Conditions: Medulloblastoma, Childhood
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
Children and adolescents diagnosed with medullablastoma and with recurrent or refractory to frontline therapy will be treated with 177Lu-DTPA-omburtamab, which is a radioactive labelling of a murine monoclonal antibody targeting B7-H3.

Detailed description:
Part 1 is a dose-escalation phase with a 3+3 sequential-group design in which patients will receive a dosimetry dose followed by maximum of two 5-week cycles of treatment doses of intracerebroventricular 177Lu-DTPA-omburtamab.

Part 2 is a cohort-expansion phase in which patients will receive a maximum of five 5-week cycles of intracerebroventricular 177Lu-DTPA-omburtamab at the recommended dose determined in Part 1.

End of treatment will take place within 5 weeks after the last cycle and thereafter the patients will be enter the follow-up period. The patients will be followed for up to 2 years after last dose.

Arms:
arm 1: Intracerebroventricular administration of 177Lu-DTPA-omburtamab for up to two cycles (Part 1) and up to five cycles (Part 2).

Interventions: intervention 1: 177Lu-DTPA-omburtamab
Intervention descriptions: intervention 1: Biological, radiolabeled DPTA-omburtamab

Protocol document:
Prot_SAP_000.pdf: 
 
 
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Protocol 
A Phase I/II Dose-escalation and Expansion Cohort Trial of Intracerebroventricular 
Radioimmunotherapy Using 177Lu-DTPA-omburtamab in Pediatric and Adolescent 
Patients with Recurrent or Refractory Medulloblastoma 
Protocol Status: Final 
Protocol Date: 25-Feb-2022 
Protocol Version: 8.0 
Investigational Product: 177Lu-DTPA-omburtamab 
Protocol Reference Number: 301 
PIND Number: 143502 
EudraCT Number: 2020-000670-22 
National Clinical Trial Identifier: NCT04167618 
 
 
Sponsor: 
Y-mAbs Therapeutics Inc. 
230 Park Avenue 
Suite 3350  
New York, NY 10169 
 
 
 
Medical Monitor: 
Geoffrey Kannan, PhD, MD 
Labcorp, Inc. 
Tel: +1 (571) 455-3645 
E-mail: Geoffrey.Kannan@labcorp.com 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 


 
 
 
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Protocol 301 
CONFIDENTIAL 
 
Y-mAbs Therapeutics 
177Lu-DTPA-omburtamab 
SPONSOR APPROVAL 
I have read the following and approve it: 
 
 
Please refer to the e-signature page. 
 
 
 
 
Lone Nørgård Troelsen, MD, PhD 
 
Date 
Medical Director 
 
 
Please refer to the e-signature page. 
 
 
 
 
Charlotte Lybek Lind, MSc 
 
Date 
Sr. Clinical Project Manager 
 
 
Please refer to the e-signature page. 
 
 
 
 
Maria Düring, MSc 
 
Date 
Sr Project Statistician 


 
 
 
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177Lu-DTPA-omburtamab 
SYNOPSIS 
Title of trial: A Phase I/II Dose-escalation and Expansion Cohort Trial of Intracerebroventricular 
Radioimmunotherapy Using 177Lu-DTPA-omburtamab in Pediatric and Adolescent Patients with 
Recurrent or Refractory Medulloblastoma 
Indication: Recurrent or refractory medulloblastoma. 
Number of investigators and trial centers: 
Part 1 will be conducted at approximately 9 sites: 4 sites in North America and 5 in Europe 
Part 2 is planned to be conducted at approximately 2 additional sites in North America and Europe 
Development phase: Phase I/II 
Objectives: 
The primary objective of Part 1 (dose-escalation phase) is to explore the tolerability of up to 2 cycles 
of intracerebroventricular 177Lu-DTPA-omburtamab treatment in pediatric and adolescent patients 
with recurrent or refractory medulloblastoma. The maximum tolerated dose (MTD) and/or the 
recommended Phase 2 dose for Part 2 (RP2D) will be determined. 
The primary objective of Part 2 (cohort-expansion phase) is to establish a safety profile of repeated 
dosing of 177Lu-DTPA-omburtamab in pediatric and adolescent patients with recurrent or refractory 
medulloblastoma. 
The secondary objectives of Part 1 are: 
• 
to evaluate the absorbed radiation doses to cerebrospinal fluid (CSF) and blood of 177Lu-
DTPA-omburtamab after intracerebroventricular administration 
• 
to evaluate organ dosimetry of 177Lu-DTPA-omburtamab 
• 
to evaluate the pharmacokinetic (PK) profile of 177Lu-DTPA-omburtamab. 
The secondary objectives of Part 2 are: 
• 
to evaluate the PK profile of 177Lu-DTPA-omburtamab 
• 
to evaluate the investigator-assessed response 
• 
to evaluate the investigator-assessed DoR 
• 
to evaluate PFS 
• 
to evaluate overall survival (OS). 
Methodology/trial design: 
This is a Phase I/II, open-label, safety and efficacy trial in pediatric and adolescent patients (3 to 
19 years) with recurrent or refractory medulloblastoma. 
Part 1 will be a dose-escalation phase with a 3+3 sequential-group design (except for the first dose 
level, which will consist of a single patient only), in which patients will receive a maximum of two 
5-week cycles of treatment with intracerebroventricular 177Lu-DTPA-omburtamab. A Data 
Monitoring Committee will review the safety data from previous dose levels and provide 
recommendations on whether dose escalation should continue. In Part 1, Cycle 1 will comprise a 
dosimetry dose on Day 1 and a treatment dose on Day 8, while Cycle 2 will comprise a treatment 
dose on Day 1. Successive dosing groups will receive escalating treatment doses of lutetium-177 
conjugated to a fixed mass dose of approximately 1 mg DTPA-omburtamab; the dosimetry dose will 
be fixed for all patients. 
Part 2 will be a cohort-expansion phase in which patients will receive a maximum of 5 cycles of 
intracerebroventricular 177Lu-DTPA-omburtamab at the RP2D determined in Part 1. All cycles in Part 
2 will comprise a treatment dose on Day 1. 
The AEs will be evaluated according to CTCAE version 5.0. 


 
 
 
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Number of patients: 
In Part 1, the chosen sample size is customary for dose-escalation studies of this nature and is not 
based on statistical considerations. It is estimated that up to 25 patients will participate in Part 1. 
Actual number of patients will depend on the number of dose-limiting toxicities (DLTs) observed. 
In Part 2, 24 patients are expected to participate, which will provide at least 90% probability to detect 
an adverse event (AE) occurring in 10% of exposed patients. 
The assumption is that 20 out of the 24 patients in Part 2 are evaluable. With 20 patients evaluable for 
response and a response rate of 25% (~ to 5 responders out of 20), the lower limit of the 95% 
confidence interval will be 9%. 
Key criteria for inclusion and exclusion: 
The key inclusion criteria are: 
1. Histologically confirmed diagnosis of medulloblastoma. 
2. SHH, Group 3, or Group 4 according to World Health Organization 2016 classification. 
3. Recurrent or refractory to frontline therapy, defined as: 
a. For Part 1 only: Recurrent (maximum of 2 recurrences) or refractory to frontline 
therapy. Prior frontline or second-line therapy may involve surgery, craniospinal 
irradiation, stereotactic radiosurgery, and multi-agent chemotherapy regimens. 
b. For Part 2 only: Recurrent (maximum of 1 recurrence) or refractory to frontline 
therapy. Patients with recurrent disease must have received second-line 
chemotherapy for progressive disease. Prior frontline or second-line therapy may 
involve surgery, craniospinal irradiation, stereotactic radiosurgery, and multi-agent 
chemotherapy regimens. 
4. Have refractory disease, focal or multifocal recurrent disease, or pure leptomeningeal disease. 
Cytological or radiographic remission is allowed; however, not simultaneously. 
5. Performance status score of 50 to 100, both inclusive, on the Lansky [<16 years] or 
Karnofsky [≥16 years] scales. 
6. Aged 3 to 19 years, both inclusive, at the time of the first planned dose of trial treatment. 
7. Life expectancy of at least 3 months, as judged by the investigator. 
8. Acceptable liver and kidney function and hematological status. 
9. Written informed consent from legal guardian(s) and/or child obtained in accordance with 
local regulations. Pediatric patients must provide assent as required by local regulations. 
The key exclusion criteria are: 
1. Obstructive or symptomatic communicating hydrocephalus as determined by Ommaya 
patency/CSF flow assessment. 
2. Any tumor lesion measuring >15 mm in the smallest diameter. 
3. Ventriculoperitoneal shunts without programmable valves. Ventriculo-atrial or ventriculo-
pleural shunts. 
4. Grade 4 nervous system disorder. Stable neurological deficits due to brain tumor or surgery 
and hearing loss are allowed. 
5. Uncontrolled life-threatening infection. 
6. Received radiation therapy (focal or cranio-spinal irradiation), systemic or intrathecal 
cytotoxic chemotherapy, or immunotherapy (including monoclonal antibodies; 
corticosteroids not included) less than 3 weeks prior to the Dosimetry Dose (or until recovery 
from clinically significant adverse events). Received nitrosoureas less than 6 weeks prior to 
the Dosimetry Dose. 
7. Received any prior anti–B7-H3 treatment. 
8. Non-hematologic organ toxicity Grade 3 or above; specifically, any renal, cardiac, hepatic, 
pulmonary, and gastrointestinal system toxicity. 


 
 
 
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9. Other significant disease or condition that in the investigator’s opinion would exclude the 
patient from the trial. 
10. Females of childbearing potential, who are pregnant, breast feeding, intend to become 
pregnant, or are not using highly effective contraceptive methods or males who are not using 
highly effective contraceptive methods. 
Test products, dose, and mode of administration: 
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. 
177Lu-DTPA-omburtamab will be administered via an indwelling intracerebroventricular access 
device (e.g., Ommaya catheter). The infusion reservoir must be flushed with human serum albumin 
(HSA) and CSF after each infusion. To avoid an additional procedure and burden to the patient, it can 
be considered to place the intracerebroventricular access device in connection with any tumor 
resection procedure that may be performed before entry into the trial. In this case, the informed 
consent form must be signed before the tumor resection. 
In Part 1 only, at the start of the first 5-week treatment cycle, a 5 mCi dosimetry dose will be 
administered on Day 1. If the dosimetry dose of 5 mCi delivers a too low acquisition of radioactivity 
count, the dosimetry dose will be increased to 10 mCi for subsequent patients, at the Sponsor’s 
discretion. A treatment dose with a fixed mass dose of approximately 1 mg DTPA-omburtamab will 
be labelled with increasing radioactivity doses of lutetium-177 and will be administered on Day 8 of 
Cycle 1. The planned radioactivity dose levels in the escalation phase are: 
• 
Dose Level 1 (1+2 patients): 10 mCi 
• 
Dose Level 2 (3+3 design): 25 mCi 
• 
Dose Level 3 (3+3 design): 50 mCi 
• 
Dose Level 4 (3+3 design): 65 mCi 
• 
Dose Level 5 (3+3 design): 85 mCi. 
A maximum of 1 additional intermediate dose level may be added to the trial if warranted based on 
the findings from previous dose levels. If a patient experiences a Grade 3 or 4 non-hematologic AE or 
other DLTs after receiving the dosimetry dose, the treatment dose will not be administered, and the 
patient will be discontinued from trial treatment. Patients who are not discontinued from treatment 
will be eligible for 1 additional treatment cycle with the same dose as administered in the first cycle. 
The second treatment cycle of Part 1 will consist of a treatment dose on Day 1. 
In Part 2, all treatment cycles will consist of a treatment dose on Day 1; the dose level will be the 
RP2D determined in Part 1. Patients who are not discontinued from treatment will be eligible for up 
to 5 treatment cycles in Part 2. Dose reductions due to toxicity are permitted in Part 2 only. 
Reference therapy, dose, dose form, and mode of administration:  
Not applicable. 
Duration of patient participation in trial: 
Planned screening duration: 29 days (longer screening period is allowed (e.g., due to logistics); 
however, screening period of >60 days with individual patient considerations to be discussed with the 
sponsor. 
Planned treatment duration: Up to two 5-week treatment cycles may be administered in Part 1 and up 
to five 5-week cycles may be administered in Part 2. 
Planned duration of trial participation: 19 weeks (Part 1); 104 weeks (Part 2). 
Estimated recruitment period: Q4-2021 to Q3-2023. 
Analysis populations: 
The following analysis sets will be included for this trial: 
Safety Analysis Set: will consist of all patients who received at least 1 dosimetry or treatment dose. 


 
 
 
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DLT Evaluable Analysis Set: will include patients in the dose escalation who as a minimum is 
evaluated during the 5 weeks DLT evaluation period, or who has a DLT during the DLT evaluation 
period. This analysis set is a subset of the Safety Analysis Set. 
Full Analysis Set (FAS): will consist of all patients in the Safety Analysis Set. 
Dosimetry Analysis Set (Part 1 only): will consist of all patients who received the dosimetry dose 
and have evaluable data for absorbed doses to CSF and blood or by whole-body planar scan. 
PK Analysis Set: will consist of all patients who received at least 1 treatment dose of trial drug and 
have evaluable pharmacokinetic (PK) data. 
Evaluation: Safety 
Primary Endpoint: 
• 
Part 1: Number of DLTs. 
• 
Part 2: Number and severity of TEAEs. 
Evaluation: Efficacy 
The secondary efficacy endpoints are: 
Part 2 
• 
Response, as defined by the RAPNO criteria (as determined from MRI assessments, 
neurological examination, and CSF cytology). 
o ORR calculated as the proportion of all evaluable patients achieving a response (PR or 
CR) as best overall response at the time of assessment. 
• 
Investigator-assessed DoR, defined as the time from response (CR or PR) to progression. 
• 
PFS defined as the time from first treatment to date of leptomeningeal progression or death 
from any cause, whichever comes first. 
• 
OS defined as the time from first treatment to date of death. 
Evaluation: Vital signs and other safety procedures 
Patients will undergo monitoring for AEs; vital sign assessments; neurological assessments and 
radiographical investigation for evaluation of neurological AEs); and assessment of performance status 
(Lansky [<16 years] or Karnofsky [≥16 years] scales). 
Evaluation: Dosimetry, imaging, and laboratory evaluations 
Patients will undergo: 
• 
Clinical chemistry and hematology assessments. 
• 
Blood and CSF draws for calculation of absorbed doses (Part 1 only). 
• 
Whole-organ dosimetry measurements based on gamma (and SPECT, if possible) scans (Part 
1 only). 
• 
Brain and spine MRI. 
• 
CSF sampling for cytology, total protein, glucose, circulating tumor DNA (ctDNA; if the 
patient has given informed consent to this analysis), and cell count. 
• 
Blood and CSF draws for PK; and blood and CSF draws for anti-drug antibody (ADA) analysis 
and for potential culture (in case of elevated body temperature). 


 
 
 
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Statistical methods: 
Summary statistics, listings, and statistical analyses will be performed for patients included in the 
relevant analysis sets. PFS will be censored at last disease evaluation with no evidence of 
progression. OS will be censored at last date known to be alive. 
Efficacy statistical methods: 
The investigator-assessed response will be assessed in Part 2 according to RAPNO criteria (MRI, 
neurological examination, and CSF cytology), as well as according to CSF cytology alone. The ORR 
and its 95% confidence intervals will be calculated using the Clopper-Pearson exact methodology. 
The investigator-assessed DoR will be estimated using Kaplan-Meier methods. The median DoR and 
corresponding 95% confidence interval will be calculated. 
PFS time will be estimated using Kaplan-Meier methods. The median PFS time as well as the 
proportion of patients without PFS events at 1 and 2 years post first dose will be estimated in Part 2, 
along with their respective 95% confidence intervals. 
Estimates of OS at 1 year and 2 years post first dose will be made in Part 2 only using Kaplan-Meier 
methods. 
Safety statistical methods: 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 22.1 or later. All AEs will be listed. Non–treatment-emergent AEs (Non-TEAEs) will be 
listed separately. All TEAEs, adverse drug reactions (ADRs), AEs of special interest, serious AEs, 
and serious ADRs will be summarized by system organ class and preferred terms for each treatment 
group. In Part 1, the DLTs will be listed. 
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 may be identified. Development of ADA will be examined. Effects on 
cognitive functions will be assessed by summarizing changes from baseline in performance testing 
results using descriptive statistics. 
Statistical methods for calculation of absorbed doses to CSF and blood (Part 1 only): 
The radioactivity measurements in CSF and blood will be used for calculation of the mean absorbed 
radiation dose after administration of the dosimetry and treatment doses. The maximum observed 
radioactivity count in blood will be determined and the elimination half-life, residence time, and the 
time-activity curves will be presented. Individual and mean absorbed radiation dose to CSF and blood 
will be summarized using descriptive statistics for all patients in the Dosimetry Analysis Set and by 
trial site. 
Dosimetry statistical methods (Part 1 only): 
Spinal cord, brain, and non-target region of interest absorbed radiation doses will be estimated based 
on whole-body planar gamma camera (and SPECT, if possible) scans, and CSF and blood mean 
absorbed radiation doses will be calculated on the basis of measurement of scintillation counts in the 
samples. Individual and mean dosimetry data will be calculated per trial site and will be summarized 
using descriptive statistics. 
Pharmacokinetic statistical methods: 
The serum and CSF PK parameters of 177Lu-DTPA-omburtamab following the treatment doses in 
Cycles 1 and 2 will be calculated using standard noncompartmental methods in both study parts. 
Standard PK parameters (such as maximum observed drug concentration, area under the 
concentration-time curve, half-life) will be calculated. 
 


 
 
 
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TABLE OF CONTENTS 
SPONSOR APPROVAL .................................................................................................................................2 
SYNOPSIS ......................................................................................................................................................3 
TABLE OF CONTENTS ................................................................................................................................8 
LIST OF TABLES AND FIGURES ............................................................................................................. 10 
LIST OF ABBREVIATIONS ........................................................................................................................ 11 
1. 
INTRODUCTION ........................................................................................................................ 13 
1.1. 
Trial Rationale ........................................................................................................................... 13 
1.2. 
Background ................................................................................................................................ 15 
1.2.1. 
Summary of Clinical Information for 131I-omburtamab ............................................................. 15 
1.2.2. 
Pharmacology of 177Lu-DTPA-omburtamab ............................................................................. 17 
1.2.2.1. 
Binding Affinity of Omburtamab for B7-H3 ............................................................................. 17 
1.2.2.2. 
Tumor-targeting and Antitumor Activity of Radiolabeled Omburtamab .................................. 17 
1.2.3. 
Toxicology of 177Lu-DTPA-omburtamab .................................................................................. 18 
1.2.3.1. 
Radiotoxicity of Omburtamab Labels Other Than Lutetium-177.............................................. 20 
1.2.4. 
Preclinical Pharmacokinetics of 177Lu-DTPA-omburtamab ...................................................... 21 
1.2.4.1. 
Dosimetry .................................................................................................................................. 22 
1.3. 
Benefit-risk Assessment ............................................................................................................ 24 
2. 
OBJECTIVES AND ENDPOINTS .............................................................................................. 25 
2.1. 
Objectives .................................................................................................................................. 25 
2.1.1. 
Primary Objectives .................................................................................................................... 25 
2.1.2. 
Secondary Objectives ................................................................................................................ 25 
2.2. 
Endpoints ................................................................................................................................... 25 
2.2.1. 
Primary Endpoints ..................................................................................................................... 25 
2.2.2. 
Secondary Endpoints ................................................................................................................. 26 
2.2.2.1. 
Part 1 .......................................................................................................................................... 26 
2.2.2.2. 
Part 2 .......................................................................................................................................... 26 
3. 
INVESTIGATION PLAN ............................................................................................................ 27 
3.1. 
Overall Trial Design and Plan Description ................................................................................ 27 
3.1.1. 
Part 1 (Dose-escalation Phase) .................................................................................................. 28 
3.1.1.1. 
Dose Escalation and Stopping Rules ......................................................................................... 30 
3.1.1.2. 
Definition of Dose-limiting Toxicity ......................................................................................... 32 
3.1.2. 
Maximum Tolerated Dose and Recommended Phase II Dose Definition ................................. 33 
3.1.3. 
Part 2 (Cohort-expansion Phase) ............................................................................................... 33 
3.2. 
Discussion of Trial Design ........................................................................................................ 34 
3.3. 
Selection of Doses in the Trial ................................................................................................... 35 
3.3.1. 
Selection of DTPA-omburtamab Mass Dose ............................................................................. 35 
3.3.2. 
Selection of Lutetium-177 Dose for Organ Dosimetry .............................................................. 36 
3.3.3. 
Selection of Lutetium-177 Treatment Dose ............................................................................... 36 
4. 
SELECTION OF TRIAL POPULATION .................................................................................... 38 
4.1. 
Inclusion Criteria ....................................................................................................................... 38 
4.2. 
Exclusion Criteria ...................................................................................................................... 39 
4.3. 
Discontinuation Criteria ............................................................................................................ 40 
4.3.1. 
Screen Failures .......................................................................................................................... 40 
4.3.2. 
End of Treatment ....................................................................................................................... 40 
4.3.2.1. 
Discontinuation of Trial Treatment ........................................................................................... 40 
4.3.2.2. 
Completion of Trial Treatment .................................................................................................. 41 
4.3.3. 
End of Trial ................................................................................................................................ 41 
4.3.3.1. 
Discontinuation from Trial ........................................................................................................ 41 
4.3.3.2. 
Completion of Trial ................................................................................................................... 41 
4.3.3.3. 
Lost to Follow-up ...................................................................................................................... 42 
4.3.4. 
Replacement Procedures ............................................................................................................ 42 
4.3.5. 
Follow-up of Patients Discontinued from Trial Treatment or from the Trial ............................ 42 
4.4. 
Data Monitoring Committee ...................................................................................................... 42 


 
 
