patients will be enrolled in this trial. With an estimated screen 
failure rate of 25% it is likely that 40-50 patients will be screened to reach 32 eligible. The 
patients will be recruited according to institutional guidelines. 
6.9 
Participant selection and withdrawal 
Eligibility will require that the patient meet all inclusion criteria and is not violating any 
exclusion criterion. 
6.9.1 
Inclusion criteria 
1. Patients must have a histologically confirmed diagnosis of NB with relapse in the CNS or 
LM.  
2. Patients need to have progressed in CNS/LM through induction therapy or have relapsed 
in CNS/LM following induction. CNS/LM progression/ relapse is defined as LM disease 
or metastatic deposits in the CNS parenchyma, (excluding skull bone-based metastases). 
3. Stable systemic disease not requiring chemo/ immunotherapy as judged by the 
investigator.  
4. VP shunt (only shunts with programmable valves can be accepted) is allowed however 
should be closed (or adjusted to highest pressure setting) during IMP infusion. It is 
recommended that the VP shunt remains closed for approximately 5 hours after treatment 
and then readjusted. The shunt readjustment times are at the discretion of the treating 
physician. Closure of VP shunt is done at the discretion of the treating physician and the 
VP shunt should at any time based on patient safety evaluation be re-opened- at the 
assessment of the treating physician. Patients with ventriculo-atrial or ventriculo-pleural 
shunts are not eligible. 
5. Patients must be between the ages of birth and 18 years at the time of screening. 
6. Patients must have a life expectancy of at least 3 months as judged by the investigator. 
7. Acceptable hematological status, defined as:  
• 
Hemoglobin ≥ 8 g/dL  
• 
WBC count ≥1000/µL 
• 
Absolute neutrophil count ≥500/µL  
• 
Platelet count ≥50,000/µL 
8. Acceptable liver function defined as: 
• 
ALT and/or AST ≤ 5 times UNL 
• 
Bilirubin ≤ 3 x UNL 
In case either AST or ALT ≥3 x ULN, bilirubin must be ≤ 2 UNL 
9. Acceptable kidney function defined as: 
• 
eGFR >60 mL/min/1.73 m2 calculated by the 2009 revised Bedside Schwartz 
Equation (Appendix 3). 

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10. Written informed consent from legal guardian(s) and/or child must be obtained in 
accordance with local regulations. Pediatric patients must provide assent as required by 
local regulations. 
6.9.2 
Exclusion criteria 
1. Patients with primary NB in CNS. 
2. Patients must not have obstructive or symptomatic communicating hydrocephalus as 
determined by Ommaya patency/CSF flow study. 
3. Patients must not have worsening of neurologic function, according to assessment by 
investigator, within 3 weeks prior to first dose of 131I-omburtamab.  
4. Patients must not have an uncontrolled life-threatening infection. 
5. Patients must not have received cranial or spinal irradiation less than 3 weeks prior to 
first dose of 131I-omburtamab in this trial.  
6. Patients must not have received systemic chemo/ immunotherapy (corticosteroids not 
included) less than 3 weeks prior to enrollment in this trial. 
7. Patients must not have received any anti-B7-H3 treatment prior to enrollment in this trial. 
8. Patients must not have severe major non-hematologic organ toxicity; specifically, any 
renal, cardiac, hepatic, pulmonary, and gastrointestinal system toxicity must fall below 
Grade 3 prior to enrollment in this trial. Patients with stable neurological deficits (due to 
brain tumor) are not excluded. Patients with Grade 3 or lower hearing loss are not 
excluded. 
9. Patients must not be pregnant or breast-feeding.  
10. Female patients of child-bearing potential (i.e. having experienced menarche) and male 
partners to female patients who do not agree to the use of effective contraception during 
treatment and for a period of 12 months after the last 131I-omburtamab dose. Effective 
contraception for women is defined as intrauterine devices or hormonal contraceptives 
(contraceptive pills, implants, transdermal patches, hormonal vaginal devices, or 
injections with prolonged release). Effective contraception for male partners is defined as 
use of condoms. To be exempt from the requirement to use contraception after 131I-
omburtamab treatment, one of the criteria described in section 9.2.11 of this protocol 
must be met. 
11. Fertile male patients who do not agree to the use of condoms during treatment and for a 
period of 12 months after the last 131I-omburtamab dose. For a sterilized male patient to 
be exempt from the requirement to use contraception after 131I-omburtamab treatment, he 
must have undergone surgical sterilization (vasectomy). 
 
6.9.3 
Treatment discontinuation criteria 
A patient must be discontinued from treatment if: 
• Treatment-related CTCAE Grade 3 or 4 anaphylaxis.  

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• CTCAE Grade 4 neurotoxicity. 
• Development of obstructive or symptomatic communicating hydrocephalus  
• Unexpected, IMP-related and clinically significant Grade 4 toxicity. 
• Disease progression before cycle 2. 
• The investigator requests discontinuation of treatment for medical or safety reasons, 
including lack of treatment response; or 
• The patient receives prohibited therapy and/or undergoes prohibited procedures during 
the trial.  
Diagnosis of chemical meningitis (symptoms of clinical meningitis but cultures for infective 
agents were negative) in which either: a) event is non-responsive to IV steroids, b) radiologic or 
operative intervention was indicated, or c) presence of focal neurologic deficit. A patient 
discontinued from treatment should as soon as possible attend the week 4 or 8 visit as applicable, 
and subsequently be followed at the short and long-term follow-up visits. The investigator 
should follow any SAE still ongoing after discontinuation until the event has been resolved or 
the investigator assesses the SAE as being chronic or stable. 
 
A patient should be withdrawn from the trial if: 
• The patient or legal guardian withdraws consent for any reason; 
If the patient is withdrawn from the trial, the investigator should:  
• Ensure the safety of the patient. 
• Offer the best possible treatment outside of the trial. 
Furthermore, after withdrawal for any reason, the investigator, in consultation with the 
patient/legal guardian, will recommend future treatment based on clinical practice at the 
investigational site. 
 

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7 
TREATMENTS 
7.1 
Investigational Medicinal Product 
Screening assessments will be evaluated before any patient receives IMP. The patient and/or 
legal guardian must have received patient information and signed the ICF. Eligible patients must 
meet all inclusion criteria and must not violate any of the exclusion criteria (please see sections 
6.9.1 and 6.9.2). 
 
Monoclonal antibody omburtamab is a murine IgG1 antibody that is raised in BALB/c mice and 
recognizes tumor associated antigen B7-H3. Omburtamab will be radiolabeled with iodine-131 
at a radiopharmacy connected to the treating institution or at a designated central radiopharmacy. 
At each clinical site, the 131I-omburtamab dose should be assayed immediately prior to 
administration to verify that the prescribed activity and the activity actually administered agree 
within 10%.  The residual activity in the dose syringe should then be assayed following 
administration to determine the net activity administered (= pre-administration activity – post-
administration residual activity). The amount of radioactivity infused in patients should be 
assessed by measuring radioactivity of the infusion syringe before and after 131I-omburtamab 
infusion into the indwelling intraventricular access device (e.g. Ommaya) and subtracting before 
and after counts. The radiolabeled 131I-omburtamab is sterile filtered before administration. 
Patients will receive up to two cycles of 131I-omburtamab. 
7.1.1 Treatment  
One 131I-omburtamab cycle takes 4 weeks and includes a treatment dose followed by an 
observation period and post-treatment evaluations. The treatment dose is administered on day 1 
of the first week in a cycle (according to Table 1). The patient will be followed for 4 weeks after 
the treatment dose. A full treatment is achieved when both cycles have been completed.  Patients 
who finish both treatment cycles and complete week-8 assessments will enter the short-term 
follow up phase. Patients who finish only one treatment cycle will be registered as early 
treatment discontinuation and continue to the short-term follow-up visit at week 26. Please see 
Duration of treatment section 6.1.4. 
 