 
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4.4.1. 
Trial Stopping Rules .................................................................................................................. 43 
4.5. 
Trial Termination ....................................................................................................................... 44 
5. 
TRIAL TREATMENTS ............................................................................................................... 45 
5.1. 
Treatments Administered........................................................................................................... 45 
5.2. 
Preparation, Storage, Handling, and Accountability ................................................................. 45 
5.2.1. 
Radiolabeling of DTPA-omburtamab ........................................................................................ 46 
5.2.2. 
Radiation Safety ........................................................................................................................ 47 
5.2.3. 
Ventriculo-peritoneal Shunts ..................................................................................................... 48 
5.3. 
Method of Treatment Assignment ............................................................................................. 48 
5.3.1. 
Dose Modification ..................................................................................................................... 48 
5.4. 
Blinding ..................................................................................................................................... 48 
5.5. 
Treatment Compliance .............................................................................................................. 49 
5.5.1. 
Overdose, Medication Errors, and Misuse ................................................................................. 49 
5.5.1.1. 
Management of Overdose of 177Lu-DTPA-omburtamab ........................................................... 49 
5.6. 
Technical complaint .................................................................................................................. 50 
6. 
CONCOMITANT THERAPIES .................................................................................................. 51 
6.1. 
Permitted Concomitant Therapy ................................................................................................ 51 
6.2. 
Prohibited Concomitant Therapy ............................................................................................... 51 
6.3. 
Treatment of Expected Toxicities .............................................................................................. 52 
7. 
TRIAL ASSESSMENTS AND PROCEDURES ......................................................................... 53 
7.1. 
Vital Signs, Physical Examination, and Other Safety Evaluations ............................................ 53 
7.1.1. 
Demographics ............................................................................................................................ 53 
7.1.2. 
Height and Body Weight ........................................................................................................... 53 
7.1.3. 
Vital Signs ................................................................................................................................. 53 
7.1.4. 
Physical Examinations ............................................................................................................... 54 
7.1.5. 
Neurological Assessments ......................................................................................................... 54 
7.1.6. 
Performance Status .................................................................................................................... 54 
7.2. 
Dosimetry, Pharmacokinetics, Imaging, and Laboratory Evaluations ....................................... 54 
7.2.1. 
Intracerebroventricular Access Device/CSF Flow Assessment ................................................. 54 
7.2.2. 
Dosimetry and Calculation of Absorbed Radiation Doses (Part 1 only) ................................... 54 
7.2.3. 
Magnetic Resonance Imaging .................................................................................................... 56 
7.2.4. 
CSF for Cytology, Total Protein, Glucose, ctDNA, and Cell Count ......................................... 56 
7.2.4.1. 
CSF Sampling for ctDNA Sequencing ...................................................................................... 56 
7.2.5. 
Blood and CSF for Culture ........................................................................................................ 57 
7.2.6. 
Clinical Chemistry and Hematology.......................................................................................... 57 
7.2.7. 
Archival Tumor Tissue .............................................................................................................. 57 
7.2.7.1. 
Analysis of B7-H3 ..................................................................................................................... 57 
7.2.7.2. 
Analysis of Primary Tumor DNA (in case of separate Informed Consent) ............................... 57 
7.2.8. 
Immunogenicity ......................................................................................................................... 58 
7.2.9. 
Pharmacokinetic Analysis ......................................................................................................... 58 
7.3. 
Efficacy Assessments ................................................................................................................ 58 
7.3.1. 
Progression-free Survival .......................................................................................................... 58 
7.3.2. 
Response Evaluation, Overall Response Rate, and Duration of Response ................................ 59 
7.3.3. 
Overall Survival (Part 2 Only) ................................................................................................... 59 
7.4. 
Adverse Events .......................................................................................................................... 59 
7.4.1. 
Definition of Adverse Events .................................................................................................... 59 
7.4.2. 
Definition of Serious Adverse Events ....................................................................................... 60 
7.4.3. 
Definition of Non-serious Adverse Events ................................................................................ 61 
7.4.4. 
Definition of Adverse Events of Special Interest ...................................................................... 61 
7.4.5. 
Adverse Event Reporting ........................................................................................................... 62 
7.4.5.1. 
Events Requiring Immediate Reporting .................................................................................... 65 
7.4.5.2. 
Pregnancy .................................................................................................................................. 66 
7.4.5.3. 
Reporting Timelines and Contact Details .................................................................................. 66 
7.4.5.4. 
Reporting of SUSARs ............................................................................................................... 66 
7.4.5.5. 
Follow-up on Adverse Events ................................................................................................... 67 


 
 
 
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7.4.5.6. 
Medical Monitoring and Communication of Significant Safety Issues ..................................... 67 
8. 
SAMPLE SIZE AND DATA ANALYSES ................................................................................. 68 
8.1. 
Determination of Sample Size ................................................................................................... 68 
8.2. 
Analysis Populations ................................................................................................................. 68 
8.3. 
General Considerations .............................................................................................................. 68 
8.4. 
Efficacy Analysis ....................................................................................................................... 69 
8.4.1. 
Part 2 Efficacy Analysis ............................................................................................................ 69 
8.5. 
Safety Analysis .......................................................................................................................... 69 
8.5.1. 
Dose-Limiting Toxicities ........................................................................................................... 69 
8.5.2. 
Adverse Events .......................................................................................................................... 70 
8.5.3. 
Other Safety Assessments.......................................................................................................... 70 
8.6. 
Analysis for Calculation of Absorbed Doses to CSF and Blood (Part 1 only) .......................... 70 
8.7. 
Dosimetry Analysis (Part 1 only) .............................................................................................. 71 
8.8. 
Pharmacokinetic Analysis ......................................................................................................... 71 
8.9. 
Interim Analysis ........................................................................................................................ 71 
9. 
REFERENCES ............................................................................................................................. 72 
10. 
APPENDICES .............................................................................................................................. 74 
Appendix 1: Clinical Laboratory Evaluations ............................................................................................... 74 
Appendix 2: Regulatory, Ethical, and Trial Oversight Considerations.......................................................... 75 
Appendix 3: Schedule of Assessments .......................................................................................................... 80 
Appendix 4: Creatinine-based 2009 Revised Bedside Schwartz Equation .................................................... 86 
Appendix 5: Contraceptive Guidance ............................................................................................................ 87 
Appendix 6: Assessment in Pediatric Neuro-oncology (RAPNO) Criteria ................................................... 89 
Appendix 7: Intracerebroventricular Access Device/CSF Flow Assessment ................................................ 90 
 
 
LIST OF TABLES AND FIGURES 
Table 1: 
Estimated Absorbed Doses for a 5-year-old Human (19 kg) ................................................................... 23 
Table 2: 
Properties of Lutetium-177 and Iodine-131 ............................................................................................. 37 
Table 3: 
Accepted Activity Ranges for Dosimetry and Treatment Doses ............................................................. 46 
Table 4: 
CSF and Blood Sampling and Scans in only Cycle 1 of Part 1 ............................................................... 55 
Table 5: 
Schedule for CSF and Blood Pharmacokinetic Sampling (Parts 1 and 2) ............................................... 58 
Table 6: 
Schedule of Assessments – Part 1, Screening and Cycle 1 ...................................................................... 80 
Table 7: 
Schedule of Assessments – Part 1, Cycle 2 (if Applicable) through Follow-up ...................................... 82 
Table 8: 
Schedule of Assessments – Part 2 (All Cycles) ....................................................................................... 84 
 
Figure 1: 
Trial Design – Part 1 Cycle 1 .................................................................................................................. 30 
Figure 2: 
Adverse Event Reporting ......................................................................................................................... 62 
 


 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
CAR 
chelator-to-antibody ratio 
CD 
cluster of differentiation 
CDR 
complementarity-determining regions 
cGy 
centigray 
Ci 
curie 
Cmax 
maximum observed drug concentration 
CNS 
central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
complete response 
CSF 
cerebrospinal fluid 
CT 
computed tomography 
ctDNA 
circulating tumor deoxyribonucleic acid 
CTA 
clinical trial agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DoR 
duration of response 
DTPA 
Used as short for p-SCN-Bn-CHX-A′′-DTPA (see this 
abbreviation) 
EC 
Ethics Committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EOT 
end of treatment 
eGFR 
estimated glomerular filtration rate 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
GMP 
Good Manufacturing Practices 
Gy 
gray 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICV 
intracerebroventricular 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IV 
intravenous 
mCi 
millicurie 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NOAEL 
no-observed-adverse-effect level 


 
 
 
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ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
p-SCN-Bn-CHX-A′′-DTPA 
[(R)-2-Amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-
cyclohexane-1,2- diamine-pentaacetic acid 
RAPNO 
Response Assessment in Pediatric Neuro-oncology 
RP2D 
recommended Phase II dose 
SAE 
serious adverse event 
SOC 
system organ class (MedDRA classification) 
SPECT 
single-photon emission computed tomography 
SPR 
surface plasmon resonance 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VP 
Ventriculoperitoneal 
Y-mAbs 
Y-mAbs Therapeutics 


 
 
 
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1. INTRODUCTION 
Y-mAbs Therapeutics (Y-mAbs) is developing 177Lu-DTPA-omburtamab for the treatment of 
B7-H3-positive tumors, including medulloblastoma. The same monoclonal antibody, 
omburtamab, radiolabeled with iodine-131 (131I-omburtamab) is currently under development for 
treatment of pediatric patients with recurrent or refractory neuroblastoma with central nervous 
system (CNS)/leptomeningeal metastasis. 
When labeled with a radionuclide, omburtamab targets B7-H3 (also known as cluster of 
differentiation 276 [CD276]) on the cell membrane and delivers a radioactive payload, including 
DNA damage and cell death, to B7-H3–expressing tumors without being internalized or 
activating effector functions1, 2. B7-H3 is a transmembrane glycoprotein of the B7/CD28 
immunoglobulin superfamily that is minimally expressed in normal tissues and modulates 
immune functions in tumor surveillance, infections, and autoimmune diseases. B7-H3 is 
overexpressed on the cell membrane of a broad range of human 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. Lutetium-177 and iodine-131 are 
β-radiation emitters with similar half-lives (approximately 6.7 and 8 days, respectively)3. 
Lutetium-177 has a lower maximum β-emission than iodine-131 (496 keV versus 610 keV), 
resulting in a shorter penetration distance (mean 0.67 mm) in soft tissue, making this 
radionuclide ideal for delivering tumoricidal β-radiation to small volumes such as minimal 
residual disease following surgery, micrometastatic disease, and tumor cells near the surface of 
cavities, while further reducing the risk of normal tissue toxicity such as neurodegeneration and 
myelosuppression and negating specific toxicity to the thyroid. In addition, 2 photon energy 
peaks (208 keV and 113 keV) can be used for gamma imaging, demonstrating its use as a 
theragnostic agent. 
Notably, while the iodogen method of preparation of 131I-omburtamab is well suited for the 
limited population with recurrent or refractory neuroblastoma with CNS/leptomeningeal 
metastasis, there are important manufacturing advantages to the use of lutetium-177 for 
radioimmunotherapy for indications in larger populations, such as the availability of carrier-free 
lutetium-177 and reduced radiation exposure during radiopharmaceutical manufacturing and 
patient administration. 177Lu-DOTATATE (Lutathera) is approved for the treatment of 
somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors and several 
lutetium-177–radiolabeled pharmaceuticals are actively under study for the treatment of multiple 
cancer indications such as prostate (177Lu-J5914, 177Lu-PSMA-6175) and non-Hodgkin’s 
lymphoma (177Lu-lilotomab6). 
This will be a first-in-human trial of 177Lu-DTPA-omburtamab in pediatric and adolescent 
patients with recurrent or refractory medulloblastoma. 
1.1. 
Trial Rationale 
Medulloblastoma is the most common pediatric brain tumor, comprising around 20% of all 
childhood brain tumors, with 25% to 35% diagnosed at <3 years of age and a peak incidence at 
5 to 9 years of age7. These embryonal tumors of the cerebellum have a propensity to invade and 
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Approximately 30% of pediatric cases present with metastases at diagnosis, with the highest 
incidence in infants. 
Standard frontline therapy for medulloblastoma includes surgery, high-dose craniospinal 
radiation, and chemotherapy. Recurrent/refractory medulloblastoma represents a marked clinical 
challenge because there is no generally accepted standard of care. Often re-surgery and systemic 
chemotherapy are pursued, in addition to autologous stem cell transplantation. However, the 
outcome is dismal and often fatal. 
The overall survival (OS) rates for medulloblastoma are 70% to 80% in standard-risk patients8 
and 30% to 60% in high-risk patients9. Significant neurocognitive deficits emerge in nearly all 
survivors and effective treatment regimens associated with less neurocognitive toxicity would 
provide an improvement over current therapeutic options10. 
Medulloblastoma is one of the many tumor types shown to express increased levels of the 
transmembrane glycoprotein B7-H3. Recent studies have shown that at least 96% of pediatric 
medulloblastomas stained positive for B7-H3 expression11, 12 and in another study in patients 
with a range of solid tumors, 2 out of 2 medulloblastoma patients exhibited binding of 
omburtamab1. Its broad expression in medulloblastoma, along with limited expression on normal 
cells and lack of expression on normal brain tissues1, 2 make B7-H3 an ideal target for an 
antibody therapy. 
In the current trial, Y-mAbs proposes to use the same intracerebroventricular route of 
administration as for 131I-omburtamab in neuroblastoma patients with CNS/Leptomeningeal 
relapse, to evaluate the safety and efficacy of 177Lu-DTPA-omburtamab radioimmunotherapy in 
recurrent or refractory medulloblastoma patients. The reasons for developing 
177Lu-DTPA-omburtamab include: 
• Lutetium-177 and iodine-131 are both β-emitters with comparable half-lives. 
• While iodine-131 is directly labeled to omburtamab via tyrosine residues in both the antigen-
binding complementarity-determining regions (CDR) and non-CDR regions, lutetium-177 
binds to the chelator, p-SCN-Bn-CHX-A’’-DTPA conjugated to omburtamab. 
• The lower maximum β-energy of lutetium-177 versus iodine-131 (496 keV versus 610 keV) 
may curtail myelosuppression observed with 131I-omburtamab. 
• Lutetium-177 is not associated with specific toxicity to the thyroid, the main organ for iodine 
uptake. 
• Lutetium-177 is an ideal radionuclide for delivering tumoricidal β-radiation to small 
volumes, including minimal residual disease following surgery, micrometastatic disease, 
and tumor cells near the surface of cavities, while further reducing the risk of normal tissue 
toxicity. 


 
 
 
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• Lutetium-177 has 2 photon energy peaks (208 keV and 113 keV) that can be used for 
imaging with the same therapeutic agent in whole-body planar scintillation camera scanning 
and most single-photon emission computed tomography (SPECT) scanners available today. 
• Manufacturing of 177Lu-DTPA-omburtamab for a larger population is more practical than 
manufacturing of 
131I-omburtamab given the availability of commercial, Good 
Manufacturing Practices (GMP), carrier-free lutetium-177 and the lower operator radiation 
exposure inherent to its lower maximum β-energy. 
This first-in-human trial will primarily evaluate the safety of intracerebroventricular (i.e., 
administered into the cerebral ventricles of the brain) 177Lu-DTPA-omburtamab and secondarily, 
the dosimetry and efficacy in pediatric and adolescent medulloblastoma patients. 
1.2. 
Background 
1.2.1. 
Summary of Clinical Information for 131I-omburtamab 
131I-omburtamab has been studied in clinical trials initiated at Memorial Sloan Kettering Cancer 
Center over 15 years. In Trial 03-133, intracerebroventricular administration of 131I-omburtamab 
is being evaluated in patients with central nervous system/leptomeningeal neoplasms in an 
open-label, single-dose trial with a dose-escalation part that has been finalized and a 
cohort-expansion part that is currently ongoing (NCT00089245). The primary objective of trial 
03-133 is to define the clinical toxicities of intracerebroventricular 131I-omburtamab. The trial 
has patients in follow-up and is closed for enrolment. 
In a separate Phase II/III trial, intracerebroventricularly administered 131I-omburtamab is under 
evaluation in neuroblastoma patients with CNS relapse as evidenced by CNS/leptomeningeal 
metastases (Investigational New Drug 009351; NCT03275402; Trial 101). 
The overall safety profile of 131I-omburtamab administered as an intracerebroventricular infusion 
to in total 133 pediatric patients with neuroblastoma and CNS/LM metastasis is based on data 
from two clinical trials (Trial 03-133, N = 109; and Trial 101, N = 24). Furthermore, 131I-
omburtamab has been administered to a total of 170 patients in Trial 03-133 and Trial 101 
without any indication of acute adverse effects on the major physiological systems (e.g., 
cardiovascular, respiratory, renal, and central nervous systems). 
Trial 03-133 
As of 30 June 2019, the most common adverse events (AEs) (≥10%) were lymphopenia, platelet 
count decreased, white blood cell count decreased, neutrophil count decreased, vomiting, 
hemoglobin decreased, cough, headache, contusion, diarrhea, rhinorrhea, decreased appetite, 
pyrexia, abdominal pain, and nausea. The most common serious adverse events (≥5%) were 
platelet count decreased, neutrophil count decreased, and white blood cell count decreased. Less 
frequent, but clinically significant serious adverse events (<5%) include myelodysplastic 
syndrome, acute myeloid leukemia, seizure, and depressed level of consciousness. 10% of 
patients discontinued from treatment with 131I-omburtamab due to adverse events, including 
decreased platelet count, chemical meningitis, and immune thrombocytopenic purpura. Serious 
infusion reactions included chemical meningitis, vomiting, pyrexia, headache, and nausea. 


 
 
 
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Trial 101 
As of 01 Jun 2020, the most common AEs (≥10%) were platelet count decreased, white blood 
cell count decreased, lymphocyte count decreased, neutrophil count decreased, nausea, headache 
and anemia, vomiting, pain, and pyrexia. The most common serious adverse reaction (≥10%) 
was platelet count decreased. Less frequent, but clinically significant serious AEs related to 131I-
omburtamab administration were chemical meningitis and intracranial hemorrhage. The most 
common AE leading to discontinuation of 131I-omburtamab was platelet count decreased. Serious 
infusion reactions occurred in one patient (chemical meningitis). 
Selected AEs in Trials 03-133 and 101 
Myelosuppression is caused by radiation-related adverse effects on the bone marrow and may 
result in severe and prolonged cytopenia. In Trial 03-133 and Trial 101, a total of 81.7% and 
87.5%, respectively, had at least one event related to cytopenia. The most commonly reported 
hematopoietic cytopenia events were lymphopenia, platelet count decreased, and white blood 
cell count decreased. 
Chemical meningitis is an inflammation of the meninges. Symptoms include fever, headache, 
nausea, and vomiting. Three patients experienced SAEs of chemical meningitis (2/109 and 1/24 
in Trial 03-133 and Trial 101, respectively). 
Serious infusion reactions in Trials 03-133 and 101 
131I-omburtamab may potentially cause serious infusion reactions. Serious infusion reactions 
were reported by 4% of patients across Trial 03-133 and Trial 101 (4/109 and 1/24 respectively). 
These included chemical meningitis, nausea (1/109 in Trial 03-133) and vomiting (1/109 in Trial 
03-133). Anaphylactic reactions have not been reported in these clinical trials. 
Recommended Phase II Dose for 131I-omburtamab 
A recommended Phase II dose (RP2D) of 50 mCi/cycle for up to 2 cycles was established for 
131I-omburtamab for the treatment of B7-H3-positive tumors with CNS/leptomeningeal 
metastases, including neuroblastoma patients. Patients with other indications were also treated in 
Trial 03-133, including those with ependymoma, medulloblastoma, and B7-H3-positive solid 
tumors with CNS/leptomeningeal metastases including malignant melanoma and ovarian cancer. 
Efficacy 
The median survival after treatment with 131I-omburtamab of the 107 neuroblastoma patients 
with CNS/leptomeningeal metastases included in the interim analysis of Trial 03-133, was 
50 months versus 6 months in various historical cohorts13-15. While survival past 3 years for 
patients with neuroblastoma CNS/leptomeningeal metastases historically is rare (<10%), the 
estimated 3- and 5-year survival for neuroblastoma patients with CNS/leptomeningeal metastases 
relapse receiving 131I-omburtamab are 56% and 43%, respectively. Survivors have been followed 
for up to 14.1 years, and 57 (53.3%) of the 107 patients treated with 131I-omburtamab remained 
alive at their last follow-up. These results have led to Breakthrough Designation by the US Food 
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In the same trial (03-133), 21 patients with recurrent medulloblastoma and 9 patients with 
ependymoma were treated with 131I-omburtamab. Although the number of patients was too low 
to evaluate the efficacy, the therapy was well tolerated in the medulloblastoma cohort. 
131I-3F8, which targets tumor expressing ganglioside GD2 is another intracerebroventricular 
β-emitter radioimmunotherapy for the treatment of medulloblastoma, which was evaluated in 
a clinical trial at Memorial Sloan Kettering Cancer Center. In the Phase II trial (NCT00445965), 
data from 43 medulloblastoma patients showed superior survival among those receiving 131I-3F8 
as part of second remission consolidation when compared to patients with radiographically 
measurable disease. The median of the total absorbed dose in CSF was 1,453 cGy (range: 350 to 
2,784 cGy). No treatment-related deaths were reported16. 
1.2.2. 
Pharmacology of 177Lu-DTPA-omburtamab 
1.2.2.1. 
Binding Affinity of Omburtamab for B7-H3 
The B7-H3 receptor is overexpressed on the cell membrane of a broad spectrum of tumor types 
and is minimally expressed in normal human tissues1, 17-19. Omburtamab, a B7-H3 antibody, was 
used to confirm specific B7-H3 expression in formalin-fixed and paraffin-embedded 
medulloblastoma tumors in an immunohistochemistry study sponsored by Y-mAbs. 
The binding affinity of omburtamab for recombinant B7-H3 antigens from mouse, rat, monkey, 
and human was determined using surface plasmon resonance (SPR). Omburtamab binds to 
monkey and human B7-H3 with high affinity and equilibrium dissociation constants of 1.6 and 
1.1 pM, respectively, while binding to mouse or rat B7-H3 was not detectable by SPR. 
The in vitro binding affinity of omburtamab for recombinant human B7-H3 protein (2Ig and 4Ig 
isoforms; 4Ig is the dominant isoform) was compared for naked, chelated, and lutetium-175–
labeled antibody using SPR. Higher conjugation ratios of CHX-A′′-DTPA reduced the affinity of 
omburtamab and 175Lu-DTPA-omburtamab to 4Ig-B7-H3. Labeling of the conjugates with cold 
lutetium-175 did not further change omburtamab binding affinity for B7-H3 protein and labeling 
with iodine-127 did not affect binding affinity. For a chelator-to-antibody ratio of 3 (CAR 3), 
binding affinity to 4Ig-B7-H3 is 5- to 7-fold lower than omburtamab or 131I-omburtamab. A 
CAR 3 was chosen for development of the clinical product. 
Accordingly, an in vitro potency test for the final product, 177Lu-DTPA-omburtamab, has been 
developed using biotinylated B7-H3–streptavidin beads. This assay has consistently shown 
immunoreactivities greater than 70% at end-of-synthesis for 177Lu-DTPA-omburtamab (CAR 3). 
1.2.2.2. 
Tumor-targeting and Antitumor Activity of Radiolabeled Omburtamab 
Athymic nude mice bearing DAOY (B7-H3–expressing medulloblastoma) xenografts were given 
a single intravenous (IV) dose of 177Lu-DTPA-omburtamab (CAR 3) or 125I-omburtamab for 
proof-of-concept tumor targeting. SPECT/computed tomography (CT) and ex vivo gamma 
counting of organs showed that over 120 hours, accumulation of 177Lu-DTPA-omburtamab in the 
tumor was similar to or greater than that observed with 125I-omburtamab. 


 
 
 
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In another study, nonclinical antitumor efficacy was evaluated in male and female nude mice 
subcutaneously inoculated with DAOY xenografts and given a single IV injection of 522 ± 
22 μCi 177Lu-DTPA-omburtamab (CAR 3) (mass dose of 50 μg), 509 ± 62 μCi 131I-omburtamab 
(mass dose of 50 μg), or 50 μg omburtamab. For 177Lu-DTPA-omburtamab, measurements taken 
prior to Day 15 post dose suggest lower percent change in tumor volume in animals that received 
radiolabeled omburtamab compared to unlabeled omburtamab. However, all animals from this 
group died on study due to non-recovering myelosuppression as measured by hematocrit and 
hematopoietic cell counts, a known dose-limiting toxicity (DLT) for radioimmunotherapy 
(euthanasia for weight loss [4/7 animals], found dead [3/7 animals]); see Section 1.2.3. The 
findings are consistent with mortality seen in female athymic nude mice given a single 
intraperitoneal injection of approximately 500 μCi 177Lu-DTPA-omburtamab, 131I-omburtamab, 
or 131I-humanized-omburtamab (CAR3) (50 μg mass dose). By Day 19, all animals in the 
177Lu-DTPA-omburtamab group were found dead or euthanized (2/8 found dead, 5/8 euthanized 
due to weight loss, 1/8 euthanized due to low hematocrit); 5/6 and 3/7 animals in the 
131I-omburtamab and 131I-humanized-omburtamab groups, respectively, were euthanized due to 
weight loss. Hematocrit and red and white blood cell counts were decreased in animals given 
177Lu-DTPA-omburtamab or 131I-omburtamab. Follow-up evaluations support the conclusion 
that 500 μCi was sufficient to cause severe, non-recovering myelosuppression due to bone 
marrow toxicity. The dose-limiting organ for IV injection was the skeleton (i.e., bone marrow) 
and dosimetry estimates indicated the maximum tolerated dose (MTD) for IV injection in this 
model are 245 μCi 177Lu-DTPA-omburtamab and 236 μCi 131I-omburtamab, levels that were 
exceeded by nearly double in the efficacy study. Given the nonclinical antitumor activity of 
131I-omburtamab in athymic nude mice bearing HTB82 xenografts20, the clinical data, the 
demonstrated binding affinity to recombinant human B7-H3 protein by both SPR and 
immunohistochemistry, tumor-to-blood ratios, mean residence time, and tissue irradiation range 
of the 2 radiolabels, it is anticipated that 177Lu-DTPA-omburtamab antitumor activity will be 
favorable compared to that of 131I-omburtamab. 
1.2.3. 
Toxicology of 177Lu-DTPA-omburtamab 
In accordance with the guidance21, 22, no standalone safety pharmacology studies have been 
conducted with 177Lu-DTPA-omburtamab. 
Safety in the cardiovascular system and CNS was evaluated in a Good Laboratory Practice 
(GLP) toxicity study in juvenile monkeys (aged 10.5 to 11 months) given a single 
intracerebroventricular infusion of DTPA-omburtamab (CAR 1). The cynomolgus monkey was 
the selected species because the intended clinical route of administration is not feasible in 
rodents. Juvenile monkeys (i.e., aged 10.5 to 11 months) were selected because of the intended 
clinical use of 177Lu-DTPA-omburtamab in the pediatric and adolescent patient population. In 
addition to the intended route of administration, monkeys were the selected species based upon 
the demonstrated binding of omburtamab with high affinity to the recombinant human and 
cynomolgus monkey B7-H3. The juvenile monkey provides an assessment of safety for any 
off-tumor, on-target toxicity not detectable by immunohistochemistry. There was no 
treatment-related effect on electrocardiogram parameters or the neurological measures of 
postural/behavioral reactions, cranial nerve functions evaluated via eye position and facial 
muscle control/symmetry, or pain. 


 
 
 
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The safety of the radiolabeled monoclonal antibody is limited by radiation-induced toxicity. The 
main animal model selected to test radiotoxicity was the naïve rat. While omburtamab does not 
bind to rodent B7-H3, this common testing model is suitable to determine normal organ 
dosimetry and acute and delayed radiotoxicity from intrathecal administration in statistically 
relevant numbers. Body weight and clinical pathology were monitored for 6 weeks post dose in 
male and female rats given a single low (target 200 µCi) or high (target 500 µCi) dose intrathecal 
injection of 177Lu-DTPA-omburtamab or 131I-omburtamab. Animals were sacrificed and 
histopathology of critical organs showed that all tissues were within normal limits and there was 
no evidence of radiation damage, in particular to the bone marrow and kidneys in any of the 
treatment groups. Body weight increases were normal in all groups. Red blood cell 
concentrations and hematocrit were stable and white blood cell concentrations decreased, 
although within or slightly above the normal range, in all groups for the duration of the study. 
Furthermore, to support repeat-dosing schedules in human, the radiotoxicity in Sprague Dawley 
rats given an intrathecal injection once every 3 weeks for a total of 3 treatments of 
177Lu-DTPA-omburtamab or 131I-omburtamab has been examined. There were no signs of 
radiotoxicity as seen by blood biomarkers or bodyweights and there was no histological evidence 
of radiation damage in any tissue including the bone marrow and the kidney. 
As mentioned, several deaths occurred in the 177Lu-DTPA-omburtamab groups of 2 mouse 
studies with different objectives than toxicity due to non-recovering myelosuppression between 
Weeks 2 and 3 on study, evidenced by decreased white and red blood cells and hematocrit. In 
1 study, IV injection of 177Lu-DTPA-omburtamab at approximately 500 µCi (mean 522 µCi) 
caused the death of all animals in the group while the injection of 131I-omburtamab at 
approximately 500 µCi (mean 509 µCi) did not. However, in another study, a dose of 
approximately 500 µCi of either 177Lu-DTPA-omburtamab or 131I-omburtamab resulted in severe 
reduction of blood counts and required euthanasia due to weight loss or were found dead by 
Day 19 (131I-omburtamab: 5/6 animals; 177Lu-DTPA-omburtamab: 7/7 animals). In vivo imaging 
data were collected from 1 animal in the 177Lu-DTPA-omburtamab group in this study, and 
accumulation of radioactivity in the bone was confirmed. We consider that these studies do not 
indicate undue risk to the patients in our study due to the following: 
• The doses used in the mice were administered IV and greatly exceeded the calculated 
limit of radiation to the bone marrow in mice (245 µCi) and was accompanied by 
myelosuppression. 
• Furthermore, on a body weight basis, the doses correspond to approximately 200 mCi in 
a 5-year-old child of 10 kg, and approximately 20× the proposed starting dose of 10 mCi 
administered intracerebroventricularly. 
• Dosimetry estimates for a 5-year-old child from biodistribution studies from intrathecal 
administration in naïve rats suggest comparable if not lower absorbed doses to the bone 
marrow for 177Lu-DTPA-omburtamab than for 131I-omburtamab (approximately 
20 cGy/10 mCi versus 25 cGy/10 mCi). This is consistent with the more favorable β-
energy for lutetium-177. 


 
 
 
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• Data from the 131I-omburtamab trials indicate that although myelosuppression was the 
main non-dose-limiting AE, radioimmunotherapy was well tolerated even after treatment 
with external beam craniospinal radiation and a boost to the primary site, which 
contribute 28 and 24 Gy, respectively, while 131I-omburtamab resulted in a mean CSF 
absorbed dose of 0.60 Gy/mCi (0.17 to 2.07 Gy/mCi)23. 131I-omburtamab therapy 
corresponds to less than 30% of the total radiation received by these patients. 
Animal-based dosimetry predicts a dose to the brain of 13.2 and 14.4 cGy/10 mCi for 
177Lu-DTPA-omburtamab and 131I-omburtamab respectively. The higher absorbed doses 
reported in patients may be due to the difference in measuring brain versus CSF and 
reflect the presence of tumor in patients versus naïve animals. 
Nevertheless, to confirm our hypothesis, a follow-up study in nude mice evaluating extended 
(8 weeks) radiotoxicity, and in particular, the threshold and reversibility of myelosuppression 
after administration of 100 or 200 μCi 177Lu-DTPA-omburtamab or 100 μCi 131I-omburtamab 
has been conducted. These doses correspond to 40 and 80 mCi on a body weight basis for a 
10-kg child. At 5 weeks post dose, no adverse findings have been noted as measured by 
mortality, morbidity, clinical signs, body weights, or clinical chemistries. Results show that 
lower levels of radioactivity are not associated with significant myelosuppression. There was no 
significant group differences in body weight. At 1 week post dose, red blood cell counts and 
hematocrit were decreased in animals given 200 μCi 177Lu-DTPA-omburtamab, and these 
changes showed continued recovery at 2 through 5 weeks post dose. 
1.2.3.1. 
Radiotoxicity of Omburtamab Labels Other Than Lutetium-177 
A non-GLP study was conducted to evaluate radiotoxicity of 131I-omburtamab in 2 male 
cynomolgus monkeys given multiple doses of 3.62 to 8.3 mCi 131I-omburtamab via intrathecal 
injection. One monkey was preimmunized with 131I-omburtamab by IV administration 210 and 
127 days prior to study initiation to evaluate anti-drug antibody (ADA) generation. 
131I-omburtamab produced detectable spikes of 131I-omburtamab in the CSF and comparatively 
lower levels of radiation in the blood. Suppressed levels in the blood of the preimmunized animal 
were likely due to a monkey anti-mouse antibody response that did not affect levels measured in 
the CSF. In general, total radioactivity elimination from the CNS was nearly complete by 
48 hours post dose. 131I-omburtamab was tolerable for nontraumatic cisternal puncture. The 
findings associated with dosing, including changes in laboratory values measured in the CSF and 
blood, were transient and reversible. Beyond the injection site, no significant gross pathology or 
histopathological findings were noted in either animal and no long-term toxicities were observed 
after extended follow-up (i.e., >1200 days after the last dose). 
Single-dose studies with the monoclonal antibody have been conducted for biotinylated 
omburtamab, 131I-omburtamab, and 124I-omburtamab in xenografted mice20, 24, naïve rats24, 25, or 
monkeys25. The test agents were administered via IV or intratumoral infusions for mice, 
intraparenchymal infusion or convection-enhanced delivery for rats, and convection-enhanced 
delivery for monkeys. There was no evidence of neurological toxicity with biotinylated 
omburtamab. The radiolabeled antibodies were well tolerated in mice, rats, and monkeys at 
radioactivity doses up to 500 μCi 131I-omburtamab or 1 mCi 124I-omburtamab, the highest levels 
of radioactivity evaluated. 


 
 
 
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1.2.4. 
Preclinical Pharmacokinetics of 177Lu-DTPA-omburtamab 
Electrochemiluminescence assays were developed and validated to support quantification of 
DTPA-omburtamab in plasma and CSF from cynomolgus monkey. 
No standalone pharmacokinetic (PK) studies have been conducted with 
177Lu-DTPA-omburtamab. Toxicokinetic parameters were determined in juvenile monkeys given 
a single intracerebroventricular infusion of vehicle or DTPA-omburtamab (CAR 1). The no-
observed-adverse-effect level (NOAEL) of 1.5 mg/kg DTPA-omburtamab corresponded to a 
maximum observed drug concentration (Cmax) of 18,200 ng/mL total omburtamab and a mean 
area under the concentration-time curve (AUC) from time 0 to 672 hours of 1,350,000 hr·ng/mL 
and AUC from time 0 to infinity of 1,300,000 hr·ng/mL. There were no sex differences in 
toxicokinetic parameters. Total omburtamab was detectable in plasma at 1 hour post dose. 
Maximum plasma concentration and AUC increased with increasing dose in a greater than dose 
proportional manner. Time to maximum concentration was 12 hours and half-life was 23.9 to 
26.1 hours. Mean clearance and volume of distribution of total omburtamab decreased with 
increasing dose. Total omburtamab was detectable in CSF in all dose groups at 24 hours post 
dose, and below the limit of quantification on Day 30. Concentrations were dose proportional for 
0.1 and 0.75 mg/kg DTPA-omburtamab. There was no further increase in CSF levels at 24 hours 
post dose for 1.5 mg/kg compared to 0.75 mg/kg. 
Biodistribution of 177Lu-DTPA-omburtamab (CAR 3.6 and 3) was evaluated in 2 studies with 
Sprague Dawley rats given a single intrathecal injection, and in 1 study with tumor-bearing 
athymic nude mice given a single IV injection of 177Lu-DTPA-omburtamab (CAR 3). The 
compound in these 3 studies was comparable to the clinical formulation (i.e., CAR ≈ 3). 
177Lu-DTPA-omburtamab concentration was significantly greater than the 125I-omburtamab 
concentration in the bone (1, 48, 144, and 192 hours), kidneys (48 and 192 hours), liver (all 
timepoints), and cervical spine (24, 48, 144, and 192 hours). 177Lu-DTPA-omburtamab 
concentration was significantly lower than 125I-omburtamab concentration in the cervical spine 
and upper thoracic spine at 1 hour and the lumbar spine at 5 hours. After 24 hours, the only 
region with 177Lu-DTPA-omburtamab concentration that was lower than the 125I-omburtamab 
concentration was the heart. 177Lu-DTPA-omburtamab gamma counts at 192 hours were 
generally increased compared to 125I-omburtamab. The liver, cervical lymph nodes, and spleen 
had the highest concentrations of 177Lu-DTPA-omburtamab at 192 hours. The highest 
concentrations of 125I-omburtamab at 192 hours were in the skin, liver, and cervical lymph 
nodes. Blood uptake for both labeled test articles was greatest at 24 hours. 
In a second rat study, rats were given a single intrathecal injection of 174.3 ± 6.4 or 
442.8 ± 17.3μCi 177Lu-DTPA-omburtamab (CAR 3) or 451 ± 37.6 μCi 131I-omburtamab. 
Biodistribution was evaluated up to 288 hours post dose. The highest levels of radioactivity were 
seen with the high dose of 177Lu-DTPA-omburtamab within the vertebral canal and brain at 
1 hour post dose with subsequent clearance of radiopharmaceutical from these regions by 
24 hours. At 24 hours and later, the highest radioactivity was in the liver and the deep and 
superficial cervical lymph nodes. Relatively little radioactivity was observed in the heart, lungs, 
spleen, kidneys, and humerus. Distribution of radioactivity over time following administration of 
the low dose was similar to high dose of 177Lu-DTPA-omburtamab. 


 
 
 
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Biodistribution was evaluated for up to 120 hours post dose and gamma counting was conducted 
at 120 hours post dose in male and female athymic nude mice bearing DAOY xenografts. 
Compared to 125I-omburtamab, 177Lu-DTPA-omburtamab accumulated 2-fold more in tumor 
relative to blood, and 2-fold less relative to liver. In vivo concentrations of 177Lu-DTPA-
omburtamab were significantly (p < 0.05) higher in tumor, blood, liver, lung, spleen, kidney, 
bladder, muscle, and bone at 120 hours post dose compared to 125I-omburtamab. Ex vivo 
concentrations of 177Lu-DTPA-omburtamab at 120 hours post dose were significantly (p < 0.05) 
higher in the tumor, liver, spleen, kidney, and bone compared to 125I-omburtamab. 
1.2.4.1. 
Dosimetry 
The biodistribution data extrapolated from the SPECT/CT images were used as the input for 
dosimetry analysis (i.e., percentage injected dose per gram in key organs of interest over time) to 
generate estimates for 5-year-old (19 kg) humans. The 3 organs with the highest absorbed doses, 
the liver, heart wall, and kidneys, were the same for both test agents, albeit with different rank 
orders, and the effective doses were similar for the 2 test articles. The absorbed doses were 
higher in the liver and lower in the heart wall and kidneys with 177Lu-DTPA-omburtamab than 
125I-omburtamab. Estimated absorbed doses for 5-year-olds are shown in Table 1. 


 
 
 
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Table 1: 
Estimated Absorbed Doses for a 5-year-old Human (19 kg) 
 
mGy/MBq 
mGy/mCi  
cGy per 25 mCi (1 dose) 
cGy per 10 mCi (1 dose) 
cGy per 10 mCi (2 dose) 
Target Organ 
Male 
Female 
Male 
Female 
Male 
Female 
Male 
Female 
Male 
Female 
Adrenals  
0.48  
0.48  
17.86  
17.63  
44.65  
44.08  
17.86 
17.63 
35.72 
35.26 
Brain  
0.31  
0.34  
11.49  
12.70  
28.72  
31.76  
11.49 
12.70 
22.976 
25.41 
Breasts  
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Esophagus  
0.44  
0.44  
16.41  
16.38  
41.02  
40.95  
16.41 
16.38 
32.82 
32.76 
Eyes  
0.42  
0.41  
15.53  
15.26  
38.83  
38.16  
15.53 
15.26 
31.06 
30.53 
Gallbladder Wall  
0.50  
0.46  
18.40  
17.05  
45.99  
42.63  
18.40 
17.05 
36.79 
34.10 
Heart Wall  
1.03  
1.02  
38.02  
37.68  
95.06  
94.21  
38.02 
37.68 
76.05 
75.37 
Kidneys  
1.20  
1.20  
44.40  
44.40  
111.00  
111.00  
44.40 
44.40 
88.80 
88.80 
Left colon  
0.44  
0.43  
16.26  
15.97  
40.65  
39.93  
16.26 
15.97 
32.52 
31.94 
Liver  
3.12  
3.12  
115.50  
115.50  
288.76  
288.76  
115.50 
115.50 
231.01 
231.01 
Lungs  
0.44  
0.43  
16.21  
16.01  
40.52  
40.02  
16.21 
16.01 
32.42 
32.02 
Osteogenic Cells  
1.90  
1.88  
70.36  
69.38  
175.90  
173.44  
70.36 
69.38 
140.72 
138.75 
Ovaries  
- 
0.43  
- 
15.82  
- 
39.54  
- 
15.82 
- 
31.63 
Pancreas  
0.45  
0.46  
16.55  
17.13  
41.36  
42.83  
16.54 
17.13 
33.09 
34.26 
Prostate  
0.42  
- 
15.66  
- 
39.16  
- 
15.66 
- 
31.33 
- 
Rectum  
0.43  
0.42  
16.05  
15.71  
40.13  
39.27  
16.05 
15.71 
32.10 
31.42 
Red Marrow  
0.62  
0.60  
22.91  
22.36  
57.27  
55.90  
22.91 
22.36 
45.82 
44.72 
Right colon  
0.44  
0.44  
16.45  
16.27  
41.13  
40.67  
16.45 
16.27 
32.90 
32.54 
Salivary Glands  
0.43  
0.42  
15.77  
15.53  
39.44  
38.82  
15.78 
15.53 
31.55 
31.06 
Small Intestine  
0.44  
0.43  
16.21  
16.01  
40.52  
40.04  
16.21 
16.02 
32.42 
32.03 
Spleen  
0.43  
0.43  
15.98  
15.89  
39.96  
39.71  
15.98 
15.88 
31.97 
31.77 
Stomach Wall  
0.44  
0.43  
16.25  
16.04  
40.62  
40.10  
16.25 
16.04 
32.50 
32.08 
Testes  
0.41  
- 
15.23  
- 
38.08  
- 
15.23 
- 
30.46 
- 
Thymus  
0.43  
0.43  
15.95  
15.73  
39.87  
39.31  
15.95 
15.72 
31.90 
31.45 
Thyroid  
0.42  
0.42  
15.69  
15.66  
39.22  
39.16  
15.69 
15.66 
31.38 
31.33 
Urinary Bladder Wall  
0.43  
0.42  
15.97  
15.61  
39.93  
39.02  
15.97 
15.61 
31.94 
31.22 
Uterus  
- 
0.43  
- 
15.85  
- 
39.62  
- 
15.85 
- 
31.70 
Total Body  
0.58 
0.58  
21.56 
21.55  
53.91 
53.88  
21.56 
21.55 
43.13 
43.10 
 


 
 
 
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1.3. 
Benefit-risk Assessment 
Medulloblastoma is a disease associated with significant mortality and morbidity for which there 
is a large unmet need for effective treatments with less neurocognitive toxicity. 
Lutetium-177 radiolabeled pharmaceuticals are currently approved (Lutathera) and being 
evaluated for treatment of multiple cancer indications, and 131I-omburtamab has known 
antitumor activity in animal models and in humans. Given the biodistribution, binding data, 
tumor uptake, and dosimetry data collected, it is reasonable to predict that 
177Lu-DTPA-omburtamab will have similar therapeutic potential and that 10 mCi is an 
acceptable starting dose in human (Section 3.3.3). In a rodent model, higher residence times in 
the brain are associated with greater tumor uptake with 177Lu-DTPA-omburtamab than with 131I-
omburtamab. However, for every organ, except liver, 177Lu-DTPA-omburtamab showed lower 
absorbed doses (estimated by scaling to effective doses of 0.19 versus 0.28 mGy/MBq in females 
weighing 60 kg) suggesting greater tolerance for higher doses when administered into the CNS 
compartment. Based on dosimetry, 10 mCi 131I-omburtamab administered to a 10-kg child would 
deliver 14.4 cGy to the brain while 10 mCi of 177Lu-DTPA-omburtamab would deliver 13.2 cGy. 
For comparison, data published by Kramer et al. 201523 indicated that the mean CSF absorbed 
dose in patients receiving 131I-omburtamab was 0.60 Gy/mCi (0.17 to 2.07 Gy/mCi) and was 
well tolerated, even for patients who had received prior external beam craniospinal irradiation (in 
some cases twice) and a boost to the primary site (i.e., in total up to 28 × 2 and 24 Gy, 
respectively). The clinical efficacy and safety of direct infusion of 131I-conjugated antibodies 
(i.e., anti-B7-H3 and anti-GD2) into the CSF via an indwelling catheter (e.g., Ommaya catheter) 
has been demonstrated (Section 1.2.1). The conjugation of lutetium-177 with omburtamab allows 
for selectively targeting B7-H3, shown to be expressed on tumor cells and minimally in normal 
tissues. Preliminary findings suggest acceptable safety of 131I-omburtamab against 
recurrent/relapsed medulloblastoma and of 131I-3F8 (anti-GD2) against medulloblastoma16. 
Taken together, the information supports the safety of intracerebroventricular administration of 
177Lu-DTPA-omburtamab for the treatment of recurrent or refractory medulloblastoma in 
pediatric and adolescent patients. 
For more detailed information about the known and expected benefits and risks and reasonably 
expected AEs of 177Lu-DTPA-omburtamab, please refer to the Investigator’s Brochure. 


 
 
 
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2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objectives 
The primary objective of Part 1 (dose-escalation phase) of this trial is to explore the tolerability 
of up to 2 cycles of intracerebroventricular 177Lu-DTPA-omburtamab treatment in pediatric and 
adolescent patients with recurrent or refractory medulloblastoma. The MTD and/or the RP2D for 
Part 2 will be determined. 
The primary objective of Part 2 (cohort-expansion phase) of this trial is to establish a safety 
profile of repeated dosing of 177Lu-DTPA-omburtamab in pediatric and adolescent patients with 
recurrent or refractory medulloblastoma. 
2.1.2. 
Secondary Objectives 
The secondary objectives of Part 1 (dose-escalation phase) are: 
• to evaluate the absorbed radiation doses to CSF and blood of 177Lu-DTPA-omburtamab 
after intracerebroventricular administration 
• to evaluate organ dosimetry of 177Lu-DTPA-omburtamab 
• to evaluate the PK profile of 177Lu-DTPA-omburtamab 
The secondary objectives of Part 2 (cohort-expansion phase) are: 
• to evaluate the PK profile of 177Lu-DTPA-omburtamab 
• to evaluate the investigator-assessed response 
• to evaluate the investigator-assessed DoR 
• to evaluate PFS 
• to evaluate OS. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoint of Part 1 is number of DLTs. 
The primary endpoint of Part 2 is number and severity of TEAEs. 