7.2 
Bleyer et al. 1977.Packaging and labelling of omburtamab 
Packaging, labelling and release of omburtamab will be completed by KLIFO Supply in 
accordance with Good Manufacturing Practice (GMP) and national regulatory requirements. 
Label content will according to Annex 13, EudraLex, volume 4, local requirements and trial 
requirements. Each kit will be uniquely numbered. 
7.2.1 
Storage and handling 
A description of IMP details is included in the IMP manual.  

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The Investigator or designee is responsible for ensuring that only eligible trial patients receive 
IMP. There is no storage of IMP at site, and the IMP is prepared on demand when a patient is 
found eligible for the trial and/or when subsequent cycles are being scheduled. The utensils used 
to ship, prepare and administer the IMP will be radioactive and should be destroyed according to 
local regulation. The destruction can be performed without sponsor approval  
Drug accountability on a patient level is documented by keeping copies of the IMP Order Form, 
and the IMP Administration Form. The documentation will be reviewed periodically and 
verified by the CRA over the course of the trial. 
7.2.2 
Radiolabeling of omburtamab 
Omburtamab will be radiolabeled with iodine-131 by a designated radio pharmacy following a 
qualified procedure outlined in a manufacturing agreement. Radiolabeling is performed by the 
iodogen method, which is based on previously published methods (Fraker and Speck 1978). Free 
iodine-131 is removed by ion exchange. Radiolabeled product will be pre-calibrated at the time 
of preparation to yield the prescribed activity at the projected time of administration as outlined 
in section 7.1 Radiolabeled product is sterilized by filtration to attain the target dose of 50 mCi, 
as applicable. Quality control is ensured according to a release specification, also including 
endotoxin testing, bioburden and radioimmunoassay.  
7.2.3 
Administration of 131I-omburtamab 
The radioactivity of the patient-specific unit doses must be within +/- 10 % of the intended dose 
(Table 4 Accepted activity ranges for treatment doses). Doses must be aseptically prepared by 
withdrawal of 131I-omburtamab from the bulk vial into a sterile syringe. The finished product in 
liquid form is drawn into a syringe and then placed in a lead container (“pig”) that is then placed 
inside a lead lined container and transported to the patient’s bedside prior to administration. For 
detailed instructions, please refer to the IMP manual. 
7.2.4 
Radiation safety                                                                                                                                     
Local safety instructions for storage and handling of radioactive IMP must be strictly followed. 
Radiation safety precautions may include patient isolation and the use of lead shielding, or 
designated rooms to ensure that the dose rate in the surrounding areas meets regulatory 
requirements.  
 
Patients can be treated in an outpatient setting or may be admitted for 131I-omburtamab 
administration. When patients are admitted, the caregiving staff will be instructed in radiation 
safety about steps required to minimize exposure to themselves according to local guidelines.  
 
The dose rate from the patient will be measured after end of infusion and at later time points to 
define the need for overnight stay(s) using portable radiation detectors as described in the local 

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safety instructions. Patient release timepoint following administration of therapeutic amounts of 
131I-omburtamab will be determined based on the dose-rate criterion specified in Column 2 in 
table U.1 for I131 in NUREG 1556, Vol 9, Rev 1 (US sites) or based on local radiation safety 
requirements (sites outside US).  That is, patients can be released following administration of 
therapeutic amounts of 131I-omburtamab if the dose rate measured with a survey meter at 1 meter 
from the patient does not exceed 7 mrem per hour or the value described by local safety 
instructions whichever is the lowest. Patient isolation will remain in effect until the dose rate is 
below what is required in accordance with local patient release regulations.  
 
Patients and legal guardians must be advised of the risks of radiation exposure of household 
contacts, pregnant women, and small children and of the steps to be taken to reduce these risks. 
Legal guardians will be given instructions by radiation safety staff on how to handle waste and 
steps and procedures to follow to minimize exposure to themselves, household contacts, the 
general public and possible patient family caregiver(s). An evaluation of patient family caregiver 
doses will be performed, and appropriate radiation safety precautions will be taken to ensure that 
doses to these caregivers is maintained less than local requirements (e.g. 500 millirem or value 
determined by local safety instructions), in accordance with applicable regulations. Patients 
and/or caregiver will be provided with a written instruction detailing radio safety precautions as 
per the local requirements. The caregiver will agree to radiation safety instructions prior to 
administration of the therapeutic agent or the procedure may be delayed or declined.  
 
The site’s radiation safety service will manage the collection, shielding, and waste disposal, as 
appropriate, for patient excreta for each case. Following release of the patient, the site’s radiation 
safety service will survey and perform decontamination procedures in the room to ensure that the 
room meets regulatory requirements. 
7.2.5 
Protection of thyroid function 
Blockade of 131I-uptake in the thyroid gland is to be ensured by administration of stable iodine 
e.g. potassium iodide. For guidance on potassium iodide dosing, the investigators should refer to 
the FDA’s guidance “Potassium iodide as a thyroid blocking agent in radiation emergencies” or 
the European Association of Nuclear Medicine (EANM) guidance on thyroid protection with 
potassium iodide during 131I-meta-iodobenzylguanidine (131I-mIBG) therapy (Giammarile et al. 
2008, Eur J Nucl Med Mol Imaging). Alternative, more intensive thyroid protective schemes 
with potassium iodide that are according to institutional or local standard of care may be 
prescribed at the discretion of the investigator but must be documented. Potassium iodide may 
be given with juice or soft drink (e.g. cola) to mask taste.  
 
In addition to potassium iodide, Cytomel (liothyronine sodium or equivalent) should be given at 
25 µg/day if weight is less than 25kg or at 50 µg/day if weight > 25 kg.  
 
Treatment with potassium iodide and Cytomel should be initiated 1 week prior to each 131I- 
omburtamab infusion in a cycle and continue until 2 weeks after 131I-omburtamab infusion in the 
same cycle. Thyroid protection is administered in each treatment cycle. Sites will document the 
treatment regimen for thyroid protection prescribed and patients or caregivers will provide a 
written diary documenting that the potassium iodide and Cytomel has been taken as instructed 
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7.2.6 
Participant compliance 
Clinical personnel at the site will record in the source notes the timing and site of all 
administrations of IMP. Any reasons for non-compliance should be documented.  
7.3 
Concomitant therapy 
7.3.1 
Therapy allowed during the 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. Detailed information 
about treatments administered following 131I-omburtamab administration will be captured in the 
electronic case report form (eCRF). Additional anti-cancer and supportive care treatments are 
allowed after MRI has been assessed after the last dose at week 9. 
 
• Prohibited therapy and procedures during weeks -3 to 9  
o Additional anti-cancer therapy during the treatment cycle(s) of 131I-omburtamab 
o Additional IMP  
o Additional hematological support is not allowed if administered within 1 week 
prior to IMP administrations  
7.4 
Treatment after discontinuation of IMP 
Any treatment deemed safe and justified by the investigator can be administered according to 
clinical practice and at the discretion of the investigator. 