 
 
 
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2.2.2. 
Secondary Endpoints 
2.2.2.1. 
Part 1 
• Lutetium-177 activity in blood and CSF including derivation of best-fit uptake and/or 
clearance parameters (maximum count, elimination half-life) of time-activity curves and 
residence times (i.e., cumulated activity in µCi·h/g). 
• Whole-body, organ, blood, and CSF radiation dosimetry. 
• PK profile of 177Lu-DTPA-omburtamab in serum and CSF. 
2.2.2.2. 
Part 2 
• PK profile of 177Lu-DTPA-omburtamab in blood and CSF. 
• Response, as defined by the RAPNO criteria (as determined from MRI assessments, 
neurological examination, and CSF cytology). 
o ORR, calculated as the proportion of all evaluable patients achieving a response 
(PR or CR) as best overall response at end of Cycle 1 and Cycle 3, EOT Visit, and 
at each Follow-up Visit. 
• Investigator-assessed DoR, defined as the time from first response (CR or PR) to 
progression. 
• PFS, defined as the time from first treatment to date of leptomeningeal progression or 
death from any cause, whichever comes first. 
• OS defined as the time from first treatment to date of death. 
 


 
 
 
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3. INVESTIGATION PLAN 
3.1. 
Overall Trial Design and Plan Description 
This is a Phase I/II, open-label, safety and efficacy trial in pediatric and adolescent patients (3 to 
19 years) with recurrent or refractory medulloblastoma. The trial will be conducted in 2 parts: 
• Part 1: a dose-escalation phase with a 3+3 sequential-group design (except for the first dose 
level, which will consist of a single patient only) of five planned dose levels, and in which up 
to 25 patients will receive a maximum of two 5-week cycles of treatment with 
intracerebroventricular 177Lu-DTPA-omburtamab. Patients will receive a dosimetry dose in 
Week 1. Treatment doses will follow in Week 2 of the first cycle, and on the first day of 
Cycle 2. Adjustments to the dosing schedule will be accommodated on a patient-by-patient 
basis depending on the clinical condition of the patient. A Data Monitoring Committee 
(DMC) will review the safety data from previous dose levels and provide recommendations 
on whether dose escalation should continue. The MTD and/or RP2D will be determined. 
• Part 2: a cohort-expansion phase in which approximately 24 patients with recurrent or 
refractory medulloblastoma will receive a maximum of five cycles of treatment with 
intracerebroventricular 177Lu-DTPA-omburtamab at the RP2D determined in Part 1. 
Patients participating in Part 1 are not permitted to participate in Part 2. 
177Lu-DTPA-omburtamab will be administered via an indwelling intracerebroventricular access 
device (e.g., Ommaya reservoir). To avoid an additional procedure and burden to the patient, it 
can be considered to place the intracerebroventricular access device in connection with any 
tumor resection procedure that may be performed before entry into the trial. In this case, the 
informed consent form (ICF) must be signed before the tumor resection. 
Potential participants will be screened to assess their eligibility to enter the trial within 29 days 
prior to the first 177Lu-DTPA-omburtamab dose; however, signing the ICF and placement of the 
intracerebroventricular access device is allowed earlier than this. Final assessment of the 
eligibility criteria is done prior to first dose. In Part 1 Cycle 1, the dosimetry and treatment doses 
should be administered under controlled conditions with inpatient care for at least 24 hours after 
investigational medicinal product (IMP) administration. As a routine precaution, patients must be 
monitored during the infusion and with close observation for two hours after the infusion with 
readily available resuscitation equipment and access to emergency units. Staff should be 
qualified in resuscitation and the physician must be readily accessible for assistance during the 
day of the infusion. The infusion reservoir must be flushed with human serum albumin and CSF 
after each infusion. The patient must be observed regularly, and the patient can be discharged 
after 24 hours if no safety issues are observed. 
In Part 1 Cycle 2 and in Part 2 Cycle 1 to 5, patients can be treated in an outpatient setting or can 
be admitted as inpatients for infusions; however, all patients should be observed for a minimum 
of 2 hours after end of each infusion and can be released if no safety issues are observed. 


 
 
 
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An external DMC will be established to review the data and recommend upon dose escalation 
(Section 4.4). 
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. 
A detailed Schedule of Assessments is included in Appendix 3. 
3.1.1. 
Part 1 (Dose-escalation Phase) 
Part 1 will comprise 1 dose level consisting of a single patient followed by additional dose levels 
that use a 3+3 design (see Figure 1). 
In the first 5-week treatment cycle, a 5 mCi dosimetry dose will be administered on Day 1 and a 
treatment dose (according to the assigned dose level, as listed below) will be administered on 
Day 8 (see Figure 1 for a schematic of a treatment cycle in Part 1). However, if a patient 
experiences a Grade 3 or 4 non-hematologic AE (including an AE considered to be a Grade 3 or 
4 nervous system disorder) or other DLT after receiving the dosimetry infusion, the treatment 
dose will not be administered, and the patient will be discontinued from trial treatment. If the 
dosimetry dose of 5 mCi turns out to deliver a too low acquisition of radioactivity count (see 
Section 7.2), the dosimetry dose will be increased to 10 mCi for subsequent patients, at the 
sponsor’s discretion. 
A fixed mass dose of approximately 1 mg DTPA-omburtamab will be labelled with increasing 
radioactivity doses. This mass dose was selected based on the clinical experience with iodine-
labelled omburtamab, in which the same mass dose has been shown to be stable and to support 
clinical use in concentrations up to 100 mCi/ml. The planned radioactivity dose levels are: 
• Dose Level 1 (1+2 patients): 10 mCi 
• Dose Level 2 (3+3 design): 25 mCi 
• Dose Level 3 (3+3 design): 50 mCi 
• Dose Level 4 (3+3 design): 65 mCi 
• Dose Level 5 (3+3 design): 85 mCi. 
A maximum of 1 additional intermediate dose level may be added to the trial if warranted based 
on the findings from previous dose levels (see Section 3.1.1.1). 
Patients who are not discontinued from treatment (according to the criteria in Section 4.3.2) will 
be eligible for a second treatment cycle at the same dose administered in the first cycle. The 
second treatment cycle will not include a dosimetry dose but will instead consist of a treatment 
dose on Day 1 of the cycle. 


 
 
 
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In Part 1, the patients will receive a maximum of 2 treatment cycles. Patients who do not 
experience a DLT will be eligible for Cycle 2 dosing at the same dose administered in Cycle 1. 
Cycle 2 dosing will not include a dosimetry dose but only a treatment dose on the first day of the 
cycle. 
Patients will undergo monitoring for AEs; routine safety assessments (vital signs, clinical 
chemistry, hematology); whole-body planar gamma camera (and SPECT, if possible) scans for 
dosimetry measurements; CSF sampling for total protein, glucose, ctDNA (if the patient has 
given informed consent to this analysis), and cell count; blood and CSF draws for PK; and blood 
and CSF draws for ADA analysis and for potential culture (only in case of elevated body 
temperature); neurological assessments and radiographical investigation for evaluation of 
neurological AEs; and assessment of performance status (Lansky [<16 years] or Karnofsky [≥ 
16 years] scales). Efficacy assessments include brain and spine MRI, CSF sampling for cytology, 
and neurological examination. 
Patients will return for an EOT Visit 5 to 6 weeks after the last dose of 177Lu-DTPA-omburtamab 
to assess safety. End of Trial data will be entered to the eCRF. In addition, all patients who are 
dosed with 177Lu-DTPA-omburtamab will enter a post-trial monitoring period in which they will 
be regularly (e.g., yearly) followed up for secondary malignancies (see Section 7.4.5.3) for at 
least 10 years after end of trial, or until death, if sooner. This post-trial monitoring can be 
conducted by contacting the patient or the general practitioner, the referral site (if applicable), or 
by checking medical records or other sources. 


 
 
 
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Figure 1: 
Trial Design – Part 1 Cycle 1 
 
Abbreviations: DMC = Data Monitoring Committee; N = number of patients. 
* If the dosimetry dose of 5 mCi turns out to deliver a too low acquisition of radioactivity count (see Section 7.2), the dosimetry 
dose will be increased to 10 mCi for subsequent patients, at the sponsor’s discretion. 
After Cycle 1, the treatment dose will be administered on Day 1 (Week 1) of the cycle. 
3.1.1.1. 
Dose Escalation and Stopping Rules 
As detailed in Section 4.4, a DMC will be formed to independently review the safety data from 
previous dose level(s) and make recommendations on whether dose escalation should continue. 
Based on the DMC recommendation, following review by the sponsor, the doses may be 
escalated or reduced and may be lower than the starting dose. 
The starting treatment dose of lutetium-177 in Part 1 will be 10 mCi. Planned dose escalations 
(with a 3+3 design) are 25, 50, 65, and 85 mCi. Up to 1 additional dose level may be recruited to 
investigate an intermediate dose of investigational medicinal product (IMP), if warranted based 
on the safety findings from previous dose level(s). The requirement for an additional dose level 
will be agreed with the sponsor in consultation with the DMC and will be documented in the 


 
 
 
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Trial Master File. Dosing at any additional dose level will be subject to the same dose-escalation 
rules as for the planned dose levels, as described below. The maximum planned dose is 85 mCi. 
Initially, 1 patient will be allocated to Dose Level 1 and subsequent dose escalations will be 
conducted using a classic 3+3 design. If no treatment-related Grade 3 or higher AEs are observed 
in the first patient, escalation from Dose Level 1 to Dose Level 2 will proceed with 3 patients 
being allocated to Dose Level 2, after DMC evaluation and recommendation. If a Grade 3 or 
higher treatment-related AE occurs, a further 2 patients will be enrolled at Dose Level 1.  
The DMC will receive all SAE on an ongoing basis. The DMC will make the final assessment of 
whether the event qualifies as a DLT. 
The first enrolled patient in each dose level will be observed for a minimum of two weeks after 
the treatment dose before subsequent patients will be dosed at the same dose. During the two 
weeks of observation, safety surveillance will focus on DLTs (including myelosuppression). If a 
DLT is observed in the first patient, a second patient will be included and observed for a 
minimum of two weeks after the treatment dose before the third patient is included. If no DLT is 
observed in the first patient, two subsequent patients will receive the treatment dose, but at least 
two days apart. 
Escalation and de-escalation decisions will then be determined by the number of DLTs (as 
defined in Section 3.1.1.2) observed during Cycle 1 and the number of patients evaluable for 
DLTs, as follows. 
• If no DLT is observed in the initial 3-patients at each dose level, 3 patients will be 
enrolled into and dosed in the next dose level. Dose escalation will continue in this 
manner until a DLT is observed or the highest planned dose level has been completed. 
• If 1 DLT is observed in the initial 3-patients at each dose level, an additional 3 patients 
will (if recommended by the DMC) be enrolled at that dose level. 
o If no further DLTs are observed among the 3 additional patients (i.e., the total 
number of DLTs in the 6-patient dose level is 1), dose escalation will proceed 
with 3 patients being enrolled into the next dose level. 
o If ≥1 DLT is observed among the 3 additional patients (i.e., the total number of 
DLTs in the 6-patient dose level is ≥2), dose escalation will be stopped by the 
sponsor, upon consultation with the DMC. 
▪ If warranted, dosing may proceed with 3 patients being enrolled into an 
additional dose level that is intermediate between that of the current and 
the previous dose level. If dose escalation is stopped, the dose level 
immediately below that at which the DLTs were observed will be 
considered the MTD. 
• If 2 or 3 DLTs are observed in the initial 3-patients at each dose level, dose escalation 
will stop. If warranted, dosing may proceed with 3 patients being enrolled into an 


 
 
 
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additional dose level that is intermediate between that of the current and the previous 
dose level. Otherwise, the dose level immediately below that at which the DLTs were 
observed will be considered the MTD. No further patients will be enrolled into the 
current dose level.  
If only 3 patients were treated at the dose level below the intolerable dose 3 more patients will be 
recruited at that dose level to ensure that no more than 1 DLT occurs out of 6 patients. 
Doses will be escalated until: 
• The highest planned dose level has been found to be tolerated (i.e., stopping criteria were 
not met), or 
• A toxic dose level has been identified. 
When the dose-escalation phase of the trial has stopped due to toxicity, the MTD is identified as 
the highest non-toxic dose level (see Section 3.1.2). 
3.1.1.2. 
Definition of Dose-limiting Toxicity 
DLTs are defined as AEs (graded according to CTCAE version 5) occurring within 5 weeks after 
first IMP administration in Cycle 1 of Part 1 and that are considered possibly or probably related 
to IMP and meet any of the following criteria: 
• Grade 4 myelosuppression (i.e., anemia, thrombocytopenia, or neutropenia) lasting more 
than 1 week, or more than 3 weeks following intervention (e.g., blood transfusion or 
granulocyte-macrophage colony-stimulating factor [GM-CSF]) 
• Any other Grade 4 hematological AE 
• Grade ≥3 thrombocytopenia associated with bleeding 
• Grade ≥3 febrile neutropenia (i.e., fever concurrent with neutropenia) lasting more than 
5 days despite use of growth factors and antibiotics 
• Grade 4 infusion-related reactions/anaphylaxis 
• Grade 3 infusion-related reactions (excluding fever and Grade 3 abnormal laboratory 
values) that do not resolve to Grade ≤1 within 5 days of onset. 
• Any non-hematological Grade ≥3 AE that is not listed in the list of exemptions below 
DLTs must be entered onto the clinical AE report form and be reported from site to sponsor 
within 24 hours of the investigator’s first knowledge of the event (see Section 7.4.5.2). If any of 
the side effects mentioned in the DLT definitions occur during Cycle 2 in Part 1, these will be 
discussed at the first upcoming preplanned DMC meeting, and the Sponsor Safety Committee 
will evaluate the DMC recommendations for further dosing. 


 
 
 
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Non-hematological Exemptions: 
The following events are expected due to IMP and administration route and, if self-limiting and 
resolved within a short timeframe, will not constitute DLTs but should be reported as AEs/SAEs 
according to reporting guidelines: 
• Grade 3 laboratory values considered not clinically significant 
• Grade 3 fever without neutropenia (lasting less than 5 days) 
• Grade 3 headache or vomiting for less than 48 hours (with adequate supportive care). 
• Grade 3 nausea and fatigue, persisting for less than 7 days (with adequate supportive care). 
3.1.2. 
Maximum Tolerated Dose and Recommended Phase II Dose Definition 
The MTD is identified as the highest non-toxic dose level on which 6 patients have been treated, 
i.e., the dose level immediately below that at which 2 or more DLTs were observed and dose 
escalation was stopped. If only 3 patients were treated at the immediately lower dose level, 
3 additional patients will be recruited at this dose level to ensure that no more than 1 DLT occurs 
out of 6 patients. 
The RP2D will be defined as the highest tolerable dose, MTD, or a lower dose. For example, the 
RP2D may be lower than the MTD if accumulated toxicity over 2 cycles at the MTD is judged or 
proved to be non-tolerable. 
3.1.3. 
Part 2 (Cohort-expansion Phase) 
Part 2 will be conducted in approximately 24 patients with medulloblastoma recurrent or 
refractory to frontline therapy and, if they have recurrent disease, they must have received 
second-line chemotherapy for progressive disease (PD). Patients with a maximum of 
1 recurrence of disease will be included. 
Patients will receive 177Lu-DTPA-omburtamab at the RP2D determined in Part 1. 
177Lu-DTPA-omburtamab will be administered via an indwelling intracerebroventricular access 
device (e.g., Ommaya catheter) on Day 1 of each treatment cycle. Patients who are not 
discontinued from treatment (according to the criteria in Section 4.3.2) will be eligible for 
another treatment cycle at the same dose administered in the first cycle, up to a maximum of 5 
treatment cycles per patient. The expected cumulated absorbed dose calculated based on the 
dosimetry data in the escalation part will assist in guiding (by the DMC) the maximum number 
of cycles feasible in the expansion phase. 
Patients can be treated in an outpatient setting or can be admitted as inpatients for infusions; 
however, all patients should be observed for a minimum of 2 hours after end of each infusion. 


 
 
 
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Patients will undergo monitoring for AEs; routine safety assessments (vital signs, clinical 
chemistry, hematology); CSF sampling for total protein, glucose, ctDNA (if the patient has given 
informed consent to this analysis), and cell count; blood and CSF draws for PK; and blood and 
CSF draws for potential culture (only in case of elevated body temperature); neurological 
assessments and radiographical investigation for evaluation of neurological AEs; assessment of 
performance status (Lansky [<16 years] or Karnofsky [≥16 years] scales). CSF and blood will be 
drawn for PK and ADA analysis. Efficacy assessments include brain and spine MRI, CSF 
cytology, and neurological examination. 
Patients will return for an EOT Visit 5 to 6 weeks after the last dose and for regular Follow-up 
Visits up to 104 weeks after the last infusion of 177Lu-DTPA-omburtamab to assess safety, 
efficacy, secondary malignancies, and long-term survival. In addition, all patients who are dosed 
with 177Lu-DTPA-omburtamab will be regularly monitored for secondary malignancies (see 
Section 7.4.5.3) for at least 10 years after end of trial, or until death, if sooner. This post-trial 
monitoring can be conducted by contacting the patient or the general practitioner, the referral site 
(if applicable), or by checking medical records or other sources. 
3.2. 
Discussion of Trial Design 
The sequential-group, escalating-dose design of Part 1 will ensure that safety and tolerability are 
assessed at lower dose levels before progressing to dosing at higher doses. The 3+3 
dose-escalation algorithm employed will prevent unnecessary exposure to the trial drug by 
allowing dose-escalation decisions to be made based on smaller, 3-patient dose levels in the 
absence of DLTs, while enabling a dose level to be expanded to 6 patients where necessary to 
provide more information on the incidence of DLTs. The first enrolled patient at each dose level 
will be observed for a minimum of two weeks after the treatment dose before subsequent patients 
will be dosed  
As there is relevant and substantial clinical experience from the comparable drug 131I-
omburtamab (see Section 1.1 and Section 1.2.1), this enrolment strategy is considered 
appropriate for this trial. 
Patients will be closely monitored for safety and efficacy throughout the treatment periods and 
up to 6 weeks (Part 1) and 104 weeks (Part 2) after the last dose. Considering the baseline 
advanced disease, and that most if not all patients have received high-dose cranial spinal 
irradiation prior to trial inclusion, 104 weeks in Part 2 appears to be a relevant follow-up 
duration in these advanced cancer patients with limited survival. A DMC will monitor safety 
data during Part 1 and make recommendations on dose escalation. All patients will be 
additionally monitored for secondary malignancies throughout the trial and for at least 10 years 
after end of trial, or until death, if sooner. 
The trial will be conducted in 2 parts. The dose-escalation phase (Part 1) of the trial will be 
conducted prior to starting the cohort-expansion phase (Part 2) so that the safety data from Part 1 
may inform the RP2D for Part 2. 
For the first treatment dose level at 10 mCi, a single patient will be dosed at an anticipated low 
first-in-human starting dose level. Given the myelosuppression observed after IV injection in our 


 
 
 
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mouse studies, a 10 mCi starting dose level is proposed which corresponds to an 8-fold safety 
margin over the highest no-adverse-events dose administered IV in the mice (200 µCi 
corresponds to 80 mCi in a 10-kg child). As limited antitumorigenic effect is expected at the 10 
mCi dose, only 1 patient is planned to receive this dose level if no Grade 3 or higher AEs are 
observed in the first patient. 
The DMC can recommend to stop the trial based on treatment-emergent safety findings (see 
Section 4.4.1). In addition, a planned cohort-expansion phase (Part 2) will enable the RP2D to be 
studied in a larger number of patients. 
A maximum of 2 cycles of treatment will be permitted in Part 1, during which the RP2D to be 
used in Part 2 will be determined based on dose-escalation findings from Part 1, primarily based 
on the overall safety and tolerability findings across both cycles in Part 1. Once the RP2D has 
been selected, patients in Part 2 of the trial will be eligible for up to 5 cycles of treatment. 
There is no effective salvage treatment for patients with recurrent medulloblastoma, and the 
prognosis for these patients is poor. With preliminary data suggesting a potential application of 
omburtamab-based radioimmunotherapy in medulloblastoma patients, an open-label design has 
been chosen and found to be ethically defendable. Patients with WNT molecular subgroup of 
medulloblastoma are excluded because Wnt+ recurrent tumors are sensitive to systemic 
chemotherapy with excellent prognosis9. 
As medulloblastoma is primarily a disease of childhood, only pediatric or adolescent patients (up 
to 19 years of age) will be recruited. Patients below the age of 3 years will be excluded because 
standard-of-care therapy for this age group differs from that for older patients. Patients in both 
parts must be recurrent or refractory to frontline therapy. In Part 2 only, patients who have 
recurrent disease must have received second-line chemotherapy for progressive disease. Patients 
with 2 or more recurrences of medulloblastoma are expected to have short OS times, which may 
compromise the ability to assess the safety of 177Lu-DTPA-omburtamab for up to five 5-week 
cycles in the expansion phase; therefore, such patients will not be eligible for Part 2. Whether the 
patient has adequate CSF flow for intrathecal therapy will be determined by Ommaya 
patency/CSF flow assessment as outlined in Appendix 7. Patients with obstructive or 
symptomatic communicating hydrocephalus are not eligible for Part 1 or Part 2. 
3.3. 
Selection of Doses in the Trial 
3.3.1. 
Selection of DTPA-omburtamab Mass Dose 
All patients dosed in this trial will receive lutetium-177 conjugated to a fixed mass dose of 
approximately 1 mg DTPA-omburtamab. A mass dose of 1 mg omburtamab has been used and 
found to be safe in a trial with >170 patients treated with 131I-omburtamab. It is expected that a 
specific activity of 100 mCi/mg DTPA-omburtamab will be achievable. The final mass will be 
determined based on the specific activity of the supplied lutetium-177 (mCi/mg), the age and 
decay of the isotope, and the efficiency of the labeling process. 
The monoclonal antibody in 177Lu-DTPA-omburtamab is identical to that used in 
131I-omburtamab and the radioimmunotherapy is to be administered via the same route, i.e., an 


 
 
 
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indwelling device directly into the third or lateral ventricle. Hence, no new toxicities due to the 
monoclonal antibody or dose route are anticipated. 
The nonclinical and clinical data package supporting this trial consists of 131I-omburtamab 
nonclinical data and previous human experience, as well as nonclinical safety data using 
177Lu-DTPA-omburtamab and DTPA-conjugated antibody product (DTPA-omburtamab). 
DTPA-omburtamab has been tested in a 28-day intracerebroventricular toxicity study in 
cynomolgus monkeys. DTPA-omburtamab, when administered as a single dose up to 1.5 mg/kg 
to juvenile cynomolgus monkeys, was well tolerated over the study period. All findings were 
considered unrelated to the test article and non-adverse. The NOAEL for DTPA-omburtamab in 
monkey was determined to be 1.5 mg/kg. 
At the NOAEL following a single infusion of DTPA-omburtamab to juvenile cynomolgus 
monkeys, safety margins for a proposed total mass dose of up to 1 mg DTPA-omburtamab are 
30-, 60-, and 75-fold in pediatric, adolescent, and adult humans, respectively (for more details, 
please see the Investigator’s Brochure). 
3.3.2. 
Selection of Lutetium-177 Dose for Organ Dosimetry  
The dosimetry dose (Day 1 of Cycle 1, in Part 1 only) will be 5 mCi of lutetium-177. This is 
considered sufficient to deliver quality whole-body planar gamma camera (and SPECT, if 
possible) scans. If the dosimetry dose of 5 mCi turns out to deliver a too low acquisition of 
radioactivity count (see Section 7.2), the dosimetry dose will be increased to 10 mCi for 
subsequent patients, at the sponsor’s discretion. 
3.3.3. 
Selection of Lutetium-177 Treatment Dose 
Lutetium-177 and iodine-131 predominantly emit β-radiation with a comparable half-life. From a 
pure radionuclide perspective, and considering small-volume tumors and minimal residual 
disease, lutetium-177 is expected to generate two thirds of the same β-ionizing radiation to the 
tumor compared to iodine-131 (Table 2). For larger tumors and normal organs, lutetium-177 is 
conservatively estimated to generate approximately 50% of the decay of iodine-131. The 
proposed escalation dose levels for 177Lu-DTPA-omburtamab take into account the energies of 
the pure radionuclide, the clinical data with 131I-omburtamab, and preclinical dosimetry 
estimations for a pediatric patient. Dosimetry calculations from the biodistribution of 
177Lu-DTPA-omburtamab given intrathecally to rats predict lower absorbed doses to all organs 
except the liver and lower effective doses than 131I-omburtamab. However, given the 
myelosuppression observed in our mouse studies, a 10 mCi starting dose level is proposed which 
corresponds to an 8-fold safety margin over the highest no-adverse-events dose (200 µCi 
corresponds to 80 mCi in a 10-kg child). 


 
 
 
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Table 2: 
Properties of Lutetium-177 and Iodine-131 
Property 
Lutetium-177 
Iodine-131 
Half-life (days) 
6.65 
8.03 
Main beta energies (average) (keV) 
134 
97 and 192 
Beta dose/decay (MeV/Bq-s) 
0.134 
0.182 
X rays intensity >5% (keV) 
None 
29-33 
Gamma energies (keV) 
113; 208 
284; 364 
Auger cascade total energy (keV) 
0.67 
0.37 
Chemistry 
Lanthanide, chelates 
Halogen, covalently bound 
Clinical safety data of intracerebroventricular administration of 131I-omburtamab are derived 
from clinical studies. The monoclonal antibody (omburtamab) used for lutetium-177 labeling is 
identical to that used for iodine-131 labeling. The radiopharmaceutical is to be administered via 
the same route (intracerebroventricular administration) via an indwelling device directly into the 
third or lateral ventricle. Hence, no new toxicities, either due to the monoclonal antibody or to 
the administration route, are anticipated. A single-center clinical trial at Memorial Sloan 
Kettering Cancer Center and a multicenter, international clinical trial are ongoing under the 
governance of Y-mAbs, where more than 200 patients have received the 131I-labeled 
omburtamab via intracerebroventricular administration. Most patients had neuroblastoma 
CNS/leptomeningeal metastases (n = 109); however, 23 patients had the diagnosis 
refractory/recurrent medulloblastoma. Overall, safety profiles were not markedly different in 
these patients as compared to the general exposed patient population. In these studies, the doses 
were reduced by 50% for patients ≤12 months old, and by 33% for patients >12 to <36 months 
old. However, based on the safety findings in the escalation phase, a flat treatment dose of 50 
mCi 131I-omburtamab was administered to patients aged 3 years and older in the expansion 
phase. As treatment with 131I-omburtamab in the 03-133 trial appeared to be safe with 
manageable acute hematological toxicities, a similar approach will be used in the current trial 
with 177Lu-DTPA-omburtamab, which does not include patients under the age of 3 years. 


 
 
 
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4. SELECTION OF TRIAL POPULATION 
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted. The World Health Organization 2016 
classification are detailed in Louis et al. 201626. 
4.1. 
Inclusion Criteria 
Patients must satisfy all of the following criteria at the Screening Visit, unless otherwise stated: 
1. Histologically confirmed diagnosis of medulloblastoma. 
2. SHH, Group 3, or Group 4 according to World Health Organization 2016 classification. 
3. Recurrent or refractory to frontline therapy, defined as: 
a. For Part 1 only: Recurrent (maximum of 2 recurrences) or refractory to frontline 
therapy. Prior frontline or second-line therapy may involve surgery, craniospinal 
irradiation, stereotactic radiosurgery, and multi-agent chemotherapy regimens. 
b. For Part 2 only: Recurrent (maximum of 1 recurrence) or refractory to frontline 
therapy. Patients with recurrent disease must have received second-line 
chemotherapy for progressive disease. Prior frontline or second-line therapy may 
involve surgery, craniospinal irradiation, stereotactic radiosurgery, and multi-
agent chemotherapy regimens. 
4. Have refractory disease, focal or multifocal recurrent disease, or pure leptomeningeal 
disease. Cytological or radiographic remission is allowed; however, not simultaneously. 
5. Performance status score of 50 to 100, both inclusive, on the Lansky [<16 years] or 
Karnofsky [≥16 years] scales. 
6. Aged 3 to 19 years, both inclusive, at the time of the first planned dose of trial treatment. 
7. Life expectancy of at least 3 months, as judged by the investigator. 
8. Acceptable hematological status prior to first dosing (hematological support is allowed if 
administered at least 1 week before administration of 177Lu-DTPA-omburtamab), defined 
as: 
a. Hemoglobin ≥8 g/dL 
b. White blood cell count ≥1000/µL 
c. Absolute neutrophil count ≥1000/µL 
d. Platelet count ≥75 000/µL. 


 
 
 
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9. Acceptable liver function prior to first dosing, defined as: 
a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤5 × upper limit of normal (ULN) 
b. Bilirubin ≤1.5 × ULN. 
10. Acceptable kidney function prior to first dosing, defined as: 
a. Estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2, calculated by 
the 2009 revised Bedside Schwartz Equation (Appendix 4). 
11. Written informed consent from legal guardian(s) and/or child obtained in accordance 
with local regulations. Pediatric patients must provide assent as required by local 
regulations. 
4.2. 
Exclusion Criteria 
Patients will be excluded from the trial if they satisfy any of the following criteria at the 
Screening Visit unless otherwise stated: 
1. Obstructive or symptomatic communicating hydrocephalus as determined by Ommaya 
patency/CSF flow assessment. 
2. Any tumor lesion measuring >15 mm in the smallest diameter. 
3. Ventriculoperitoneal (VP) shunts without programmable valves. Ventriculo-atrial or 
ventriculo-pleural shunts. 
4. Grade 4 nervous system disorder. Stable neurological deficits due to brain tumor or 
surgery and hearing loss are allowed. 
5. Uncontrolled life-threatening infection. 
6. Received radiation therapy (focal or cranio-spinal irradiation), systemic or intrathecal 
cytotoxic chemotherapy, or immunotherapy (including monoclonal antibodies; 
corticosteroids not included) less than 3 weeks prior to the Dosimetry Dose (or until 
recovery from clinically significant adverse events). Received nitrosoureas less than 6 
weeks prior to the Dosimetry Dose. 
7. Received any prior anti-B7-H3 treatment. 
8. Non-hematologic organ toxicity Grade 3 or above; specifically, any renal, cardiac, 
hepatic, pulmonary, and gastrointestinal system toxicity. 
9. Other significant disease or condition that in the investigator's opinion would exclude the 
patient from the trial. 


 
 
 
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10. Females of childbearing potential (as defined in Appendix 5) who are pregnant, breast 
feeding, intend to become pregnant, or are not using highly effective contraceptive 
methods as defined in Appendix 5 or males who are not using highly effective 
contraceptive methods as defined in Appendix 5. 
4.3. 
Discontinuation Criteria 
4.3.1. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical trial but do not 
meet all eligibility criteria and are not dosed in the trial. A minimal set of information is required 
to ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demographics, reason for screen failure, eligibility 
criteria, and any SAEs. 
Final assessment of the eligibility criteria is done prior to first dose. Patients who do not meet the 
criteria for participation in this trial may be rescreened. 
4.3.2. 
End of Treatment 
The end of treatment (EOT) is defined as the day the last dose of 177Lu-DTPA-omburtamab is 
received. The EOT Visit should occur 5 to 6 weeks after the last dose, whether this is a 
premature treatment discontinuation or treatment completion. 
4.3.2.1. 
Discontinuation of Trial Treatment 
Patients may withdraw from the trial treatment at any time at his/her own request or may be 
discontinued from trial treatment at any time at the discretion of the investigator for safety, 
behavioral, or administrative reasons. If the patient withdraws consent for disclosure of future 
information, the sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. Additionally, patients may request destruction of any samples taken and 
not tested, and the investigator must document this in the site trial records. Refer to the Schedule 
of Assessments (Appendix 3) for data to be collected at the time of treatment discontinuation 
(EOT visit) and follow-up and for any further evaluations that need to be completed. 
The patient must be permanently discontinued from treatment if any of the following occur: 
• After receiving the dosimetry dose only, Grade 3 or 4 non-hematologic AE (including an 
AE considered to be a Grade 3 or 4 nervous system disorder; see Section 7.1.5)  
• DLT occurring before the end of Cycle 1 in each dose level in Part 1 
• Grade 4 infusion-related reaction/anaphylaxis, or Grade 3 infusion-related reactions 
(excluding fever and Grade 3 abnormal laboratory values) that do not resolve to Grade ≤ 
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• Grade 4 neurological AE 
• Development of obstructive or symptomatic communicating hydrocephalus 
• Grade 4 treatment-related AEs (excluding infusion-related fever, and non–life-threatening 
laboratory values) 
• Disease progression before Cycle 2 in Part 1 or Cycle 5 in Part 2 
• Any medical or safety reason, in the opinion of the investigator or sponsor 
• Chemical meningitis (symptoms of clinical meningitis but cultures for infectious agents 
were negative) in which either: a) event is non-responsive to IV steroids, b) radiologic or 
operative intervention was indicated, or c) focal neurologic deficit was present 
• The patient receives prohibited therapy and/or undergoes procedures during the trial that, 
in the opinion of the investigator, warrant treatment discontinuation 
• Patient decision 
• Pregnancy. 
A patient who is discontinued from treatment, but for whom consent is not withdrawn, shall 
continue to be followed for the entire trial period. 
4.3.2.2. 
Completion of Trial Treatment 
Patients will be regarded as having completed the trial treatment if they received 2 cycles of IMP 
in Part 1 or up to 5 cycles in Part 2. 
4.3.3. 
End of Trial 
The end of the trial is defined as the date the last patient completes the last Visit or the date of 
death of the last patient, whichever comes first. 
4.3.3.1. 
Discontinuation from Trial 
A patient should be discontinued from the trial if: 
• The patient or legal guardian withdraws informed consent for any reason. 
4.3.3.2. 
Completion of Trial 
Patients will be regarded as having completed the trial if they received all the planned cycles and 
attend the EOT visit (Part 1) and follow-up period (Part 2) until the end of trial. 


 
 
 
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4.3.3.3. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the trial site. 
If a patient fails to return to the clinic for a required trial visit, the site must attempt to contact the 
patient and reschedule the missed visit as soon as possible, counsel the patient on the importance 
of maintaining the assigned visit schedule, and ascertain whether or not the patient wishes to 
and/or should continue in the trial. 
In cases in which the patient is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record. 
Should the patient continue to be unreachable, he/she will be considered to have discontinued 
from the trial with a primary reason of lost to follow-up. 
4.3.4. 
Replacement Procedures 
Patients in Part 1, who discontinue treatment after the Dosimetry dose (i.e., prior to the first 
treatment dose), will be replaced. Patients in Part 1, who are discontinued during the DLT 
reporting period for reasons not related to IMP may be replaced following discussion between 
the investigator and the sponsor. If a patient is discontinued as a result of AEs considered to be 
related to the IMP, the DMC will be consulted as to whether the patient should be replaced. 
4.3.5. 
Follow-up of Patients Discontinued from Trial Treatment or from the Trial 
A patient discontinued from treatment should as soon as possible attend the EOT Visit, and be 
followed at all scheduled Follow-up Visits (Part 2) and for post-trial monitoring of secondary 
malignancies at least 10 years after end of trial, or until death, if sooner (Appendix 3). 
The investigator should: 
• Ensure the safety of the patient. Follow any SAE and Grade 3 or higher non-serious AEs 
that are considered treatment related and still ongoing after withdrawal until the event has 
been resolved or the investigator assesses the SAE as being chronic or stable. 
• Offer the best possible treatment outside of the trial based on clinical practice at the 
investigational site. 
4.4. 
Data Monitoring Committee 
An external DMC will be established to assure patient safety and will function independently of 
all other individuals associated with the conduct of the trial, including site investigators 
participating in the trial. The DMC will consist of a minimum of 2 physicians whose expertise 
covers relevant specialties. 


 
 
 
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During the conduct of Part 1, following completion of the first 5-week treatment cycle (Cycle 1) 
for the last patient in each dose level, the DMC will evaluate available safety information and 
recommend trial continuation or termination. If continuation is recommended, the DMC will 
recommend to the sponsor whether the dose should be escalated, de-escalated, or held at the 
same level. In the absence of DLT during the first two weeks of the first patient enrolled in each 
dose level, the enrollment to the dose level will continue without the need of feedback from the 
DMC. 
If any of the side effects mentioned in the DLT definitions (Section 3.1.1.2) occurs during 
Cycle 2 in Part 1, these will be discussed at the first upcoming preplanned DMC meeting, and 
the internal Sponsor Safety Committee will evaluate the external DMC recommendations for 
further dosing. During Part 1 and until the DMC meeting in Part 2, the sponsor will share with 
the DMC all SAEs occurring during the trial and an unplanned DMC meeting can be held at the 
request of either the DMC or the Sponsor Safety Committee. 
The DMC will evaluate the totality of cumulated absorbed dose calculated based on the 
dosimetry data from Part 1, and all available DLTs and other non-DLT toxicities from cycles 1 
and 2 in all patients dosed in Part 1, to guide whether the maximum of five cycles is feasible in 
Part 2. 
During the conduct of Part 2, an additional DMC meeting will be held when the eighth patient 
has completed dosing in Cycle 1 to evaluate whether the trial should be modified, stopped, or 
continue unchanged. The Sponsor Safety Committee will evaluate the recommendations from the 
DMC after each DMC meeting. Any significant finding/recommendation from the DMC and 
endorsed by the Sponsor Safety Committee will be communicated to the regulatory authorities 
and Institutional Review Board (IRB)/Ethics Committee (EC) as appropriate, and to the sites. 
Responsibilities, procedures, content of the DMC packages, and workflow of the DMC are 
specified in the DMC Charter. 
4.4.1. 
Trial Stopping Rules 
If any of the following occur, administration of the IMP will be stopped, and recruitment will be 
put on hold at least temporarily until DMC feedback is received to confirm if the trial can 
continue: 
1. AEs or frequency of AEs that, in the judgment of the sponsor, are deemed to warrant 
immediate review by the DMC 
2. Any other safety finding assessed as related to 177Lu-DTPA-omburtamab that, in the 
opinion of the DMC or sponsor, contraindicates further dosing of trial patients. 
If any of these occur, an immediate cumulative review of safety data with focus on the AE in 
question will be conducted by the DMC to determine whether dosing and further recruitment 
should be resumed, the protocol modified, or whether the trial should be discontinued. Review 
and approval of the Sponsor Safety Committee and approval by the regulatory authorities is 


 
 
 
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required for resumption of the trial, should the trial be interrupted due to one of the above-
mentioned safety findings. 
Any patients who have received the IMP and are currently in the trial at the time trial stopping 
criteria are met will continue to be followed by the investigator for safety. 
4.5. 
Trial Termination 
The sponsor reserves the right to close a trial site or terminate the trial at any time for any reason 
at the sole discretion of the sponsor. Trial sites will be closed upon trial completion. A trial site is 
considered closed when all required documents and trial supplies have been collected and a trial 
site closure visit has been performed. Reasons for trial termination may include, but are not 
limited to: 
• Related AEs not previously reported with any similar investigational trial treatment with 
respect to their nature, severity, and/or duration 
• Increased frequency and/or severity and/or duration of known, anticipated, or previously 
reported AEs or pre-existing conditions 
• Medical or ethical reasons affecting the continued performance of the trial 
• Difficulties in the recruitment of patients 
• Cancellation of drug development. 
The investigator may initiate trial site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. Reasons for the early closure of 
a trial site by the sponsor or investigator may include, but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/EC or 
local regulatory authorities, the sponsor's procedures, or Good Clinical Practice (GCP) 
guidelines 
• Inadequate recruitment of participants by the investigator. 


 
 
 
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5. TRIAL TREATMENTS 
5.1. 
Treatments Administered 
Omburtamab is a murine IgG1 monoclonal antibody that recognizes tumor-associated antigen 
B7-H3. DTPA-omburtamab will be radiolabeled with lutetium-177 at a dedicated GMP facility. 
177Lu-DTPA-omburtamab is a clear, colorless to slightly yellow, and particle free solution. 
177Lu-DTPA-omburtamab will be administered via an indwelling intracerebroventricular access 
device (e.g., Ommaya catheter). The infusion reservoir must be flushed with human serum 
albumin (HSA) and autologous CSF after each infusion. For detailed instructions, please refer to 
the IMP manual. For all infusions, emergency support for anaphylaxis must be readily available, 
including epinephrine, diphenhydramine, hydrocortisone, and/or dexamethasone at the bedside. 
In Part 1 Cycle 1, the dosimetry and treatment doses should be administered under controlled 
conditions with inpatient care for at least 24 hours after IMP administration. As a routine 
precaution, patients must be monitored during the infusion and with close observation for two 
hours after the infusion with readily available resuscitation equipment and access to emergency 
units. Staff should be qualified in resuscitation and the physician must be readily accessible for 
assistance during the day of the infusion. The infusion reservoir must be flushed with human 
serum albumin and CSF after each infusion. The patient must be observed regularly, and the 
patient can be discharged after 24 hours if no safety issues are observed. 
In Part 1 Cycle 2 and in Part 2, patients can be treated in an outpatient setting or can be admitted 
as inpatients for infusions; however, all patients should be observed for a minimum of 2 hours 
after the end of infusion and can be released if no safety issues are observed. 
For radiation safety, see Section 5.2.2. 
In Part 1 only, for the first 5-week treatment cycle, a 5 mCi dosimetry dose will be administered 
on Day 1 and a treatment dose will be administered on Day 8. However, if a patient experiences 
a Grade 3 or 4 non-hematologic AE or other DLT after receiving the dosimetry dose, the 
treatment dose will not be administered, and the patient will be discontinued from trial treatment. 
If the dosimetry dose of 5 mCi turns out to deliver a too low acquisition of radioactivity count 
(see Section 7.2), the dosimetry dose may be increased to 10 mCi for subsequent patients, at the 
sponsor’s discretion. In the second treatment cycle of Part 1 (if applicable) and throughout 
Part 2, a treatment cycle will consist of a treatment dose on the first day of each cycle. Patients 
who are not discontinued from treatment will be eligible for treatment at the same dose 
administered in the first cycle, up to a maximum of 2 cycles in Part 1 and 5 cycles in Part 2. 
5.2. 
Preparation, Storage, Handling, and Accountability 
Only patients enrolled in the trial may receive trial treatment and only authorized site staff may 
supply or administer trial treatment. The investigator, institution, or the head of the medical 
institution (where applicable) is responsible for trial treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). There is no 
long-term storage of IMP at site, and the IMP will be prepared on demand when a patient is 


 
 
 
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found to be eligible for the trial and when further cycles (if applicable) are scheduled. The 
utensils used to ship, prepare, and administer the IMP will be radioactive and should be 
destroyed according to local regulations. The destruction can be performed without sponsor 
approval but only after accountability (see Section 5.5) has been conducted. 
Doses must be aseptically prepared at a designated radiopharmacy by withdrawal of 177Lu-
DTPA-omburtamab from the single-use vial into a sterile syringe to the target activity confirmed 
by dose calibration. 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. 
At each clinical site, the actual 177Lu-DTPA-omburtamab dose administered should be assayed 
immediately prior to administration to verify that the prescribed activity and the activity actually 
administered agree within ±10% (see Table 3). The amount of radioactivity infused in patients 
should be assessed by measuring radioactivity of the infusion syringe before and after 
177Lu-DTPA-omburtamab infusion into the indwelling intracerebroventricular access device 
(e.g., Ommaya catheter) and subtracting the post infusion count from the pre infusion count. The 
radiolabeled 177Lu-DTPA-omburtamab is administered via a catheter with an inline filter. 
Table 3: 
Accepted Activity Ranges for Dosimetry and Treatment Doses 
 
Nominal Dose (Acceptable Range) of Lutetium-177 
Dosimetry Dose (Day 1, Cycle 1, prior to all 
treatment dose levels in Part 1) 
5 (4.5 – 5.5) mCi 
Dose Level 1 Treatment Dose 
10 (9.0 – 11.0) mCi 
Dose Level 2 Treatment Dose 
25 (22.5 – 27.5) mCi 
Dose Level 3 Treatment Dose 
50 (45.0 – 55.0) mCi 
Dose Level 4 Treatment Dose 
65 (58.5 – 71.5) mCi 
Dose Level 5 Treatment Dose 
85 (76.5 – 93.5) mCi 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit to the radiopharmacy. Temperature-controlled shipment from 
radiopharmacy to the clinical department is not required. 
All trial treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff. 
Further guidance and information for the final disposition of unused trial treatment will be 
provided in the IMP manual. 
5.2.1. 
Radiolabeling of DTPA-omburtamab 
177Lu-DTPA-omburtamab is manufactured by conjugating the monoclonal antibody omburtamab 
with p-SCN-Bn-CHX-A’’-DTPA followed by radiolabeling of the conjugate DTPA-omburtamab 
(DTPA-omburtamab drug product intermediate) with lutetium-177 to create the final 
177Lu-DTPA-omburtamab drug product. 