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8 
ENDPOINTS 
8.1 
Efficacy 
8.1.1 
Primary endpoint 
1. OS rate at 3 years after the first treatment dose of 131I-omburtamab. 
8.1.2 
Secondary endpoints 
1. CNS/LM PFS at 6 and 12 months will be estimated based on the time from first treatment 
dose to CNS/LM progression or death from any cause. Patients alive without CNS/LM 
progression at time of analysis, will be censored at last date of disease evaluation without 
evidence of progression. 
2. OS at 12 months will be estimated based on the time from first treatment dose to death by 
any cause. Patients alive at time of analysis, will be censored at last date known to be alive.  
3. ORR assessed as a combination of partial response and complete response as defined by the 
Response assessment in Neuro-Oncology (RANO) group criteria for brain metastasis (Lin et 
al, 2015) or leptomeningeal metastases as defined by EANO-ESMO criteria (Le Rhun et al, 
2017). ORR will be assessed at 6 months after the first treatment dose of 131I-omburtamab 
4. ORR according to CSF cytology. Response is defined as a complete response when CSF 
converts from positive at baseline to negative after treatment with 131I-omburtamab 
5. Whole-body, organ, blood, and CSF radiation dosimetry. 
6. Pharmacokinetic analysis of activity in blood and CSF including derivation of best-fit uptake 
and/or clearance parameters (half-times, maximum value) of time-activity concentration 
curves and of I-131 residence times (i.e., cumulated activity) concentrations (in Ci-h/g). 
7. The frequency, type, and duration of treatment-emergent severe adverse events and serious 
adverse events, including clinically significant laboratory abnormalities. All adverse events 
will be graded according to Common Terminology Criteria for Adverse Events (CTCAE), 
version 4.0.  
8. Performance assessment to monitor gross changes in neurological function is performed at 
week 26 and subsequently every 6 months during trial period. 
9. The rate of ADA occurrence assessed three weeks after the first and second treatment dose of 
131I-omburtamab 
8.2 
Safety 
8.2.1 
Safety endpoints 
Safety data will be collected via AE and SAE reporting during the trial and graded according to 
CTCAE, version 4.0. Abnormal findings at physical examination and vital signs will also be 
monitored and any clinically significant abnormalities should be reported as AEs. Adverse 
events including Clinical Laboratory Adverse Event (CLAE; as defined in section 10.1.1). 

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9 
PROCEDURES AND ASSESSMENTS 
9.1 
Efficacy assessments 
9.1.1 
Primary endpoint 
OS rate at 3 years. The time frame for assessment of OS will be from the first treatment dose of 
131I-omburtamab to time of death from any cause. OS will be censored at last date of contact. 
Survival at 3 years will be estimated by Kaplan-Meier methods. 
9.1.2 
Secondary endpoints 
9.1.2.1 
CNS/LM Progression-Free Survival (CNS/LM PFS) at 6 and 12 
months 
The time frame for CNS/LM PFS will be from first treatment dose of 131I-omburtamab to time of 
documented CNS/LM progression or death from any cause. CNS/LM PFS will be censored at 
last date of disease evaluation without evidence of CNS/LM progression. CNS/LM PFS at 6 and 
12 months will be estimated using Kaplan-Meier methods.  
9.1.2.2 
OS at 12 months 
OS at 12 months will be estimated by Kaplan-Meier methods following the same time and 
censoring scheme as the primary endpoint. 
 
9.1.2.3 
Objective response rate (ORR) 
Response will be assessed at 6 months (week 26 visit) after the first treatment dose of 131I-
omburtamab as a combination of best overall partial or complete response at 5, 10, and 26 
weeks. Assessments will follow the Response assessment in Neuro-Oncology (RANO) group 
criteria for parenchymal metastasis (Lin et al, 2015) or as defined by EANO-ESMO for 
leptomeningeal metastases (Le Rhun et al, 2017). The evaluation comprises MRI scans, CSF 
cytology, and clinical assessments. ORR at week 26 is defined as the proportion of patients with 
response at week 26 from the total population of patients with radiographically evaluable disease 
at baseline.  
9.1.2.4 
Dosimetry and PK analysis for 131I-omburtamab 
An interim analysis, evaluating the dosimetry and pharmacokinetic endpoints as well as 
available safety and efficacy data, will be conducted on data from patients having received at 
least one treatment cycle1 (both dosimetry and treatment dose) prior to January 1st, 2020.  
Starting January 1st, 2020, no further patients will be administered dosimetry doses. 
 
 
9.1.2.5 
Performance assessment 
Since most if not all patients will have received prior cranio-spinal and/or whole brain 
irradiation, late side effects for such previous therapies are difficult to distinguish from 131I-
Omburtamab inflicted toxicities in CNS. However, to evaluate gross changes in neurological 

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function, performance test will be conducted during screening and at weeks 26, 52, 78, 104, 130 
and 156. The scales to be used are: Lansky  16 years and Karnofsky ≥ 16 years. 
 
9.1.2.6 
Anti-Drug-Antibodies characterization  
A quantitative assay to assess anti-drug antibodies (ADAs) will be developed. The assay will be 
developed and validated using “cold” labeled omburtamab (125I-omburtamab).  
 
 
9.1.2.7 
Anti-Drug-Antibody effects on PK and Safety. 
The ADA characterization will deliver occurrence rate of neutralizing antibodies in blood and 
cerebrospinal fluid (CSF) of exposed patients. Potential associated effects of any neutralizing 
ADA’s on 131I-omburtamab pharmacokinetics (PK) in blood and CSF and safety will be 
investigated.  
 
9.1.2.7.1 ADA effects on PK  
Radioactivity counts in blood and CSF will be measured at the following time points after 
treatment with 131I-omburtamab: 
• 
1h after treatment 
• 
6h after treatment 
• 
24 after treatment 
• 
7 days after treatment. 
 
The analysis will comprise an intra-patient comparison of PK parameters from the two dose 
administrations in patients with and without presence of neutralizing ADAs in blood or CSF.    
 
9.1.2.7.2 ADA effects on Safety 
The analysis will comprise a comparison of reported safety events after the second dose 
administration in patients with and without presence of neutralizing ADAs in blood or CSF.   
 
9.2 
Other assessments 
9.2.1 
Hematology and clinical chemistry 
Hematology and clinical chemistry will be measured by a local laboratory during screening and 
in all following treatment cycles and will assess liver and kidney function (ALT, AST, alkaline 
phosphatase, albumin, bilirubin, BUN, glucose and creatinine), total protein and serum 
electrolytes (sodium, potassium, chloride and bicarbonate). Complete differential blood count, 
including eosinophils and platelets, will be performed during screening and in the cycles up to 
the follow-up at week 26. Thyroid stimulating hormone (TSH)/ free and total T4 to be assessed 
at screening, pre-dose week 1 and 4, pre-dose week 5 and 8, week 26 if applicable and weeks 52, 
78, 104 130 and 156..  

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If abnormal serum glucose (CTCAE ≥ Grade 2) is obtained, a fasting serum glucose is to be 
obtained at next patient visit. AE reporting of hyperglycemia will require fasting values to assess 
CTCAE grading. 
9.2.2 
CSF for cytology, total protein, glucose and cell count 
CSF for cytology, total protein, glucose and cell count should be assessed during screening and 
at week 4, 8, and 26. If positive, it must be repeated within 4 weeks of the positive sampling. 
 