 
 
 
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The conjugation of omburtamab is performed by a conjugation of p-SCN-Bn-CHX-A’’-DTPA 
([(R)-2-Amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-
pentaacetic acid) to lysine side chains of the monoclonal antibody in a chelator-to-antibody ratio 
(CAR) of 3. 
The DTPA-omburtamab drug product intermediate is then radiolabeled with the β-emitter 
lutetium-177, and shipped to the radio pharmacy affiliated with the clinical trial site. 
The required activity should be withdrawn into a syringe using aseptic technique using a dose 
calibrator and the rest of the activity should be discarded in accordance with local regulations. 
Radiolabeled product is sterilized by filtration. Quality control is ensured according to a release 
specification, also including endotoxin testing, bioburden, and radioimmunoassay. 
5.2.2. 
Radiation Safety 
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. 
For treatment in Part 1 Cycle 1, see Section 5.1. In Part 1 Cycle 2 and in Part 2, patients can be 
treated in an outpatient setting or can be admitted for 177Lu-DTPA-omburtamab administration; 
however, all patients should be observed for a minimum of 2 hours after end of each infusion. 
When patients are admitted, the caregiving staff will be instructed in radiation safety 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 timepoints to 
define the need for overnight stay(s) using portable radiation detectors as described in the local 
safety instructions. Patient release timepoint following administration of a dose of 177Lu-DTPA-
omburtamab will be determined based on the dose rate criterion specified in § 35.75 in NUREG 
1556, Volume 9, Rev 327 and Regulatory Guide 8.39, Rev 128 (US sites) or based on local 
radiation safety requirements (sites outside US). Patients can be released following 
administration of dosimetry or treatment doses of 177Lu-DTPA-omburtamab if the total effective 
dose equivalent to any other individual from exposure to the released individual is not likely to 
exceed 5 mSv (~ 500 mrem) 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. 
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. 
Patients and legal guardians will be given instructions by radiation safety staff on how to handle 
waste and steps and procedures to follow to minimize radiation exposure to themselves, 
household contacts, the general public, and possible patient family caregiver(s), including 
pregnant women, and small children. Safety precautions will be taken to ensure that doses to 


 
 
 
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these caregivers are maintained as less than local safety instructions (e.g., 5 mSv [~ 500 mrem]). 
Patients and/or caregivers will be provided with a written instruction detailing radiation safety 
precautions as per the local requirements. The caregiver will agree to radiation safety instructions 
prior to administration of the IMP. 
Safety instructions must include the following general precautions: Close contact (less than 1 
meter) with other people should be limited for 7 days following an administration of 177Lu-
DTPA-omburtamab. For other children and/or pregnant women, close contact (less than 1 meter) 
should be limited to less than 15 minutes per day for 7 days. Patients should sleep more than 1 
meter from other people for 7 days and in a separate bedroom from other children and/or 
pregnant women for 15 days following an administration of 177Lu-DTPA-omburtamab. 
5.2.3. 
Ventriculo-peritoneal Shunts 
Ventriculo-peritoneal shunts with programmable valves are allowed; however, the VP shunt 
must be closed (or adjusted to highest pressure setting) during IMP infusion and up to 
approximately 5 hours after IMP administration and then re-adjusted. The shunt re-adjustment 
times are at the discretion of the treating physician. Closure of the 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. 
5.3. 
Method of Treatment Assignment 
This is an open-label trial and is not subject to randomization. After dose level 1 in Part 1, 
patients will be allocated to the highest dose level cleared by the DMC. 
5.3.1. 
Dose Modification 
Dose reductions will not be allowed in Part 1. If a dose reduction is needed in Part 1, the patient 
should be discontinued from treatment and all EOT Visit assessments completed. 
In Part 2, dose reductions in individual patients are permitted where warranted due to toxicity. If 
dose reduction is needed in Part 2, the reduced dose will be decided upon agreement between the 
treating investigator and sponsor, guided by the safety and calculated absorbed doses to CSF and 
blood findings from Part 1. 
For patients in Part 1 or 2 presenting with ongoing Grade 3 or 4 myelosuppression in the fifth 
week of a treatment cycle, and who are otherwise eligible for an additional treatment cycle, a 
delay of dosing in the next cycle for up to 8 weeks can be introduced, provided that the 
myelosuppression has sufficiently declined to Grade ≤2. Dose delay will be enforced at the 
discretion of the treating investigator. 
5.4. 
Blinding 
This is an open-label trial; blinding procedures are not applicable. 


 
 
 
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5.5. 
Treatment 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. 
Drug accountability on a patient level will be documented by keeping copies of the IMP order 
form and the IMP administration form and the completed appendices to the IMP manual. The 
documentation will be reviewed periodically and verified by the Trial Monitor over the course of 
the trial. 
5.5.1. 
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. 
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 
treatment 
• 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/underdose and medication errors (exceeding ± 10% as compared to protocol-specified 
dose) should be reported in the electronic case report form (eCRF), including information on the 
quantity of the excess dose as well as the duration (if an overdose) and of the type (if a 
medication error). 
If an overdose, medication error, or misuse result in an AE this should be reported as an AE in 
the eCRF and (if serious) to safetymailbox@ymabs.com using the clinical AE report form. 
5.5.1.1. 
Management of Overdose of 177Lu-DTPA-omburtamab 
Rescue medication to reverse the action of 177Lu-DTPA-omburtamab is not available. In case of 
overdose or other medication errors of 177Lu-DTPA-omburtamab patients, should receive 
supportive care according to local guidelines and potential side effects of 177Lu-DTPA-
omburtamab should be treated systematically. 


 
 
 
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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. 
5.6. 
Technical complaint 
A technical complaint is any written or oral communication that states any dissatisfaction with 
the product characteristics and alleges a product defect. A complaint can be related to e.g., the 
product appearance (discoloration, presence of particles, or sediment), product container 
(damaged or missing seal), product label (damaged, missing, misleading), or consignment 
(wrong number of vials in the package). Complaint should also be initiated if the product is 
suspected to be falsified. 
Please refer to the IMP manual for information regarding reporting of a technical complaint. 
 


 
 
 
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6. CONCOMITANT THERAPIES 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrolment or receives 
during the trial must be entered on the eCRF, including: 
• reason for use 
• dates of administration, including start and end dates, and 
• dosage information including dose and frequency. 
Prior anti-cancer therapy must be entered in the eCRF. The Medical Monitor should be contacted 
if there are any questions regarding concomitant or prior therapy. 
6.1. 
Permitted Concomitant Therapy 
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. Additional 
anti-cancer and supportive care treatments are allowed after the EOT Visit. If an MRI is 
scheduled at that visit, the MRI should be completed before starting the additional treatments. 
Medical marijuana is permitted if the patient was receiving this therapy prior to signing the ICF. 
After discontinuation of the IMP, any treatment deemed safe and justified by the investigator can 
be administered according to clinical practice and at the discretion of the investigator. 
6.2. 
Prohibited Concomitant Therapy 
The following therapies are prohibited within 3 weeks prior to the first dose and until completion 
of the EOT Visit: 
• Additional cytotoxic anti-cancer therapy. 
• Any other IMP. 
• Any live viral vaccines. 
• Herbal medications with known risk of hepatotoxicity. 
The following is prohibited in Part 1 Cycle 1 within 1 week prior to first IMP administration and 
until 5 weeks after: 
• Additional hematological support. 


 
 
 
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6.3. 
Treatment of Expected Toxicities 
Premedication 
Starting 24 hours prior to each 177Lu-DTPA-omburtamab infusion, dexamethasone will be 
administered orally at 0.6 mg/kg/day or an IV equivalent (subject to a maximum total dose of 20 
mg/day) divided into twice-daily doses for a total of 3 days to alleviate infusion-related AEs. 
An anti-pyretic (e.g., oral acetaminophen/paracetamol [15 mg/kg, 650 mg maximum]) and an 
antihistamine (e.g., diphenhydramine [1 mg/kg, 50 mg maximum]) or equivalents will be 
administered within 1 to 2 hours before all intracerebroventricular infusions. 
Expected Toxicities 
Expected toxicities will be treated at the discretion of the investigator and could include the 
following: 
• Urticaria will be treated with antihistamines. 
• Fever will be treated with paracetamol/acetaminophen. 
• During administration of 177Lu-DTPA-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, GM-CSF, or 
granulocyte–colony-stimulating factor according to local standard of care. If indicated, 
patients also may have banked stem cells reinfused. 


 
 
 
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7. TRIAL ASSESSMENTS AND PROCEDURES 
Trial procedures and their timing are summarized in the Schedule of Assessments (Appendix 3). 
As protocol waivers or exemptions are not allowed, with the exception of immediate safety 
concerns, these should be discussed with the sponsor immediately upon occurrence or awareness 
to determine if the patient should continue or discontinue the IMP. Adherence to the trial design 
requirements, including those specified in the Schedule of Assessments, is essential and required 
for trial conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure 
(Section 4.3.1), as applicable. Procedures conducted as part of the patient’s routine clinical 
management (e.g., blood count) and obtained before signing the ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified criteria and 
was performed within the timeframe defined in the Schedule of Assessments (Appendix 3). 
The maximum amount of blood collected from each dosed patient over the duration of the trial, 
including any extra assessments that may be required, will not exceed 300 mL, and the 
maximum amount of CSF collected from each dosed patient over the duration of the trial, 
including any extra assessments that may be required, will not exceed 20 mL. In case the patient 
will participate in the ctDNA analysis, additional 3-5 ml CSF will be collected. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
7.1. 
Vital Signs, Physical Examination, and Other Safety Evaluations 
7.1.1. 
Demographics 
The following demographic information will be entered in the eCRF during screening: 
• Age or date of birth, if allowed by local legislation 
• Gender 
• Ethnic origin and race, if allowed by local legislation 
7.1.2. 
Height and Body Weight 
Height (without shoes and rounded to the nearest centimeter) and body weight (without overcoat 
and shoes and rounded to kilogram with 1 decimal) will be measured at screening and entered in 
the eCRF. 
7.1.3. 
Vital Signs 
Measurements of heart rate, respiratory rate, temperature, and blood pressure will be performed 
before and 30 minutes after the end of the IMP infusion on dosing days and at the times specified 


 
 
 
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in the Schedule of Assessments (Appendix 3). Temperature must be measured by using the same 
method on each occasion (e.g., an ear thermometer). 
7.1.4. 
Physical Examinations 
Physical examinations should be performed at screening and as clinically indicated and should 
include assessment of general appearance, mental status, and various organ systems 
(neurological, skin, head, eyes, ears, nose, mouth, throat, neck, thyroid, lymph nodes, respiratory, 
cardiovascular, gastrointestinal, extremities, and musculoskeletal systems). 
7.1.5. 
Neurological Assessments 
Neurological examination will be done according to the National Cancer Institute (NCI) criteria 
for clinical assessment of nervous system disorders (CTCAE version 5) at the timepoints detailed 
in the Schedule of Assessments (Appendix 3). Typical signs and symptoms of medulloblastoma 
will be entered in the eCRF. Signs and symptoms of medulloblastoma may include headaches, 
nausea, vomiting, tiredness, dizziness, double vision, poor coordination, unsteady walk, and 
other concerns. According to RAPNO, any clinical deterioration not attributable to other causes 
is, by definition, PD. In the absence of clear evidence of PD, it may be assumed that new signs 
and symptoms are treatment related. Any patient who develops an AE considered to be a Grade 3 
or 4 nervous system disorder after the dosimetry infusion will not receive the treatment dose. 
7.1.6. 
Performance Status 
Since most if not all patients will have received prior craniospinal and/or whole-brain irradiation, 
late side effects for such previous therapies are difficult to distinguish from 
177Lu-DTPA-omburtamab inflicted CNS AEs. However, to evaluate gross changes in 
neurological function, a performance test (Lansky [<16 years] or Karnofsky [≥16 years]) will be 
conducted at the Screening, EOT, and all Follow-up Visits in both parts of the trial. 
7.2. 
Dosimetry, Pharmacokinetics, Imaging, and Laboratory Evaluations 
7.2.1. 
Intracerebroventricular Access Device/CSF Flow Assessment 
The patency of the intracerebroventricular access device shunt will be assessed at screening by 
injecting a small volume (about 0.3 mL) of a radiotracer into the shunt reservoir. The flow of 
CSF will be measured (for details, see Appendix 7). Only patients with sufficient flow should be 
dosed. Efforts to correct CSF flow can be installed and if sufficient flow is established, the 
patient can be dosed. Abnormal scan findings (ventricular outflow obstruction, obstruction 
within spinal canal, or failure to ascend to the convexities by 6 hours and spread over the 
convexities by 24 hours) will result in screening failure and must be documented in the patient’s 
file. 
7.2.2. 
Dosimetry and Calculation of Absorbed Radiation Doses (Part 1 only) 
This will be conducted in Part 1 Cycle 1 only, and the timepoints for CSF/blood sampling and 
imaging scans are outlined in Table 4. 


 
 
 
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Table 4: 
CSF and Blood Sampling and Scans in only Cycle 1 of Part 1 
Time point (after dosimetry dose) 
CSF 
Blood 
Whole-body planar Gamma Camera Scan 
SPECTa 
Baseline 
× 
× 
 
 
30 (± 10) minb 
× 
× 
 
1 h (± 10 min) 
× 
× 
 
4 h (± 10 min) 
× 
× 
× (+ 1 h) 
 
24 (± 2) h 
× 
× 
× (± 2 h) 
× (± 2 h) 
48 (± 2) h 
× 
× 
× (± 2 h) 
 
72 (± 4) h 
× 
× 
× (± 2 h) 
Day 5-7c 
× 
× 
× 
× 
Day 15 (± 12 h)d 
× 
× 
× 
× 
Abbreviations: CSF = cerebrospinal fluid. 
a SPECT scan is optional. 
b Both CSF and blood sampling; however, if both are not possible, CSF should be prioritized. 
c Can be performed on Day 8; however, must be prior to the treatment dose. 
d To be performed 7 days (± 12 h) after the treatment dose. 
A dosimetry dose of 5 mCi was selected, with a possibility to increase to 10 mCi at the 
Sponsor’s discretion in case of too low acquisition of radioactivity count. 
Organ Dosimetry 
Organ dosimetry by whole-body planar gamma camera scan (and regions of interest) will be 
conducted at site at the timepoints mentioned in Table 4 and calculation of the absorbed radiation 
doses will take place centrally. If a hybrid planar/SPECT imaging scanner is available, SPECT 
images may be acquired to improve the quantitative assessment of tumor target absorbed doses 
in particular. 
Regions of interest in each planar dataset will be defined for the following source organs at each 
timepoint if signal is visibly above the immediate background: brain, spinal cord, liver, thyroid, 
salivary glands, lungs, kidneys, bladder, gallbladder, stomach, spleen, heart, gastrointestinal tract 
(large and small intestines), and any other organs demonstrating appreciable uptake. The mean 
absorbed radiation dose in CSF and whole blood will be estimated via imaging-based estimation 
(CSF) and serial sample-based estimation (CSF and blood) as described in the technical 
operations manual. 
Whole-body planar gamma camera (and SPECT, if possible) scans will be performed using a 
dual-headed gamma camera (e.g., ADAC dual-headed VERTEX gamma camera, Milpitas, CA) 
for both planar gamma and SPECT scans) or comparable dual-detector system with medium-
energy collimation. A photopeak energy window of 208 keV (±10%) and 113 keV (±10%) is 
used for lutetium-177. A known activity (e.g., 100 µCi) of 177Lu-DTPA-omburtamab is placed 
alongside the patient (a minimum of 10 cm from an extremity) and serves as a calibration 
standard. Whole body and regions of interest are manually drawn. Spinal CSF is manually drawn 
on the posterior whole-body images. 


 
 
 
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Absorbed Radiation Doses in CSF and Blood 
The radioactivity in CSF and blood after administration of the dosimetry dose (seven 
measurements) and treatment dose (one measurement) in Part 1 Cycle 1 will be measured at site 
using a scintillation well counter, following qualified procedures outlined in the technical 
operations manual. The patients will have approximately 0.5 mL of CSF and 2 mL of peripheral 
blood drawn at each timepoint mentioned in Table 4. 
Upon local analysis, the data will be transferred to a vendor located in US for central evaluation 
of the radiation doses delivered to the CSF and blood (derived from radioactivity versus time 
data). 
7.2.3. 
Magnetic Resonance Imaging 
Brain and spine MRI for assessment of response should be done locally in accordance with the 
recommendations outlined by the RAPNO committee10, including: 
• Central review for eligibility by neuroradiologists (at site) with expertise in pediatric 
brain tumor imaging. 
• Absence of movement artifacts- if judged necessary, the patient must be sedated. 
• Available preoperative contrast-enhanced MRI, to allow sufficient delineation of primary 
tumor and assessment of leptomeningeal metastases. 
• Slice thickness according to the recommendations in RAPNO (see Table 1 in Warren et 
al. 201810). 
• Spinal MRI with full visualization of the dural sac, performed in 2 planes without skip 
regions and with adequate slice thickness and resolution. 
• Tumor measurements should be made using the sequence that best demonstrates the 
extent of tumor; non-enhancing and enhancing primary lesions should be measured 
similarly. 
7.2.4. 
CSF for Cytology, Total Protein, Glucose, ctDNA, and Cell Count 
Samples of CSF for cytology, total protein, glucose, ctDNA, and cell count should be collected 
according to the Schedule of Assessments (Appendix 3). The CSF is sampled from the 
intracerebroventricular access device (e.g., Ommaya). 
7.2.4.1. 
CSF Sampling for ctDNA Sequencing 
Samples of CSF for ctDNA will be collected in standard CSF collection kit via the Ommaya 
reservoir at screening and at the EOT Visit if the patient has given informed consent to DNA 
analysis. ctDNA will be sequenced using high-throughput DNA sequencing. Samples will be 


 
 
 
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stored at site until testing at a central facility. As per protocol version 8, this analysis will not be 
performed, and samples should no longer be shipped from sites. 
7.2.5. 
Blood and CSF for Culture 
Blood and CSF will be sampled up to 6 hours after each IMP dose and held for potential culture 
(including the dosimetry dose in Part 1). Samples will be cultured only if body temperature is 
elevated (defined as ≥38°C [≈100°F]) after dosing and clinical infection is suspected. 
7.2.6. 
Clinical Chemistry and Hematology 
Blood samples for biochemistry and hematology will be analyzed by local laboratories; see 
Appendix 1 for a list of analytes to be analyzed. 
7.2.7. 
Archival Tumor Tissue 
7.2.7.1. 
Analysis of B7-H3 
Archival tumor tissue from primary tumor and/or from CNS/leptomeningeal metastasis (if 
available) obtained as standard of care at site should be sent to the central laboratory in the US 
for semi-quantitative immunohistochemistry analysis of B7-H3. The histological diagnosis will 
be confirmed. The analyses will be performed in batches. As per protocol version 8, this analysis 
will not be performed, and samples should no longer be shipped from sites. 
At least 5 (preferably 10 to 15) formalin-fixed, paraffin-embedded slides of 3 to 5 µm thickness 
(or a paraffin-embedded tissue block [enough for at least 5 sections]) will be needed. A detailed 
description of the procedures for sampling, handling, storage, and shipment of the samples will 
be provided by the central laboratory. Date of sampling, etc. will be recorded in the eCRF. 
7.2.7.2. 
Analysis of Primary Tumor DNA (in case of separate Informed Consent) 
Archival tumor tissue from primary tumor (if available) obtained as standard of care at site 
should be sent to the central laboratory in the US for DNA sequencing and analysis for 
comparison with the ctDNA derived from the CSF. The analyses will be performed in batches. 
As per protocol version 8, this analysis will not be performed, and samples should no longer be 
shipped from sites. 
At least 10 formalin-fixed, paraffin-embedded sections of 3 to 5 µm thickness (or a paraffin-
embedded tissue block [enough for at least 10 sections]) will be needed. If less than 10 are 
available, fewer sections are accepted. A detailed description of the procedures for sampling, 
handling, storage, and shipment of the samples will be provided by the central laboratory. Date 
of sampling, etc. will be recorded in the eCRF. 
Upon issuance of the report, any leftover material will be discarded. 


 
 
 
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7.2.8. 
Immunogenicity 
The presence of ADAs to 177Lu-DTPA-omburtamab in serum and CSF will be measured at the 
timepoints specified in the Schedule of Assessments (Appendix 3). No more than 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. Unscheduled sampling triggered by suspected 
immunologically related AEs may be conducted and collected until ADAs return to baseline. 
Dependent on the clinical data and occurrence of ADAs in Part 1, an assay to determine whether 
ADAs in CSF are neutralizing will be developed for Part 2. Samples will be stored frozen until 
testing at a central laboratory. ADAs will be evaluated using a validated enzyme-linked 
immunosorbent assay (ELISA) method. 
7.2.9. 
Pharmacokinetic Analysis 
To test the potential effect of ADAs on blood and CSF clearance of 177Lu-DTPA-omburtamab, 
PK exposure differences between Cycle 1 and Cycle 2 will be compared. Blood and CSF PK 
samples will be drawn at the following timepoints after the treatment doses in Cycle 1 and 2 
(Table 5). No more than 2 mL of blood will be collected per timepoint and sampling. Samples 
will be stored frozen until testing at a central laboratory. Procedures for collection, processing, 
and shipping of PK blood and CSF samples will be detailed in a separate document. 
Serum and CSF concentrations of 177Lu-DTPA-omburtamab will be determined using a validated 
analytical procedure. Specifics of the analytical method will be provided in a separate document. 
Table 5: 
Schedule for CSF and Blood Pharmacokinetic Sampling (Parts 1 and 2) 
Time of sampling following Cycle 1 Treatment Dose 
Cycle 2 Treatment Dose 
Baseline (prior to the treatment dose) 
Baseline (prior to the treatment dose) 
30 (±10) min1 
30 (±10) min 
1 h (±10 min) 
1 h (±10 min) 
4 h (±10 min) 
4 h (±10 min) 
24 (±2) h 
24 (±2) h 
48 (±2) h 
48 (±2) h 
7 (±1) days after (blood only)*,** 
7 (± 1) days after (blood only)* 
* Only drawn in Part 1; may be performed on Day 8; however, must be pre-dose. 
** In Part 1, Cycle 1, this is Day 15 as treatment dose is administered on Day 8. 
1 Both CSF and blood sampling; however, if both are not possible, CSF should be prioritized. 
7.3. 
Efficacy Assessments 
7.3.1. 
Progression-free Survival 
Progression-free survival (PFS) will be assessed by MRI, neurological examination, and CSF 
cytology. As detailed in the RAPNO criteria (Appendix 6), progression is defined when any of 
the PD criteria are met. The timeframe for assessment of PFS will be from the first treatment 
dose of 177Lu-DTPA-omburtamab to time of disease progression or death from any cause. 
Patients lost to follow-up without any sign of progression will be censored at the date of last PFS 
assessment. 


 
 
 
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7.3.2. 
Response Evaluation, Overall Response Rate, and Duration of Response 
Response, as defined by the RAPNO criteria (Warren et al. 201810; see Appendix 6) will be 
assessed in Part 1 at the EOT Visit. In Part 2, response will be assessed at end of Cycle 1 and 
Cycle 3, EOT Visit, then 26, 39, and 52 weeks post first dose, followed by 78 and 104 weeks 
post first dose of 177Lu-DTPA-omburtamab. Notably, objective response and stable disease 
requires that all criteria are met, while progression is defined when any of the PD criteria are 
met. 
The ORR will be calculated from baseline MRI scans and from scans after the dosing of 
177Lu-DTPA-omburtamab using 2 methods: firstly, by considering MRI data, neurological 
examination, and CSF cytology data together (RAPNO criteria); secondly, by considering CSF 
cytology data only. ORR will be defined as the proportion of all evaluable patients achieving a 
CR or PR as best overall response at the time of assessment. 
Investigator-assessed DoR (Part 2) is defined as the time from response (CR or PR) to 
progression. Patients without any sign of progression will be censored at the date of their last 
PFS assessment. 
In Part 1 and Part 2, the baseline CSF cytology assessment must be completed within 3 weeks 
prior to the first 177Lu-DTPA-omburtamab treatment dose infusion. Cerebrospinal fluid cytology 
should be assessed as positive/negative. Cerebrospinal fluid cytology will be assessed in Part 1 at 
screening, the EOT Visit, and in Part 2 at screening, end of Cycle 1 and Cycle 3, EOT Visit, and 
at each Follow-up Visit. 
7.3.3. 
Overall Survival (Part 2 Only) 
The timeframe for assessment of OS will be from the first dose of 177Lu-DTPA-omburtamab to 
date of death from any cause. OS will be estimated using Kaplan-Meier methods.  
7.4. 
Adverse Events 
7.4.1. 
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 AE: a clinical laboratory abnormality which is clinically significant, 
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requires active management. Active management includes interventional treatment or 
further investigations, for example change of medicine dose or more frequent follow-up 
due to the abnormality. 
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. 
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. 
7.4.2. 
Definition of Serious Adverse Events 
Each AE is to be classified by the investigator as either serious or non-serious. This classification 
of the seriousness of the AE determines the reporting procedures to be followed. An AE that 
meets 1 or more of the following criteria/outcomes is classified as serious: 
• Is fatal or life threatening1 
• Requires inpatient hospitalization or prolongation of existing hospitalization2 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is a medically important event.3 
1 The term "life threatening" in the definition of "serious" refers to an event in which the patient, in view of either the 
investigator or sponsor, was at risk of death at the time of the event; it does not refer to an event that hypothetically 
might have caused death if it 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 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. 
 
2 Hospitalization is defined as admission to a hospital/inpatient (irrespective of the duration of physical stay) or is not 
admitted to a hospital/not an inpatient but stays at the hospital for treatment or observation for more than 24 hours. 
Events leading to hospitalizations for the following reasons should not be reported as SAEs: 
• 
Trial-related purposes, not associated with any deterioration in condition 
• 
Social reasons in the absence of any deterioration in the patient’s general condition 
• 
Elective surgery or other scheduled hospitalization periods that were planned before the patient was included 
in this trial. 
 
3 Medical and scientific judgment must be exercised in deciding whether an AE is believed to be “medically 
important”. Medically important events may not be immediately life threatening or result in death or hospitalization 
but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition 
above. 
 


 
 
 
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7.4.3. 
Definition of Non-serious Adverse Events 
A non-serious AE is any AE which does not fulfil the definition of an SAE. 
7.4.4. 
Definition of Adverse Events of Special Interest 
The following AEs (serious and non-serious) are selected as Adverse Events of Special Interest 
(AESIs) and should be reported within 24 hours to the sponsor: 
• Nervous system disorder Grade 3 and above (see Section 7.1.5) 
• Severe infections related to placement of intracerebroventricular device. 
• Chemical meningitis (symptoms of clinical meningitis but cultures for infectious 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. 
• Suspicion of liver injury, defined as: 
o ALT or AST >3 × ULN and total bilirubin >2 × ULN* if baseline was within the 
normal reference ranges, or 
o ALT or AST increasing more than 3-fold from baseline value, if baseline was 
above normal reference ranges* 
*Either criterion requires that no other reason can be found to explain the 
increased laboratory parameters, such as viral hepatitis A, B, or C, pre-existing 
liver disease, or another drug capable of causing the observed injury. 
In cases of suspected liver injury, testing should be repeated within 48 to 72 hours for evaluation 
of the event course/confirmation. Furthermore, additional information needs to be provided by 
the site, such as physical examination, information on alcohol consumption, or concomitant 
therapy (including herbal medications). Aspects like abdominal pain/tenderness, nausea, 
vomiting, jaundice, fever, rash, hepatomegaly, splenomegaly, peripheral edema, and recent 
weight gain should be considered and described. 


 
 
 
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7.4.5. 
Adverse Event Reporting 
Figure 2: 
Adverse Event Reporting 
 
* This post-trial monitoring can be conducted by contacting the patient or the general 
practitioner, the referral site (if applicable), or by checking medical records or other sources. 
Any related SAE that the investigator becomes aware of after end of trial must be reported to 
sponsor using the clinical AE report form, see Section 7.4.5.3. 
Non-serious Events: 
Non-serious AEs should be reported from the day of first IMP administration until 5 weeks after 
the patient’s last dose. Thereafter and during the follow-up and post-trial monitoring periods, 
new onset of cancers regardless of causality, should be reported, until death or at least 10 years 
after end of trial, whichever comes first. During the follow-up period, Grade 3 or higher non-
serious AEs considered related to IMP or related to the presence of the indwelling catheter 
system should be reported. Non-serious AEs occurring between signing the ICF and the first 
IMP administration must be recorded as medical history. 
Serious Adverse Events: 
Serious AEs should be reported from signing the ICF until 5 weeks after the patient’s last dose. 
Thereafter and during both the follow-up and post-trial monitoring periods, only SAEs 
considered related to IMP or related to the presence of the indwelling catheter system, or new 
onset of cancers regardless of causality, should be reported, until death or at least 10 years after 
end of trial, whichever comes first. 
All events meeting the definition of an AE must be collected and reported in the eCRF. SAEs, 
DLTs (Part 1), and AESIs (whether serious or non-serious) should be reported both in the eCRF 
and on the clinical AE report form. 
During each contact with the trial site staff, the patient must be asked about AEs, for example by 
asking: “Have you experienced any problems since the last contact?” All AEs observed by the 
Screening
Treatment
Follow-up period
Post trial monitoring
All SAEs
All AEs & SAEs & AESIs
Grade 3 or higher AEs and SAEs related to the IMP or 
the presence of the indwelling catheter system
Secondary malignancies
Secondary malignancies*
ICF
End of Trial
First IMP
5 weeks after last IMP
10 years after end of Trial


 
 
 
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investigator or patient must be reported by the investigator and evaluated unless specifically 
excluded. All SAEs and AEs leading to discontinuation of IMP either observed by the 
investigator or patient must be reported by the investigator and evaluated. 
Diagnosis 
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. 
Onset Date and Time 
Start date for an (S)AE is the date of occurrence of the first symptom. The time should be 
entered if the event starts on a dosing day or if the duration of the event is less than 24 hours. 
End Date and Time 
The end date should be entered if the outcome of an event is fatal, recovered/resolved, or 
recovered/resolved with sequelae. The time should be entered if the event starts on a dosing day 
or if the duration of the event is less than 24 hours. 
Severity 
The investigator will use NCI CTCAE Version 5.0 to describe the severity of the AE. The grade 
assigned by the investigator should indicate the grade at the onset of the event and the most 
severe grade that occurred during the AE period. 
Outcome 
The 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 
• Recovering 
• Fatal 
• Unknown* 
* 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 
will be provided in the instructions that accompany the AE form in the eCRF. 


 
 
 
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Relationship to Investigational Medicinal Product 
The investigator must assess whether the event is related to the IMP. A suspected adverse drug 
reaction (ADR) is defined as one in which there is a reasonable possibility that the drug caused 
the AE. Relatedness must be assessed and reported from the first time the AE is being reported. 
When assessing the causal relationship of an AE to the IMP, the following should be taken into 
consideration: 
Not Related (Unlikely) 
The AE is not related to the IMP, which means the AE: 
• Does not follow a reasonable temporal sequence from IMP administration. 
• Is readily explained by the patient’s clinical state or by other modes of therapy 
administered to the patient. 
• Is clearly not related to the IMP. 
For AEs assessed as “Not Related”, an alternative etiology should be stated detailing the more 
likely reason for the AE. 
Possibly Related 
The AE follows a reasonable temporal sequence from IMP administration but could have been 
produced by the patient’s clinical state, medical history, or the trial procedures/conditions. 
Alternative etiology should be provided for all AEs assessed as possibly related to IMP. 
Probably Related 
The AE is probably related to the IMP, which means the AE: 
• Follows a reasonable temporal sequence from IMP administration. 
• 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) (if 
applicable). 
• Cannot be reasonably explained by the known characteristics of the patient’s clinical state 
or medical history. 


 
 
 
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Action Taken with Investigational Medicinal Product 
The action taken with the IMP should be noted as: 
• Dose Decreased* 
• Dose Administration Rate Decreased 
• Interrupted 
• Postponed 
• Discontinued 
• None 
• Not Applicable** 
• Unknown. 
*Only applicable in Part 2. 
**Not Applicable should be used if the AE occurs before first treatment or after end of treatment 
(i.e., the IMP was already discontinued). 
7.4.5.1. 
Events Requiring Immediate Reporting 
The following events (for reporting periods, see Figure 2) require immediate reporting (within 24 
hours) (for details, see Section 7.4.5.3): 
• SAE 
• DLT 
• AESI 
• Pregnancy. 
Starting five weeks after the last dose, only SAEs or Grade 3 or higher AEs at least possibly 
related to 177Lu-DTPA-omburtamab or to the presence of the indwelling catheter system, or new 
onset of cancers regardless of causality, should be reported until end of trial. Subsequently, in the 
post-trial monitoring period, SAEs considered related to IMP or new onset of cancers regardless 
of causality, should be reported until death or at least 10 years after end of the trial, whichever 
comes first, using the clinical AE report form, see Section 7.4.5.3. 


 
 
 
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7.4.5.2. 
Pregnancy 
Any pregnancy that occurs during trial participation must be reported to the sponsor within 
24 hours of knowledge using the pregnancy form. Pregnant trial patients must be discontinued 
from treatment immediately. Should pregnancy of female partners of male patients occur, a 
separate informed consent will be obtained from the female partner for collection of information 
regarding the pregnancy. 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 1 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. 
7.4.5.3. 
Reporting Timelines and Contact Details 
• Initial SAEs (including DLTs and predefined AESIs, whether serious or not): The clinical 
AE report form must be reported from site to sponsor within 24 hours of the 
investigator’s first knowledge of the event. The clinical AE report form is to be e-mailed 
as detailed below. The AE eCRF page should be updated in accordance with agreed data 
entry timelines and the eCRF completion instructions. New follow-up information 
available at site must be reported within 24 hours. 
• Follow-up information requested from the sponsor must be replied to within 3 working 
days using a data clarification form. The AE eCRF page should be updated in accordance 
with agreed data entry timelines. 
• If an ongoing SAE/AESI changes in intensity, relationship to IMP, or as new information 
becomes available for the event, a clinical AE report form should be completed and sent 
to the sponsor within 24 hours of the change in assessment. 
Contact Details for Reporting 
Completed clinical AE report forms and pregnancy forms must immediately be reported using 
the following e-mail address: 
safetymailbox@ymabs.com 
In emergency situations, the completed clinical AE report forms or pregnancy forms can be 
faxed to: 
FAX:+45 7879 6060 
7.4.5.4. 
Reporting of SUSARs 
All relevant information about Suspected Unexpected Serious Adverse Reactions (SUSARs) will 
be reported to regulatory authorities in accordance with regulatory requirements. 
Investigators will be notified 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 


 
 
 
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procedure. Labcorp will inform the IRBs/ECs of SUSARs in accordance with local requirements, 
unless locally this is an obligation of the investigator. The Sponsor assessment of expectedness 
for 177Lu-DTPA-omburtamab will be performed according to the current version of the 
investigator’s brochure. 
7.4.5.5. 
Follow-up on Adverse Events 
Non-serious AEs should be followed until they are either resolved, returned to baseline, or until 
end of trial, whichever comes first. Grade 3 or higher non-serious AEs that are considered 
treatment related and all SAEs (including AESIs and DLTs) should be followed on a regular 
basis, according to the investigator’s clinical judgment, until the event has been resolved or until 
the investigator can assess it as chronic or stable. This includes follow-up during the long-term 
monitoring periods. 
7.4.5.6. 
Medical Monitoring and Communication of Significant Safety Issues 
In the event of any significant safety related issues, the investigator should: 
• Closely monitor the patient 
• Contact the Medical Monitor (for contact details, see the protocol front page) 
Sponsor will decide upon immediate action to be taken including prompt notification of the 
DMC and will communicate to regulatory authorities, investigators, ECs/IRB, and patients as 
needed within regulatory timelines. 
The Sponsor will ensure that all Investigators across sites and ongoing trials with the same IMP 
(177Lu-DTPA-omburtamab) are promptly notified of significant safety issues and required 
actions including urgent safety measures (e.g., holding further dosing) to protect trial participants 
against an immediate hazard. 
In addition, the Sponsor will inform all Investigators across sites and ongoing trials with the 
same IMP (177Lu-DTPA-omburtamab) of DMC recommendations including dose escalation 
decisions. 


 
 
 
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8. SAMPLE SIZE AND DATA ANALYSES 
8.1. 
Determination of Sample Size 
In Part 1, the chosen sample size is customary for studies of this nature and is not based on 
statistical considerations. It is estimated that up to 25 patients will participate in Part 1, based on 
5 dose levels being recruited. Actual number of patients will depend on the number of DLTs 
observed. 
For Part 2, a sample size of 24 patients provides at least 90% probability to detect an AE 
occurring in 10% of exposed patients. 
The assumption is that 20 out of the 24 patients in Part 2 are evaluable. With 20 patients 
evaluable for response and a response rate of 25% (~ to 5 responders out of 20), the lower limit 
of the 95% confidence interval will be 9%. 
8.2. 
Analysis Populations 
The following analysis sets will be included for this trial: 
Safety Analysis Set: will consist of all patients who received at least 1 dose of trial treatment 
(treatment dose or dosimetry dose). 
DLT Evaluable Analysis Set: will include patients in the dose escalation who as a minimum is 
evaluated during the 5 weeks DLT evaluation period, or who has a DLT during the DLT 
evaluation period. This analysis set is a subset of the Safety Analysis Set. 
Full Analysis Set (FAS): will consist of all patients in the Safety Analysis Set. 
Dosimetry Analysis Set (Part 1 only): will consist of all patients who received the dosimetry 
dose and have evaluable data for absorbed doses to CSF and blood or for whole-body planar 
scan. 
PK Analysis Set: will consist of all patients who received at least 1 treatment dose of trial drug 
and have evaluable PK data.  
Efficacy will be analyzed using the FAS. Safety will be analyzed using the Safety Analysis Set. 
Dosimetry and absorbed doses to CSF and blood will be analyzed using the Dosimetry Analysis 
Set. Pharmacokinetics will be analyzed using the PK Analysis Set. 
8.3. 
General Considerations 
Summary statistics, listings, and statistical analyses will be performed for patients included in the 
relevant analysis sets. 
For continuous data, summary statistics will include the arithmetic mean, arithmetic standard 
deviation, median, minimum, maximum, and number. For log-normal data (e.g., the PK 
parameters, the activity-time curve and elimination half-life of absorbed doses to CSF and 


 
 
 
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blood), the geometric mean and geometric coefficient of variation will be presented instead of 
mean and SD. For categorical data, frequency counts and percentages will be presented. Data 
listings will be provided for all patients up to the point of withdrawal, with any patients excluded 
from the relevant analysis set highlighted. For the calculation of summary statistics, listings, and 
statistical analysis, unrounded data will be used. 
For the time to event efficacy endpoints, patients who do not have an event will be censored at 
the date of their last evaluation. If partial dates are present, a conservative approach will be used. 
If partial dates are present for efficacy time to event endpoints, missing months and/or days will 
be imputed as January and the first day of the month, respectively. AEs with a missing start date 
or time that leads to ambiguity in whether the AE is treatment-emergent will be considered 
treatment-emergent. It is unlikely that other missing of safety data will occur in the targeted 
patient population, but in case it happens the data will not be imputed. 
When the last patient in Part 1 has completed the EOT visit, all available data for that part will be 
reported. 
For Part 2, full efficacy and safety analyses will be performed when the last patient completes 
week 52 assessments, dies, or is lost to follow up. An updated long term survival analysis will be 
performed when the last patient has reached the 104 week visit, dies, or is lost to follow-up. 
Data analysis will be performed using SAS® Version 9.3 or higher. 
8.4. 
Efficacy Analysis 
The FAS will be used for all efficacy endpoints. 
8.4.1. 
Part 2 Efficacy Analysis 
Overall survival at 1 and 2 years post first dose will also be estimated using Kaplan-Meier 
methods. Patients not deceased will be censored at the last date known to be alive. The median 
PFS time and the proportion of patients without PFS events at 1 and 2 years post first dose will 
be estimated using Kaplan-Meier methods, along with their 95% confidence intervals. Results 
will be displayed in Kaplan-Meier plots. The ORR according to RAPNO criteria (MRI, 
neurological examination, and CSF cytology), as well as according to CSF cytology alone, will 
be assessed. The 95% confidence intervals will be calculated using the Clopper-Pearson exact 
methodology. Investigator-assessed DoR will be estimated using Kaplan-Meier methods. The 
median DoR and corresponding 95% confidence interval will be calculated. 
8.5. 
Safety Analysis 
8.5.1. 
Dose-Limiting Toxicities 
DLTs observed during the DLT evaluation period, i.e., within 5 weeks after the dosimetry dose 
in Cycle 1 of the dose escalation will be listed and summarized by Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class (SOC) and preferred term (PT). DLTs 
observed outside the DLT evaluation period will be presented in a listing. The information from 


 
 
 
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the DLTs will be used to guide the escalation and ultimately determine the MTD. Furthermore, 
the information will be used to make recommendations regarding the RP2D. The evaluation of 
DLTs will be based on the DLT evaluable analysis set. 
8.5.2. 
Adverse Events 
The Safety Analysis Set will be used for all safety analyses except for evaluations of DLTs. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 22.1 or later. Adverse events will be regarded as TEAEs if they occur after first 
administration of 177Lu-DTPA-omburtamab. Related AEs are defined as ADRs. 
Listings will be made of all AEs. Non-TEAEs will be listed separately. All TEAEs, ADRs, 
AESIs, SAEs, and serious ADRs will be summarized by MedDRA SOC and preferred terms for 
each treatment group. The summaries will include number of AEs, number of patients, and 
percentage of patients reporting these AEs and will be tabulated by SOC and preferred term. 
TEAEs will also be summarized by severity and by relationship to IMP.  
8.5.3. 
Other Safety Assessments 
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 may be identified. Development of ADA will be examined. Effects 
on cognitive functions will be assessed by summarizing changes from baseline in performance 
testing results using descriptive statistics. 
Baseline is defined as the latest assessment prior to first dose. 
8.6. 
Analysis for Calculation of Absorbed Doses to CSF and Blood (Part 1 only) 
The mean absorbed radiation dose in CSF and blood will be calculated from radioactivity 
measured in CSF and blood samples taken at predefined timepoints after the dosimetry and the 
treatment doses in Cycle 1. 
Analysis of lutetium-177 activity in blood and CSF will include derivation of best-fit uptake 
and/or clearance parameters (elimination half-times, maximum value) of time-activity curves and 
of residence times (i.e., cumulated activity in µCi·h/g). Blood and CSF time-activity curves will 
be modeled using exponential retention functions to estimate clearance following the last 
sampled timepoint, and cumulated activities for both will be computed using a combination of 
trapezoidal integration of sampling data and analytical integration of clearance curves 
(re-incorporating physical decay). Absorbed doses in the blood and CSF will then be derived 
from cumulated activity by applying the equilibrium absorbed dose constant for lutetium-177 
under the assumption of complete local β-absorption, consistent with prevailing practice. 
Individual and mean absorbed radiation dose to CSF and blood will be summarized using 
descriptive statistics for all patients in the Dosimetry Analysis Set and by trial site. 


 
 
 
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8.7. 
Dosimetry Analysis (Part 1 only) 
Spinal cord, brain, and non-target region of interest absorbed radiation doses will be estimated 
and CSF mean absorbed radiation doses will be calculated on the basis of whole-body planar 
gamma camera scans. Tumor target absorbed doses will be calculated on the basis of SPECT 
scan, if possible. 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 
predefined timepoints after the dosimetry and the treatment doses in Cycle 1. 
Individual and mean dosimetry data will be calculated per trial site and will be summarized using 
descriptive statistics. 
8.8. 
Pharmacokinetic Analysis 
The serum and CSF PK parameters of 177Lu-DTPA-omburtamab following the treatment doses 
in Cycles 1 and 2 will be calculated using standard noncompartmental methods in both study 
parts. Standard PK parameters (such as Cmax, AUC, half-life) will be calculated. 
8.9. 
Interim Analysis 
Ad hoc interim analyses will be performed in connection with communication with regulatory 
authorities. 


 
 
 
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9. REFERENCES 
1. 
Modak S, Kramer K, Gultekin SH, Guo HF, Cheung NK. Monoclonal antibody 8H9 
targets a novel cell surface antigen expressed by a wide spectrum of human solid tumors. 
Cancer Res. 2001;61(10):4048-54. 
2. 
Xu H, Cheung IY, Guo HF, Cheung NK. MicroRNA miR-29 modulates expression of 
immunoinhibitory molecule B7-H3: potential implications for immune based therapy of 
human solid tumors. Cancer Res. 2009;69(15):6275-81. 
3. 
Dash A, Pillai MR, Knapp FF. Production of (177)Lu for Targeted Radionuclide Therapy: 
Available Options. Nucl Med Mol Imaging. 2015;49(2):85-107. 
4. 
Vallabhajosula S, Goldsmith SJ, Kostakoglu L, Milowsky MI, Nanus DM, Bander NH. 
Radioimmunotherapy of prostate cancer using 90Y-and 177Lu-labeled J591 monoclonal 
antibodies: effect of multiple treatments on myelotoxicity. Clinical cancer research. 
2005;11(19):7195s-200s. 
5. 
Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [177 Lu]-
PSMA-617 Radionuclide Treatment in Patients With Metastatic Castration-Resistant 
Prostate Cancer (LuPSMA Trial): A Single-Centre, Single-Arm, Phase 2 Study. Lancet 
Oncol. 2018;19(6):825-33. 
6. 
Blakkisrud J, Holtedahl JE, Løndalen A, Dahle J, Bach-Gansmo T, Holte H, et al. 
Biodistribution and Dosimetry Results from a Phase 1 Trial of Therapy with the Antibody-
Radionuclide Conjugate 177Lu-Lilotomab Satetraxetan. J Nucl Med. 2018;59(4):704-10. 
7. 
Pomeroy SL, Wen PY, Gajjar A. Clinical presentation, diagnosis, and risk stratification of 
medulloblastoma. Waltham, MA. 2019. 
8. 
Packer RJ, Zhou T, Holmes E, Vezina G, Gajjar A. Survival and secondary tumors in 
children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results 
of Children's Oncology Group trial A9961. Neuro Oncol. 2013;15(1):97-103. 
9. 
Khatua S, Song A, Citla Sridhar D, Mack SC. Childhood Medulloblastoma: Current 
Therapies, Emerging Molecular Landscape and Newer Therapeutic Insights. Curr 
Neuropharmacol. 2018;16(7):1045-58. 
10. 
Warren KE, Vezina G, Poussaint TY, Warmuth-Metz M, Chamberlain MC, Packer RJ, et 
al. Response assessment in medulloblastoma and leptomeningeal seeding tumors: 
recommendations from the Response Assessment in Pediatric Neuro-Oncology committee. 
Neuro Oncol. 2018;20(1):13-23. 
11. 
Majzner RG, Theruvath JL, Nellan A, Heitzeneder S, Cui Y, Mount CW, et al. CAR T 
Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity 
Against Pediatric Solid Tumors and Brain Tumors. Clin Cancer Res. 2019;25(8):2560-74. 
12. 
Maachani UB, Tosi U, Pisapia DJ, Mukherjee S, Marnell CS, Voronina J, et al. B7-H3 as a 
Prognostic Biomarker and Therapeutic Target in Pediatric central nervous system Tumors. 
Transl Oncol. 2020;13(2):365-71. 
13. 
Kramer K, Kushner B, Heller G, Cheung NK. Neuroblastoma metastatic to the central 
nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature 
Review. Cancer. 2001;91(8):1510-9. 
14. 
Berthold F, Spix C, Kaatsch P, Lampert F. Incidence, Survival, and Treatment of Localized 
and Metastatic Neuroblastoma in Germany 1979-2015. Paediatr Drugs. 2017;19(6):577-93. 