9.2.3 
Blood and CSF for culture 
Blood and CSF will be sampled and held for potential culture after treatment doses in both cycle 
1 and the conditional cycle 2. Samples will be cultured only if body temperature is elevated 
(defined as ≥ 38o C [≈ 100.4oF]) after dosing and clinical infection is suspected. 
9.2.4 
Demographics 
The following demographic information will be recorded in the eCRF during screening: 
1. Age or date of birth if allowed by local legislation 
2. Gender 
3. Ethnic origin 
4. Race 
5. Other baseline characteristics, if applicable 
9.2.5 
Height and body weight 
Height (without shoes and rounded to the nearest centimeter) must be measured at screening and 
recorded in the eCRF. Body weight (without overcoat and shoes and rounded to kilogram with 
one decimal) will be measured and recorded in the eCRF.  
9.2.6 
Medical and surgical history 
Medical and surgical history if any relevant medical and/or surgical event(s) previously have 
been experienced by the patient. Information on the patient’s medical history and general health 
will be collected during screening and comprises of, but is not limited to: 
• General medical history 
• Metastases location and characterization (unifocal parenchymal, multifocal parenchymal, 
leptomeningeal, parenchymal and leptomeningeal)  
• Tumor characteristics that allow calculation of risk classification, e.g. V-Myc 
Myelocytomatosis Viral Related Oncogene (MYCN) status, DNA diploidy, disease stage 
and LDH at the time of diagnosis, and pathology classifications. 
• Any prior treatment for neuroblastoma, e.g. frontline therapy and salvage regimens, 
responses to prior therapy, duration of responses, sites of relapse etc.  

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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 
• Date of relapse, including date of CNS relapse 
Any clinically significant worsening of a concomitant illness must be reported as an AE (see 
section 10). 
9.2.7 
Concomitant medication  
A concomitant medication is any medication other than the IMP. All concomitant medications 
must be recorded in the eCRF with the following information: 
• Start date 
• Stop date of administration or ongoing at trial termination 
• Indication/ reason for use 
• Dose 
• Frequency 
• Outcome (for anti-cancer treatments) 
Any changes to concomitant medication during the trial will be recorded in the eCRF. All doses 
of allowed pain relief medication should be recorded as concomitant medication in the eCRF.  
9.2.8 
Physical examination 
Physical examination should be performed as clinically indicated from screening to the EOT 
and includes assessment of general appearance, mental status and various organ systems (skin, 
head, eyes, ears, nose, mouth, throat, neck, thyroid, lymph nodes, respiratory, cardiovascular, 
gastrointestinal, extremities, musculoskeletal, and neurologic systems). 
9.2.9 
Vital signs 
Pulse oximetry and measurements of heart rate, respiratory rate, temperature, and blood pressure 
before and 30 minutes after 131I-omburtamab infusion. Temperature must be measured by using 
the same method (e.g., an ear thermometer). 
9.2.10 
Neurotoxicity 
Neurotoxicity will be assessed by the National Cancer Institute clinical neurotoxicity criteria 
during screening and weeks 1, 4, 5, 8, 26. All neurologic abnormalities present prior to 131I-
omburtamab infusions will be recorded as medical history. Any neurologic changes during the 
trial period which meet the criteria for Grade 3 or 4 neurotoxicity will be assessed by the trial 
physicians as being unrelated, possibly or probably caused by the infusion. In the absence of 
clear evidence progressive disease (PD), it may be assumed that new signs and symptoms are 

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treatment related. Any patient that develops Grade 4 neurotoxicity after the IMP infusion is to be 
discontinued from treatment. 
 
Neurotoxicity also will be assessed clinically and radiographically. Assessment of cranial 
nerves, gross motor function and sensory function will be performed. Assessment and grading of 
radiographically cortical atrophy, cerebral ventricular size, white matter changes or other 
abnormalities will be made by a neuro-radiologist. Altered CSF flow will be interpreted by the 
trial nuclear medicine physicians. 
 
Clinical neurotoxicity evaluation is to be conducted at screening and weeks 1, 4, 5, 8 and 26, as 
indicated in the flowchart. The radiographic assessment of neurotoxicity and disease progression 
(by MRI) is to be conducted at screening, weeks 4 and 8 and week 26 only.  
 
 
Lansky (Karnovsky for children ≥ 16 years) performance score will be analyzed to evaluate 
gross neurologic function and a measure of a patient’s long-term function.  
9.2.11 
Non-childbearing potential 
Non-childbearing potential in women will be confirmed by one of the following: 
• Women/girls who have not reached menarche or 
• Women/girls who have not had menses within the past 12 months and who do have a 
follicle-stimulating hormone level ≥40 IU/L or 
• Women/girls who have not had menses within the past 24 consecutive months if a 
follicle-stimulating hormone measurement is not available 
• Women/girls who have undergone surgical sterilization (e.g., hysterectomy, or bilateral 
oophorectomy, or bilateral salpingectomy). 
9.2.12 
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 
Definitions 
10.1.1 
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 clinical laboratory adverse event (CLAE): a clinical 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 active 
treatment or further investigations, for example change of medicine dose or more 
frequent follow-up due to the abnormality. 
Throughout the clinical trial a DMC will monitor the patients’ safety according to the DMC 
charter (section 6.2). 
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 event determines the reporting procedures to be followed. 
An AE that meets one or more of the following criteria/outcomes is classified as serious: 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Medical important medical  
• Results in death 
• Is life threatening 
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, which hypothetically might have caused death if it were more severe. 
Death alone is not considered an AE; it is an outcome of an AE. Reports of death should be 
accompanied by the corresponding AE term for the event that led to the outcome of death. 
However, sudden death or death due to unexplainable cause(s) should be reported as an SAE, 
while follow-up is pursued to determine the cause.  
 
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. Exceptions are hospitalizations for 

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administrative, surgical procedures planned before trial inclusion, trial-related and social 
purposes do not constitute AEs. 
  
Elective surgery or other scheduled hospitalization periods that were planned before the patient 
was included in this trial are not to be considered serious. However, the event must be reported 
on the AE page in the eCRF and commented upon.  
 
Medical and scientific judgment must be exercised in deciding whether an AE is believed to be 
“medically important”. Medical 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 AE 
• A non-serious AE is any AE which does not fulfil the definition of an SAE.  
10.4 
Pre-defined AEs of Special Interest 
The following AEs are selected as Adverse Events of Special Interest (AESIs)based on 
previously experience with 131I-Omburtamab and should be reported within 24 hours to 
sponsor: 
 
• Neurotoxicities Grade 3 and above 
• Severe infections related to placement of cerebroventricular device 
• Chemical meningitis 
10.5 
Adverse Event Recording 
10.6 
Pre-existing conditions 
In this trial, a 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.  
10.6.1 
Procedures 
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. Additionally, any 
procedures pre-planned before entering the trial (e.g. for pre-existing conditions) can be 
excluded.  
10.6.2 
Overdose, medication errors and misuse  
An overdose is defined as a patient receiving a dose of the IMP in excess of that specified in this 
protocol. 
 

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Medication errors and uses outside what is foreseen in the protocol, including misuse of the 
product may include:  
  
• Administration of wrong drug  
• Wrong route of administration, such as IV instead of intracerebroventricular 
• Administration of an overdose with the intention to cause harm or misuse of trial product.  
• Accidental administration of a lower or higher dose than intended. The administered dose 
must deviate from the intended dose to an extent where clinical consequences for the trial 
patient were likely to happen as judged by the investigator, although the clinical 
consequences  did not necessarily occur. 
Overdose and medication errors (exceeding ± 10% as compared to protocol-specified dose) 
should be reported as protocol deviations to the sponsor . If an overdose, medication error, or 
misuse  results in an AE, the AE must also be reported in the eCRF. If the event qualifies as 
serious it must be reported using the paper the clinical AE report form in addition to the AE form 
in the eCRF. 
 
10.6.2.1 Management of Overdose of 131I-omburtamab 
Rescue medication to reverse the action of 131I-omburtamab is not available. In case of overdose 
or other medication errors of 131I-omburtamab patients, should receive supportive care according 
to local guidelines and potential side effects of 131I-omburtamab should be treated 
systematically. 
In the event of an overdose, the Investigator should:  
• Contact Medical Monitor (for contact details, see the protocol front page) 
• Closely monitor the patient for any AE and laboratory abnormalities 
• In case of an AE, close medical supervision and monitoring should continue until the 
patient recovers.  
 
10.6.3 
Pregnancy 
Any pregnancy that occurs during trial participation must be reported to sponsor within 24 hours 
of learning of its occurrence using the pregnancy form. Pregnant trial patients must be 
withdrawn from treatment immediately. 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. 

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10.6.4 
Severity 
The Investigator will use the National Cancer Institute (NCI) CTCAE version 4.0 to describe the 
maximum severity of the AE, see below (US Department of Health and Human Services 2010). 
The grade assigned by the investigator should be the most severe, which occurred during the AE 
period: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living. 
o Instrumental Activities of Daily Living refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
Activities of Daily Living. 
o Self-care Activities of Daily Living refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden. 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 
Any change in severity grade represents a new AE subsequently, when an AE change 
severity, a new AE should be created with the changed severity. 
10.6.5 
Relationship to IMP 
The Investigator must assess the AE as either Related or Not Related to IMP. A suspected 
adverse reaction is defined as one in which there is a reasonable possibility that the drug caused 
the adverse event. Relatedness has to be assessed and reported from the first time the AE is 
being reported. When assessing the causal relationship of an AE to the IMP, the following 
should be taken into consideration: 
 
Not related (unlikely) 
The AE is not related to the IMP, which means the event: 
• 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.  
• The AE is clearly not related to the IMP. 
For AEs assessed as” Not Related”, an alternative etiology should be stated detailing the more 
likely reason for AE. 
 
Related (possible/probable) 
The AE is related to the IMP, which means the event: 
• Follows a reasonable temporal sequence from IMP administration. 

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• Abates spontaneously upon discontinuation of the IMP (de-challenge) without any 
curative treatment. 
• Is confirmed by reappearance of the same reaction on repeat exposure (re-challenge).  
• Cannot be reasonably explained by the known characteristics of the patient’s clinical 
state or medical history.  
• Alternative etiology should be provided for all AEs assessed as possible related to IMP 
10.6.6 
Outcome 
Investigator must judge outcome of the AE by the following terms: 
• Recovered 
• Recovered with sequelae 
o Description of the sequelae should be provided 
• Not recovered 
• Death 
• Unknown 
o Should only be used if patient is lost to follow-up 
Instructions for reporting changes in an ongoing AE during a patient's participation in the trial 
are provided in the instructions that accompany the AE case report forms. 
10.7 
Expected side-effects related to 131I-omburtamab and dexamethasone 
 
131I-omburtamab:  
For detailed description, please refer to current IB. 
 
The risks of 131I-omburtamab include thyroid suppression, neutropenia and myelosuppression 
requiring red blood cell and/or platelet transfusions. Expected toxicities in the acute phase 
include the known risks associated with intraventricular infusions: headache, vomiting, and fever 
in the first few hours post-infusion.  
 
Dexamethasone:  
The expected toxicities of dexamethasone include lymphopenia, anemia and hyperglycemia. 
10.8 
Reporting of Adverse Events 
All events meeting the definition of an AE must be collected and reported in the eCRF. AEs 
occurring between Screening and first treatment must be recorded as Medical History.  
SAEs and AESIs (whether serious or non-serious) should be reported both in the eCRF and on 
the paper clinical AE report form. SAEs must be reported from the first trial related activity after 
the patient has signed the informed consent until 3 weeks after last IMP administration. 
Subsequent SAE reporting (occurring later than after 3 weeks after last IMP administration)  
 

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 and during the long-term FU period (3 years) only SAEs considered related to the trial 
medication or new onset of cancers regardless of causality should be reported. The investigator 
should report these SAEs within the same timelines as for SAEs during the trial. 
 
For patients withdrawn from the trial, please see section 6.9.3. 
 
 
  
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 and evaluated unless specifically 
excluded. All SAEs and AEs leading to discontinuation of trial product either observed by the 
investigator or patient must be reported by the investigator and evaluated. All AEs must be 
recorded by the investigator on an AE form in the eCRF. 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. All pre-defined Adverse Events of Special 
Interest must be reported as SAEs. 
 
For SAEs & AESIs, the clinical AE report form must be completed in addition to the AE form in 
the eCRF. If several symptoms or diagnoses occur as part of the same clinical picture, one safety 
information form can be used to describe all the SAEs. For all non-serious AEs, the applicable 
forms in the eCRF should be signed when the event is resolved or at the end of the trial at the 
latest. 
 
 
 

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Timelines for initial reporting of AEs:  
  
• Initial 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 by e-mail or 
courier. Please ensure the eCRF AE form is updated in accordance to agreed data entry 
timelines. New FU information available at site must be reported within 24 hours 
• FU information requested from Sponsor must be replied to within three working days by 
using the paper data clarification form. Please ensure the eCRF AE form is updated in 
accordance to agreed data entry timelines. 
• If the eCRF is unavailable, the concerned SAE information must be entered when the 
eCRF becomes available again.  
Contact details for reporting:  
SAEintake@covance.com 
 
In emergency situations the completed safety reporting forms or pregnancy forms can be faxed 
to: 
FAX +1-888-887-8097 
 
Sponsor assessment of AE expectedness: 
The sponsor assessment of expectedness for 131I-omburtamab is performed according to the 
current version of the Investigator’s Brochure. 
Reporting of trial product related SUSARs by Sponsor CRO 
Sponsor CRO Covance Inc. will inform the regulatory authorities of any suspected unexpected 
serious adverse reactions (SUSARs) in accordance to regulatory requirements. Sponsor CRO 
Klifo A/S 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. Sponsor CRO Klifo A/S 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. 
10.9 
Follow-Up on AEs 
All non-serious AEs should be followed until they are either resolved, i.e., returned to baseline 
or until the end of the post-treatment FU period (3 weeks after last IMP administration) 
whichever comes first. AEs meeting one of the serious criteria (including AEs of Special 
Interest), still ongoing after ending trial participation, 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. 
 
If an ongoing SAE changes in intensity, relationship to IMP or as new information becomes 
available and/or known for the event, a FU SAE report form should be completed and sent to the 
sponsor within 24 hours of the change in SAE assessment. 
 

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If the investigator becomes aware of an SAE after the long-term FU period with a suspected 
causal relationship to the IMP, the investigator should report this SAE within the same timelines 
as for SAEs during the trial. 
 

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11 
LABORATORIES 
Nuclear scanning (whole-body planar gamma camera scans) and radioactivity measurements in 
CSF and blood will take place on-site following qualified procedures outlined in respective 
manuals. The calculation of the absorbed radiation doses will take place centrally following a 
predefined methodology. Pharmacokinetic parameter derived from radioactivity concentration 
vs. time data will be calculated centrally. 
 
A detailed description of the procedures for sampling, handling, storage, and measurement of the 
specimen and all material such as test tubes and labels will be provided in the Technical Binder. 
Blood samples for biochemistry and hematology will be analyzed by local laboratories. 
11.1 
Clinical chemistry and hematology 
Chemistry Panel 
Liver and renal function tests (ALT, AST, alkaline phosphatase, TSH, T4, albumin, total bilirubin, 
total protein, LDH, BUN, and creatinine), serum glucose and serum electrolytes (sodium, 
potassium, chloride, and bicarbonate). If abnormal serum glucose (CTCAE ≥ Grade 2) is obtained, 
a fasting serum glucose is to be obtained at next patient visit. 
Hematology Panel 
Complete blood count will be performed during screening and during all treatment cycles with 
regards to hematocrit, hemoglobin, Mean Cell Hemoglobin (MCH), Mean Cell Hemoglobin 
Concentration (MCHC), Mean Cell Volume (MCV), platelets, red blood cells (RBC), WBC, 
basophils, eosinophils, lymphocytes, monocytes and neutrophils. All Grade 4 laboratory 
abnormalities must be retested within 24 hours of receiving results. 

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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. All statistical analyses will be performed and data appendices will be created by 
using SAS version 9.0 or later. 
 
All statistical tests will be two-sided with an  level of 0.05. 
 
The Statistical Analysis Plan (SAP) will describe in detail the analyses presented below. 
Furthermore, handling and presentation of data including baseline data and other trial 
assessments will be described in the SAP. The selection of an appropriate control group from 
available external data is briefly described below but will be described in full detail in the SAP. 
Patient characteristics that may be considered in the selection of the control group include, but 
are not limited, age at diagnosis, MYCN amplification status, International Neuroblastoma 
Staging System stage at diagnosis, International Neuroblastoma Pathology Classification 
(favorable vs. unfavorable), time to first relapse, site of relapse, and lactase dehydrogenase level.   
12.2 
Populations of Interest 
• Full Analysis Set 
The full analysis set (FAS) will include all patients enrolled in the trial who begin an 
infusion of 131I-omburtamab 
• Per Protocol Analysis Set (PPS) 
The PPS will include all FAS patients who have no major protocol violations. 
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 
The safety analysis set will include all enrolled patients who receive at least one dose 
of IMP 
• External control group 
External controls will be primarily obtained from a query to the Central German Childrens 
Cancer Registry (CGCCR). CGCCR initiated in 1980, registers approximately 2,000 children 
per year who are diagnosed with a malignant disease. CGCCR receives patient data from all 
paediatric oncology centers across Germany. 99% of all paediatric patients diagnosed with 
cancer in Germany were included in the national trials, with continuous update of the clinical 
data within the CGCCR.  
 
  

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The CGCCR data will be used to obtain an estimate of the 3-year survival rate in a contemporary 
systemically treated cohort of children. To explore the development of systemic treatment we 
will employ cut-offs in 2000 and 2004. 
 
 
 
 
 
 
  
12.3 
Efficacy Analysis 
The FAS will be used for all efficacy endpoints. Additionally, the primary and secondary 
endpoint analyses will also be performed on the PPS. The primary endpoint of the OS rate at 3 
years as well as OS at 12 months, and CNS/LM PFS at 6 and 12 months with corresponding 
95% confidence intervals, will be estimated using Kaplan-Meier methods using the FAS. The 
comparison to external controls (OS only) will be exploratory and performed using multiple cox 
regression taking into account the most important prognostic factors identifiable in the historic 
data. The median OS and CNS/LM time and associated 95% confidence interval will be 
calculated. Results will be displayed with Kaplan Meier plots. ORR according to RANO criteria 
and CSF cytology as well as CSF cytology alone, will be assessed, 95% confidence intervals 
will be calculated using the Clopper-Pearson exact methodology. 
12.4 
Safety Analysis 
The safety analysis set will be used for all safety analyses. Adverse event data will be listed 
individually, and the incidence of adverse events will be summarized by system organ class 
(SOC) and preferred terms for each treatment group. AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 19.0 or later. AEs will be regarded as 
treatment-emergent adverse events (TEAEs) if they occur after first administration of 131I-
omburtamab. Related AEs are defined as adverse drug reactions (ADRs). 
 
Listings will be made of all AEs, including non-TEAEs. All TEAEs, ADRs, SAEs and serious 
adverse reactions (SARs) will be summarized. The summaries will include number of events, 
number of patients, and percentage of patients reporting these events and will be tabulated by 
SOC and preferred term (PT). TEAEs will also be summarized by severity and by relationship to 
IMP. When calculating the incidence of adverse events, each adverse event will be counted only 
once for a given patient within a specified SOC, preferred term. If the same adverse event occurs 
on multiple occasions for a patient, the occurrence with the highest severity and relationship to 
IMP will be reported. Changes in vital signs, hematology, and clinical chemistry parameters 
from baseline to the end of the trial will be examined. Treatment-emergent changes from normal 
values to abnormal values in key laboratory parameters will be identified. Effects on cognitive 
functions will be assessed summarizing changes from baseline in performance testing results 
with descriptive statistics. 

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12.5 
Dosimetry Analysis 
Spinal cord, brain and non-target ROI absorbed radiation doses will be estimated and CSF mean 
absorbed radiation doses will be calculated on the basis of nuclear imaging scans (whole-body 
planar gamma camera scans). Additionally, the mean absorbed radiation dose in CSF and blood 
will be calculated from CSF and blood radioactivity measured in CSF and blood samples taken 
at pre-defined timepoints (section 9.1.2.4) after the dosimetry and the treatment doses in cycle 1 
from all patients enrolled before January 1st, 2019.  
 
Individual and mean dosimetry data will be calculated per trial site and will be summarized with 
descriptive statistics. 
12.6 
Pharmacokinetic Analysis 
The radioactivity measurements in CSF and blood that are used for calculation of the mean 
absorbed radiation dose after administration of the dosimetry and treatment doses are also used 
for pharmacokinetic analysis. Cmax in blood is determined and the elimination half-life as well as 
the areas under the radioactivity vs. time curves are calculated. 
 
Individual and mean pharmacokinetic parameter (if applicable) will be summarized with 
descriptive statistics for all patients and by trial site. 
12.7 
Interim Analysis 
An interim analysis, evaluating the dosimetry and pharmacokinetic endpoints as well as 
available safety and efficacy data, will be conducted on data from patients having received at 
least treatment cycle 1 prior to January 1st, 2020.  Starting January 1st, 2020, no further patients 
will be administered dosimetry doses. Progression in CNS/LM will be assessed at 6 and 12 
months for the full analysis. The primary efficacy endpoint for the interim analysis will be 
CNS/LM PFS at 6 months. 
 
12.8 
Sample Size 
Assuming an 
 
 
 
 
Power was estimated by simulation using an exponential model and an assumed lost to follow-
up rate of 10%.     

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12.9 
Handling of missing data 
For the primary time to event efficacy endpoint, patients who do not have an event will be 
censored at their date of their last evaluation. It is unlikely that missing of safety data will occur 
in the targeted patient population, but in case it happens the data will not be imputed. 

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13 
ETHICS 
13.1 
Independent ethics committee 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 of the trial 
protocol/protocol amendments, the patient information and the Informed Consent from the 
IRB/IEC before enrolment of any patient into the trial. 
13.2 
Ethical conduct of the trial 
The trial will be conducted in accordance with the protocol, applicable regulatory requirements, 
ICH GCP and the ethical principles of the Declaration of Helsinki 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 Paediatric Population (recommendations of the ad hoc group for 
the development of implementing guidelines for Directive 2001/20/EC relating to good clinical 
practice in the conduct of clinical trials on medicinal products for human use). The guideline is 
referenced in Appendix 5.  
13.3 
Participant 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. Patients deemed eligible for the trial should be 
presented with the patient information in their native language. The written patient information 
must not be changed without prior discussion with the Sponsor and approval by the IRB/IEC. 
Participant 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, as and when applicable 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. The consent shall be given in interest of the child, meaning that he/she is 
presumed willing to participate. 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.  

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Before signing the Informed Consent, 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 participant’s family doctor of the participant’s consent to participate in the trial.  
 
 
13.4 
Special considerations for patients having the Ommaya reservoir implanted at 
the referring hospital or locally but before entering the screening period. 
 
The Ommaya reservoir is to be placed after the written informed consent has been obtained. 
In cases where placing of the Ommaya is considered in association with the surgical procedure 
that is recommended before enrollment in the trial, informed consent may be obtained up to 
three months before the start of the screening period. This is considered acceptable since placing 
of the Ommaya in association with the anesthesia induced for the surgical resection of the tumor 
will reduce the burden to the patient by avoiding an extra surgical procedure. Furthermore, the 
patient may receive high dose chemotherapy in the period leading up to the screening period 
which may be associated with myelosuppression and therefore rendering an invasive procedure 
like Ommaya placement not feasible.   
In cases where the potential patient is a referral patient, the investigator must as a first step 
discuss inclusion and exclusion criteria with the referring physician. Additionally, the 
Investigator must arrange for an information meeting where patients and parents have an 
opportunity to discuss details of the trial with the investigator. The meeting can be a telephone 
conference call with participation of patient, parents and referring doctor prior to Ommaya 
placement. The investigator is responsible for the documentation of this. In addition to the 
signature from patients/ parents and the investigator, the referring doctor must sign the ICF to 
testify that he/she has been present at the information meeting.  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), ICH guidelines, or with the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the trial patient.  
14.1.1 
Protocol compliance 
The investigator is responsible for ensuring the trial is conducted in accordance with the 
procedures and evaluations described in this protocol. 
14.1.2 
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. 
14.2 
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 extent of 
monitoring will be based on a risk assessment and will be described in a monitoring plan 
produced by the contract research organization (CRO).  CRA will ensure that accountability of 
IMPs is performed and will review source documents for verification of consistency with the 
data recorded in the eCRFs (source data verification). The CRA will also provide information 
and support to the investigational sites. 
In order to assure quality standards, the trial sites may be audited by the sponsor or its designee 
as well as inspected by a Regulatory Authority. The investigator and other responsible personnel 
must be available during the monitoring visits, audits and inspections and should devote 
sufficient time to these processes. 
The investigator should provide a curriculum vitae or equivalent documentation of suitability to 
be responsible for the trial including valid GCP training, 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  

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• 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 authentic, accurate, and complete  
• 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. 
14.3 
Source data verification 
14.3.1 
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 recorded 
in the hospital records: 
• Clinical trial identification. 
• Participant identification. 
• Date when patient information was given and when signed Informed Consent was 
obtained. 
• Diagnosis. 
• Fulfilment of inclusion criteria. 
• Specification of visit dates, concomitant medication 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. 
14.3.2 
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. During monitoring, the 
data recorded in the eCRFs by the investigator will be compared for consistency with the source 
data/hospital records by the CRA. Any discrepancies of data will be documented and explained 
in the monitoring reports. 

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14.3.3 
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 recorded 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. 
14.3.4 
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 medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or sponsor access to records, facilities, and 
personnel for the effective conduct of any inspection or audit. 
14.4 
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 relevant documents and will 
allocate ample time and the time of the personnel to the auditor as may be required to discuss 
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15 
DATA HANDLING AND RECORD KEEPING 
15.1 
Electronic case report forms 
For each patient enrolled, 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 and reason for failure to enroll must 
be captured in the eCRF. 
15.1.1 
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 original eCRF data are the sole property of the sponsor and 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 recorded in the eCRFs. 
15.2 
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. 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. The investigator is required to complete a source data list, defining where the specific 
source data can be found (patient record/trial specific patient record). All clinical trial documents 
must be retained by the investigator until at least 2 years after the last approval of a marketing 
application in an ICH region (i.e., United States, Europe, or Japan) and until there are no 
pending or contemplated marketing applications in an ICH region; or, if no application is filed or 
if the application is not approved for such indication, until 2 years after the investigation is 
discontinued and regulatory authorities have been notified. 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 

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samples at the conclusion of this trial may be retained in storage by the sponsor for a period up 
to 10 years for purposes of this trial. 
15.3 
Data management 
All data, except laboratory data, will be collected using an eCRF compliant with 21 CFR Part 11 
regulation. Laboratory data 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, these checks will be programmed 
by CRO. Manual medical checks as well as programmed validation checks must be signed off by 
Y-mAbs Data Management and Y-mAbs Clinical Project Management. The investigator will 
approve the data using an electronic signature and thereby confirm the accuracy of the data 
recorded. Medical history and AEs will be coded using the MedDRA dictionary. Concomitant 
medication will be coded using the World Health Organization (WHO) Drug dictionary.  

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16 
REPORTING AND COMMUNICATION OF RESULTS 
16.1 
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 at 
latest 1 year after final CSR is completed. 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. 
16.2 
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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17 
INSURANCE 
Insurance and liability will be in accordance with applicable local laws and regulations and 
GCP. 

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18 
CHANGES AND DEVIATIONS 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. 
Any protocol or other deviations that occur during the trial will be documented and reported to 
the sponsor. Depending on the nature of the deviation, this may be reported to the appropriate 
regulatory authority. 
No change in the trial procedures shall be effectuated without the mutual agreement of the 
investigator and the sponsor (except where necessary to eliminate an immediate hazard to 
patients). 

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19 
PREMATURE TERMINATION OF THE TRIAL 
This trial may be terminated by the sponsor. The trial may also be terminated prematurely at any 
time when agreed to by both investigators and the sponsor as being in the best interest of patients 
and justified by either medical or ethical grounds. In terminating the trial, sponsor and 
investigators will ensure that adequate consideration is given to the protection of the patient’s 
interest. 
19.1 
Criteria for halting participant enrollment 
Enrolment will be halted if the following criteria is met: 
• One or more patients experience IMP-related, unexpected, clinically life-threatening 
toxicity (excluding Grade 4 lab values without clinically significant symptoms) 
• One or more patients experience unexpected, sudden death during a treatment cycle  
If the abovementioned criteria are met, the DMC will review the safety results and determine 
how to proceed as described in section 6.2. 
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. 
19.2 
Criteria for termination of the trial 
The sponsor reserves the right to discontinue the trial prior to inclusion of the intended number 
of patients but intends to exercise this right only for valid scientific or administrative reasons. 
After such a decision, all delivered unused investigational medicinal products 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 
scientific standards. 
• The DMC recommends discontinuation. 
 

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multidisciplinary treatment', Chin J Cancer, 34: 531-7. 
  
  
 
 
 

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Appendix 1 Contact details of clinical trial team 
Sponsor 
Y-mAbs Therapeutics 
Agern Alle 11 
2970 Hørsholm 
Denmark 
 
Clinical Project Manager 
 
 
 
Associate Medical Director 
 
 
Pharmacovigilance 
Covance Clinical & Periapproval Services Ltd 
Osprey House, Maidenhead Office Park,  
Westacott Way, 
Maidenhead, SL6 3QH,  
UK 
 
Drug Safety Project Manager 
MSR Vaishnavi,  
No 29 Union Street, 
Off Cubbon Road 
Bangalore 560001 
India 
 
 
Clinical Trial Supply Coordination  
Packaging and labelling 
KLIFO A/S 
Smedeland 36 
DK-2600 Glostrup 
 
Clinical Supply Manager  
   
  
Biostatistical Analysis & Data Management 
BioStata ApS 
Bregnerødvej 132,  
DK-3460 Birkerød 
 
Chief Executive Officer  
 
 
 
 
 

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Appendix 2 Salvage Treatments Recommended Prior to Trial 101 Entry* 
 
Time 
Treatment 
Week -12 
Resection of CNS disease when possible 
Week -11 
Irinotecan 50 mg/m2/dose IV daily x5 
Week -10 
Craniospinal irradiation 2160 cGy/boost at tumor bed to 3000 cGy **  
Week -5 
Irinotecan 50 mg/m2/dose IV daily x5 
Temozolamide 250 mg/m2/dose daily x5 
Carboplatin 500 mg/m2/dose daily x2 (only if systemic NB present) 
Stem cell rescue *** 
Trial start 
First administration of IMP 
 
* all salvage treatments will be depending on patient's condition and are ultimately at the treating 
physician's discretion  
** to be acknowledged and agreed to by the local radiation-oncologist. For patients with 
unifocal resected CNS disease, a reduction in the craniospinal radiation dose to 1800cGy is 
recommended 
*** if needed 
 
 
 
 

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Appendix 3 Creatinine-based 2009 revised Bedside Schwartz Equation 
 
eGFR = 0.413 x (height/Scr) if height is expressed in centimeters 
 
Abbreviations / Units 
 
eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2 
 
SCr (standardized serum creatinine) = mg/dL 
 
 
 

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Appendix 4 Ommaya patency/CSF flow study 
CSF CISTERNOGRAM 
INDICATIONS:  
Evaluate CSF circulation 
Determine patency and flow from indwelling 
intracerebroventricular access device (e.g. Ommaya) 
 
PATIENT PREPARATION:  
 
None 
Radiopharmaceutical: 
 
Indium (In) 111 Diethylenetriamine Pentaacetic Acid (111In-
DTPA) or Technetium-99m Diethylenetriamine Pentaacetic Acid 
(99mTc-DTPA) 
 
Dose: 
0.5 mCi for cisternal infusion via indwelling 
intracerebroventricular access device (e.g. Ommaya). 
 
Instrument: 
Dual detector Gamma Camera 
 
Collimator:  
Medium Energy General Purpose (MEGP) 
 
Isotope Energy Peak: 
 
173, 247 keV 
Energy Window Width: 
20% 

Y-mAbs Therapeutics 
Omburtamab 
Clinical Trial Protocol 101
Version 10.0, 01 May 2020
 
Confidential 
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Technique 
 
1. 
Only fresh, undiluted radiopharmaceutical from a newly opened vial should be used. 
 
2. 
Patients infused in an indwelling intracerebroventricular access device (e.g. Ommaya) should have 
anterior, posterior and lateral images of the head as well as anterior and posterior images of the 
spine and chest recorded immediately following infusion. Additional views may be recorded at 4, 
24 48 and 72 hours as necessary. 
 
3. 
The collimator should be placed as close as possible to the patient. Ten minute acquisitions are 
obtained for each pair of views (anterior posterior and lateral views of the head, as well as anterior 
and posterior views of the spine are obtained at each time period). 
4. 
SPECT images (optional) may be recorded in a 128x128 matrix for 30 seconds/stop, 3-degree 
steps, using a 360-degree acquisition. The detectors should be as close as possible to the head — 
preferably positioning the detectors above the shoulders. 
 
5. 
Data are reviewed to determine the timing and of tracer entry and clearance from each of the 
cisterns and the region of the pacchionian granulations in region of the superior sagittal sinus. 
   
Abnormal scan findings:  
a. ventricular outflow obstruction — no egress beyond basal cisterns;  
b. obstruction within spinal canal;  
c. failure to ascend to the convexities by 6 hours, and spread over the convexities by 24 hours 
 
 
 
 

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Omburtamab 
Clinical Trial Protocol 101
Version 10.0, 01 May 2020
 
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Appendix 5 Ethical Considerations for Clinical Trials on Medicinal Products Conducted 
with the Paediatric Population 
http://ec.europa.eu/health/files/eudralex/vol-10/ethical_considerations_en.pdf 
 
 

Y-mAbs Therapeutics 
Omburtamab 
Clinical Trial Protocol 101
Version 10.0, 01 May 2020
 
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Page 76 of 77 
 
Appendix 6 Template letter to referring oncologist 
 
 
 
Dear Colleague, 
 
Thank you for referring patient (patient name) to the Y-mAb's 101 study for which I am 
responsible at (site name). 
 
I am pleased to inform you that your patient now has the opportunity to receive re-treatment with 
131I- omburtamab equivalent to two cycles in case your patient is suffering from subsequent 
relapse in the CNS/LM after the initial 131I-omburtamab therapy during the follow-up period.  
 
As your patient has relocated back to your clinic, we need to make an agreement under which we 
can coordinate collection of the follow-up data stated below every six months. 
  
From completion of the initial treatment in the 101 study, safety and efficacy must be 
investigated with follow-up visits every six months for up to three years. to ensure the best 
possible treatment and safety for your patient – and possibility of re-treatment in the event of re-
lapse. This also comprises patients referred by other oncologists from other hospitals and other 
countries, 
 
To be able to fulfill this, please provide the following information at the indicated time points: 
 
 
 
Date of 
Week 26 
 
Date of 
Week 52 
Date of 
Week 78 
Date of 
Week 104 
Date of 
Week 130  
Date of 
Week 156 
Any safety concerns 
 
 
 
 
 
 
Cancer related medications used since 
 
 
 
 
 
 
Status of TSH (free and total T4 
 
 
 
 
 
 
Status of performance (test by using 
Lansky Scale  16 years, Karnofsky 
Scale ≥16 years),  
 
 
 
 
 
 
 
MRI assessment report of the brain and 
spine for week 26 
 
 
 
 
 
 
 
Collection of information on systemic 
disease progression and CNS/LM 
disease 
 
 
 
 
 
 
 
I kindly ask you to return with confirmation, that your patient has received the information about 
the possibility to be re-treated if suffering from subsequent relapse in the CNS/LM. 
 
Thank you for your attention and willingness to enter into this collaboration so we can give your 
patient the best possible follow-up and in the event of relapse the possibility of re-treatment. 
 
Sincerely yours,  
 

Y-mAbs Therapeutics 
Omburtamab 
Clinical Trial Protocol 101
Version 10.0, 01 May 2020
 
Confidential 
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Signature Page for CLIN-000005 v10.0
Signature Page for CLIN-000005 v10.0
Approval
01-May-2020 13:24:35 GMT+0000
Approval
01-May-2020 14:33:29 GMT+0000