 
 
 
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15. 
Berthold F, Hömberg M, Baadsgaard O. Neuroblastoma metastatic to the central nervous 
system: Survival analyses from the German Childhood Cancer Registry and the literature 
2017 [Available from: http://meetinglibrary.asco.org/record/153150/abstract. 
16. 
Kramer K, Pandit-Taskar N, Humm JL, Zanzonico PB, Haque S, Dunkel IJ, et al. A phase 
II study of radioimmunotherapy with intraventricular. Pediatr Blood Cancer. 2018;65(1). 
17. 
Merino ME, Navid F, Christensen BL, Toretsky JA, Helman LJ, Cheung NK, et al. 
Immunomagnetic purging of Ewing's sarcoma from blood and bone marrow: quantitation 
by real-time polymerase chain reaction. J Clin Oncol. 2001;19(16):3649-59. 
18. 
Modak S, Gerald W, Cheung NK. Disialoganglioside GD2 and a novel tumor antigen: 
potential targets for immunotherapy of desmoplastic small round cell tumor. Med Pediatr 
Oncol. 2002;39(6):547-51. 
19. 
Zhou Z, Luther N, Ibrahim GM, Hawkins C, Vibhakar R, Handler MH, et al. B7-H3, a 
potential therapeutic target, is expressed in diffuse intrinsic pontine glioma. J Neurooncol. 
2013;111(3):257-64. 
20. 
Modak S, Guo HF, Humm JL, Smith-Jones PM, Larson SM, Cheung NK. 
Radioimmunotargeting of human rhabdomyosarcoma using monoclonal antibody 8H9. 
Cancer Biother Radiopharm. 2005;20(5):534-46. 
21. 
U.S. Department of Health and Human Services Food and Drug Administration. ICH 
Guidance for Industry: S9 Nonclinical Evaluation for Anticancer Pharmaceuticals. 2010. 
22. 
U.S. Department of Health and Human Services Food and Drug Administration. Oncology 
Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations 
Guidance for Industry. Center for Drug Evaluation and Research (CDER). 2019. 
23. 
Kramer K, Pandit-Taskar N, Zanzonico P, Wolden SL, Humm JL, DeSelm C, et al. Low 
incidence of radionecrosis in children treated with conventional radiation therapy and 
intrathecal radioimmunotherapy. J Neurooncol. 2015;123(2):245-9. 
24. 
Luther N, Cheung NK, Dunkel IJ, Fraser JF, Edgar MA, Gutin PH, et al. Intraparenchymal 
and intratumoral interstitial infusion of anti-glioma monoclonal antibody 8H9. 
Neurosurgery. 2008;63(6):1166-74; discussion 74. 
25. 
Luther N, Zhou Z, Zanzonico P, Cheung NK, Humm J, Edgar MA, et al. The potential of 
theragnostic ¹²⁴I-8H9 convection-enhanced delivery in diffuse intrinsic pontine glioma. 
Neuro Oncol. 2014;16(6):800-6. 
26. 
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, 
et al. The 2016 World Health Organization Classification of Tumors of the Central 
Nervous System: a summary. Acta Neuropathol. 2016;131(6):803-20. 
27. 
United States Nuclear Regulatory Commission. Consolidated Guidance About Materials 
Licenses. Program-Specific Guidance About Medical Use Licenses. NUREG-1556. 
2019;Volume 9 Rev. 3. 
28. 
U.S. Nuclear Regulatory Commision. REGULATORY GUIDE 8.39 [REVISION 1]. 
RELEASE OF PATIENTS ADMINISTERED RADIOACTIVE MATERIAL 2020. 
29. 
European Union. Ethical considerations for clinical trials on medicinal products conducted 
with minors. Recommendations of the expert group on clinical trials for the 
implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products 
for human use. Revision 1 2017 [07-May-2021]. Available from: 
https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-
10/2017_09_18_ethical_consid_ct_with_minors.pdf. 
 
 


 
 
 
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10. APPENDICES 
Appendix 1: Clinical Laboratory Evaluations 
The following clinical laboratory analytes will be assessed locally at the site: 
Chemistry: 
Hematology (CBC): 
Albumin 
Hematocrit 
ALP 
Hemoglobin 
ALT 
MCH 
AST 
MCHC 
BUN 
MCV 
Calcium 
Platelet count  
Chloride  
Red blood cell (RBC) count 
Creatinine  
White blood cell (WBC) count 
Glucose 
WBC differential 
LDH 
(% & absolute): 
Potassium 
Basophils 
Sodium 
Eosinophils 
Total bilirubin 
Lymphocytes 
Total CO2 (measured as bicarbonate) 
Monocytes 
Total protein 
Neutrophils 
Triglycerides 
 
Uric acid 
For females of childbearing potential only: 
Urine or serum pregnancy test (only at the 
timepoints indicated in Appendix 3) 
CSF 
Total protein 
Glucose 
Cell count 
Cytology 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CO2 = carbon dioxide; 
LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cell; WBC = white 
blood cell. 
If clinical signs of infection are observed following IMP infusion, the drawn CSF and 
blood samples must be cultured at the local microbiological laboratory. 
 


 
 
 
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Appendix 2: Regulatory, Ethical, and Trial Oversight Considerations 
Regulatory and Ethical Considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
• Ethical considerations for clinical trials on medicinal products conducted with minors29 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• Applicable laws and regulations. 
The protocol, protocol amendments, patient information, ICF, investigator’s brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an Institutional Review Board 
(IRB)/Ethics Committee (EC) by the investigator and reviewed and approved by the IRB/EC 
before the trial is initiated. 
• Any amendments to the protocol will require regulatory and IRB/EC approval before 
implementation of changes made to the trial design, except for changes necessary to 
eliminate an immediate hazard to trial patients. 
The investigator will be responsible for the following: 
• Ensuring the trial is conducted in accordance with the procedures and evaluations 
described in this protocol. Deviations from the protocol should not occur. If deviations do 
occur, the investigator has to inform the CRA for discussion and decision on required 
action(s). Deviations should be documented in writing including an explanation. 
Documentation of deviations will be filled in the investigator’s site file and a copy in the 
Sponsor’s file. Depending on the nature of the deviation, this may be reported to the 
appropriate regulatory authority 
• Providing written summaries of the status of the trial to the IRB/EC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC 
• Notifying the IRB/EC of serious adverse events or other significant safety findings as 
required by IRB/EC procedures 
• Providing oversight of the conduct of the trial at the site and adherence to requirements of 
21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations. 


 
 
 
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Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. Insurance and liability will 
be in accordance with applicable local laws and regulations and GCP. 
Informed Consent 
The investigator or his/her designee must obtain the written informed consent from each patient, 
and/or the patient’s acceptable authorized representative, before any trial-related procedures are 
performed, as applicable to local regulations. If 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. However, if 
this is placed as part of a standard of care at site, this is not considered as a trial procedure and 
hence not requiring informed consent prior to the procedure. A separate ICF will be issued for 
the circulating tumor DNA (ctDNA) and primary tumor DNA assessments, for patients who wish 
to consent to that analysis. 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]), if applicable, 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 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 or legal representative), 
and if applicable informed assent (child/adolescent), must be signed in accordance with local 
regulations. The patient information will be updated in case of new information that may affect a 
patient’s decision to participate in or remain in the trial. 
If applicable to local regulations: if a child turns 18 during his/her participation in the trial, a 
written consent must be obtained from him/her before the trial can continue. 
Before signing the ICF, the patient/parents must be given sufficient time to consider the possible 
participation. Further, each patient must be informed about their right to withdraw 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 ICF has been signed, the 
patient/parent(s) receives a copy of the signed form and the original is retained in the 
investigative site file. A second copy may be kept in the patient’s medical notes. The ICFs must 
be signed and dated both by the signee and by the person providing the information to the 
patient/parents. It is recommended to notify the patient’s family doctor of the patient’s consent to 
participate in the trial. 


 
 
 
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Informed consent must be obtained before any trial-related procedures. The placement of the 
indwelling intracerebroventricular access device (e.g., Ommaya reservoir) is a surgical procedure 
requiring general anesthesia. Having the neurosurgeon place the Ommaya in association with the 
anesthesia induced for the surgical resection of the tumor will reduce the burden of the trial 
procedures by avoiding an extra surgical procedure. Another consideration is that since the 
patient may receive high-dose chemotherapy in the period leading up to the screening period, 
this may be associated with myelosuppression rendering an invasive procedure like Ommaya 
placement not feasible. There is, therefore, a rationale for allowing placement of the Ommaya 
reservoir prior to screening for patients who are potential candidates for trial participation, in 
particular for patients who are not being resected to R0 classification. In cases where the 
potential patient is a referral patient, the investigator should discuss trial inclusion and exclusion 
criteria with the referring physician, and only patients deemed eligible for the trial should be 
considered for Ommaya placement in connection with tumor resection. In this case, the informed 
consent must be obtained prior to the surgery, and may be done so up to 2 months before the start 
of the screening period. 
Patient Data Protection 
Patients will be assigned a unique identifier and will not be identified by name in electronic case 
report forms (eCRFs), trial-related forms, study reports, or any related publications. Patient and 
investigator personal data will be treated in compliance with all applicable laws and regulations. 
In the event the trial protocol, study report, or trial data are included in a public registry, all 
identifiable information from individual patients or investigators will be redacted according to 
applicable laws and regulations. 
The patient must be informed that his/her personal trial-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient. The patient must also be informed that his/her medical records may be examined by 
sponsor or Contract Research Organization auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/EC members, and by inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the trial, as well as all information collected and/or 
documented during the course of the trial, will be regarded as confidential. The investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All patient data relating to the trial will be entered on eCRFs, unless directly transferred 
to the sponsor or designee electronically (e.g., laboratory data). 
• All directly transferred data to the sponsor must be described in a Data Transfer 
Agreement (DTA) which must be signed by sponsor and the laboratory transferring data. 


 
 
 
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• The investigator must maintain accurate documentation (source data) and complete a 
source data list, defining where the specific source data that supports the information 
entered in the eCRF can be found. 
• The investigator must permit trial-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• The sponsor or designee is responsible for the data management of this trial including 
quality checking of the data. Predefined, agreed risks, monitoring thresholds, quality 
tolerance thresholds, controls, and mitigation plans will be documented in Xcellerate 
Risk and Issue Management system (XRIM). Additional details of quality checking to be 
performed on the data may be included in the data management plan and the data review 
plan. 
• Trial monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of patients are being protected; and that the 
trial is being conducted in accordance with the currently approved protocol and any other 
trial agreements, ICH GCP, data management plan, and all applicable regulatory 
requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this trial 
must be retained by the investigator in accordance with 21 CFR 312.62(c) (US sites) or in 
the trial site archive for at least 25 years after the end of the trial (European sites) unless 
local regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification to 
the sponsor. 
Investigator Documentation Responsibilities 
All individual, patient-specific trial data will be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system on an eCRF, containing edit checks on individual fields 
where deemed necessary, in a timely fashion. It is expected that data is entered in the eCRF 
within 5 working days; however, dosing and any AEs in Part 1 Cycle 1 should be entered within 
24 hours. In case of data entry delay for Part 1 Cycle 1, the site is to confirm that the patient 
received the dose as per protocol and that any AEs (including DLTs) have been reported. All 
data generated from external sources (e.g., central laboratory, pharmacokinetics central readers) 
and transferred to the sponsor or designee electronically will be integrated with the patient’s 
eCRF data in accordance with the data management plan and the applicable Data Transfer 
Agreements. 
An eCRF must be completed for each patient who signs an ICF and undergoes any pre-screening 
or screening procedures, according to the eCRF completion instructions. The investigator will 
ensure that corrections are made to the eCRFs and that data queries are resolved in a timely 
fashion by the trial staff. 


 
 
 
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The investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the investigator reviewed and approved the 
accuracy of the data on the eCRF, the data queries, and the site notifications. The data will be 
considered clean and final upon signature from the investigator. 
Publications 
If on completion of the trial the data warrant publication, the investigator may publish the results 
in recognized (refereed) scientific journals subject to the provisions of the clinical trial 
agreement (CTA). Unless otherwise specified in the CTA, the following process shall occur: 
The institution and investigator shall not publish or present data from an individual trial center 
until the complete multicenter trial has been presented in full or for 2 years after the termination 
of the multicenter trial, whichever occurs first. Subsequent publications must refer to the 
multicenter findings. Thereafter, if the investigator expects to participate in the publication of 
data generated from this site, the institution and investigator shall submit reports, abstracts, 
manuscripts, and/or other presentation materials to the sponsor for review before submission for 
publication or presentation. The sponsor shall have 60 days to respond with any requested 
revisions, including (without limitation) the deletion of confidential information. The 
investigator shall act in good faith upon requested revisions, except the investigator shall delete 
any confidential information from such proposed publications. The investigator shall delay 
submission of such publication or presentation materials for up to an additional 90 days in order 
to have a patent application(s) file


 
 
 
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Appendix 3: Schedule of Assessments 
Table 6: 
Schedule of Assessments – Part 1, Screening and Cycle 1 
Dosing/Measurements/Evaluations 
Screening 
177Lu-DTPA-omburtamab Treatment Period1,2 – Cycle 1 
Day -29* to -1 
Day 1  
Day 8 
(±1) 
Day 15 
(±1) 
Day 22 
(±1) 
End-of-Cycle Visit (Day 29 
[±1]) 
Informed consent3 
X 
 
 
 
 
 
Eligibility check 
X 
 
 
 
 
 
Demographics, height, body weight 
X 
 
 
 
 
 
Medical, surgical, and disease history 
X 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
Physical examination4 
X 
 
 
 
 
 
Vital signs5 
X 
X 
X 
X 
X 
X 
Performance test6 
X7 
 
 
 
 
 
MRI of the brain and spine8 
X7 
 
 
 
 
 
Neurological examination9 
X 
X 
 
 
 
 
Placement of indwelling ICV access device 
X3 
 
 
 
 
 
ICV access device patency/CSF flow assessment 
X 
 
 
 
 
 
Premedication (oral dexamethasone/IV equivalent)10 
 
X 
X 
 
 
 
Anti-pyretic and anti-histaminergic premedication11 
 
X 
X 
 
 
 
ICV 177Lu-DTPA-omburtamab dosimetry dose 
 
X 
 
 
 
 
ICV 177Lu-DTPA-omburtamab treatment dose  
 
 
X 
 
 
 
Whole-body planar gamma camera scan12 
 
X12 
X12 
X12 
 
 
Blood and CSF for calculation of absorbed doses13 
 
X13 
 
X13 
 
 
Clinical chemistry and hematology14 
X 
X 
X 
X 
X 
X 
CSF for cytology15, total protein, glucose, and cell count 
X7 
 
 
 
 
 
Blood and CSF for culture  
 
X16 
X16 
 
 
 
Blood and CSF sampling for ADA17 
X17 
 
 
 
 
 
Blood and CSF sampling for pharmacokinetics 
 
 
X18 
X18 
 
 
Pregnancy testing19 
X 
X 
X 
 
 
Adverse events20 
X 
X 
 
X 
X 
X 
Abbreviations: ADA = anti-drug antibody; AE = adverse event; CSF = cerebrospinal fluid; ctDNA = circulating tumor deoxyribonucleic acid; EOT = end of treatment; HSA = 
human serum albumin; ICF = informed consent form; ICV = intracerebroventricular; IMP = investigational medicinal product; IV = intravenous; MRI = magnetic resonance 
imaging; NCI = National Cancer Institute; SAE = serious adverse event. 


 
 
 
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* A longer screening period (e.g., due to logistics, COVID-19 situations etc.) are allowed; however, eligibility evaluation must be re-confirmed. Screening period of >60 days with 
individual patient considerations to be discussed with the sponsor. 
1 The 177Lu-DTPA-omburtamab Treatment Period is divided into 5-week cycles. In Part 1, the patient can receive up to 2 cycles at the discretion of the investigator. Cycle 1 starts 
with a dosimetry dose on Day 1 and continues with the first treatment dose on Day 8 (adjustments to the dosing schedule will be accommodated on a patient-by-patient basis 
depending on the clinical condition of the patient). The infusion reservoir must be flushed with HSA and CSF after each infusion. On dosing days, all assessments are done before 
dosing. 
2 If the IMP is discontinued after Cycle 1, the Day 29 Visit is replaced by the EOT Visit. 
3 Informed consent must be obtained before any trial-related procedures. If the indwelling ICV 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, unless this is placed as part of a standard of care procedure at site. If any 
procedures/tests are from before informed consent is obtained, it must be clear from source documents that this was not performed for the purpose of the present trial. In these 
cases, the procedures/tests do not need to be repeated at the Screening Visit if they were performed within the allowed timelines. The investigator is responsible for documenting 
this properly. 
4 Physical examinations to be performed at screening and as clinically indicated. 
5 Measurements of heart rate, respiratory rate, temperature, and blood pressure. On dosing days, measurements to be taken before and 30 min after the end of the IMP infusion. 
6 Lansky Scale 16 years, Karnofsky Scale ≥16 years. 
7 To be performed within 3 weeks prior to the first IMP infusion. May be performed on the first dosing day but it must be before IMP administration. 
8 MRI of the brain and spine will be completed before first IMP administration, at the EOT Visit (preferably ±4 days of the actual visit date). MRI can be performed on a separate day 
to the other visit assessments, if required, in accordance with investigational site standards. 
9 Will be used to evaluate safety and efficacy. 
10 Beginning 24 hours before IMP administration, divided into twice-daily doses for a total of 3 days. 
11 Given 1-2 hours prior to IMP administration, including oral acetaminophen/paracetamol and antihistamine (e.g., diphenhydramine). 
12 Following the dosimetry dose, whole-body planar gamma camera scans will be performed at 4 h (4-5 h), 24 h (22-26 h), 48 h (46-50 h), and Day 5-7 (may be performed on Day 8; 
however, must prior to the treatment dose), and on Day 15 (±12 hours), i.e., 7 days after administration of the treatment dose (see Table 4). SPECT imaging is optional at 24 h (22-
24 h), 72 h (70-74), Day 5-7 (or Day 8 pre-dose), and on Day 15 (±1) (i.e., 7 days after the treatment dose). 
13 Approximately 0.5 mL of CSF and 2 mL of peripheral blood will be drawn at each timepoint (see Table 4), i.e., before treatment (baseline; to avoid withdrawing too high volumes 
of CSF on the day of the dosimetry dose, baseline sample should be drawn in the time between placement of the ICV access device and 1 day before dosing) and following the 
dosimetry dose at 30 min (±5 min), 1 h (±10 min), 4 h (±10 min), 24 h (±30 min), 48 h (±1 h) and 72 h (±4 hour) In addition, samples are drawn on Day 5-7 (may be on Day 8; 
however, must be prior to the treatment dose) and on Day 15 (±12 hr), i.e., 7 days after administration of the treatment dose. 
14 In accordance with Appendix 1. 
15 If CSF cytology sample is positive, it must be repeated within 4 weeks of the positive sampling. 
16 Drawn and held for culture only if elevated body temperature after dosing suggests infection rather than expected response to ICV dosing. Samples to be taken within 6 hours after 
completion of IMP infusion. 
17 The baseline ADA samples must be drawn prior to the dosimetry dose and to avoid withdrawing too high volumes of CSF on the day of the dosimetry dose, the samples should be 
drawn in the time between placement of the ICV access device and 1 day before dosing. Serum and CSF samples for ADA analyses will be drawn at baseline and after last 
treatment. Presence of ADA will be analyzed at a central laboratory. 
18 Blood and CSF samples for pharmacokinetics will be drawn as per Table 5. On Day 15 (i.e., 7 days after the treatment dose), blood collection only. 
19 Pregnancy testing (serum or urine) is mandatory for women of childbearing potential at screening, within one week prior to each dose, and at the EOT Visit. 
20 Non-serious AEs should be reported from the day of first IMP administration until 5 weeks after the patient’s last dose of IMP. Non-serious AEs occurring between signing the 
ICF and the first IMP administration must be recorded as medical history. Serious AEs should be reported from signing the ICF until 5 weeks after the patient’s last dose of IMP. 
Thereafter and during the follow-up period, only SAEs or Grade 3 or higher AEs at least possible related to 177Lu-DTPA-omburtamab or to the presence of the indwelling catheter 
system should be reported until end of trial. In the post-trial monitoring period, new onset of cancers, regardless of causality, should be reported. 


 
 
 
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Table 7: 
Schedule of Assessments – Part 1, Cycle 2 (if Applicable) through Follow-up 
Dosing/Measurements/Evaluations 
177Lu-DTPA-omburtamab Treatment Period1,2 – 
Cycle 2 
EOT and End of Trial 
 
Day 1 of cycle 
Day 8 (±1), Day 15 (±1) of cycle 
5 to 6 weeks after last dose  
Prior/concomitant medications 
X 
X 
X 
Physical examination3 
 
 
 
Vital signs4 
X 
X 
X 
Performance test5 
 
 
X 
MRI of the brain and spine6 
 
 
X 
Neurological examination7 
X 
 
X 
Premedication (oral dexamethasone/IV equivalent)8 
X 
 
 
Anti-pyretic and anti-histaminergic premedication9 
X 
 
 
ICV 177Lu-DTPA-omburtamab treatment dose 
X 
 
 
Clinical chemistry and hematology10 
X 
X 
X 
CSF for cytology11, total protein, glucose, and cell count 
 
 
X 
Blood and CSF for culture 
X12 
 
 
Blood and CSF sampling for ADA 
X13 
 
X 
Blood and CSF sampling for pharmacokinetics 
X14 
X14 
 
Pregnancy testing15 
X 
 
X 
Adverse events16 
X 
X 
X 
Abbreviations: ADA = anti-drug antibody; AE = adverse event; CSF = cerebrospinal fluid; ctDNA = circulating tumor deoxyribonucleic acid; EOT = end of treatment; HSA = 
human serum albumin; ICF = informed consent form; ICV = intracerebroventricular; IMP = investigational medicinal product; IV = intravenous; MRI = magnetic resonance 
imaging; NCI = National Cancer Institute; SAE = serious adverse event. 
1 The 177Lu-DTPA-omburtamab Treatment Period is divided into 5-week cycles. In Part 1, the patient can receive up to 2 cycles at the discretion of the investigator. Cycle 2 will start 
35 days (adjustments to the dosing schedule will be accommodated on a patient-by-patient basis depending on the clinical condition of the patient.) after the first dose (dosimetry 
dose) of Cycle 1 and will consist of a treatment dose only (i.e., no dosimetry dose), on Day 1 of the cycle. The infusion reservoir must be flushed with HSA and CSF after each 
infusion. 
2 If the IMP is discontinued after Cycle 1, the Cycle 2 visits should be skipped, and after the EOT Visit should be done. 
3 Physical examinations to be performed as clinically indicated. 
4 Measurements of heart rate, respiratory rate, temperature, and blood pressure. On dosing day, measurements to be taken before and 30 min after the end of the IMP infusion. 
5 Lansky Scale 16 years, Karnofsky Scale ≥16 years. 
6 MRI of the brain and spine will be completed before first IMP administration, at the EOT Visit (preferably ±4 days of the actual visit date). MRI can be performed on a separate day 
to the other visit assessments, if required, in accordance with investigational site standards. 
7 Will be used to evaluate safety and efficacy. 
8 Beginning 24 hours before 177Lu-DTPA-omburtamab administration, divided into twice-daily doses for a total of 3 days. 
9 Given 1-2 hours prior to 177Lu-DTPA-omburtamab administration, including oral acetaminophen/paracetamol and antihistamine (e.g., diphenhydramine). 
10 In accordance with Appendix 1. 
11 If CSF cytology sample is positive, it must be repeated within 4 weeks of the positive sampling. 


 
 
 
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12 Drawn and held for culture only if elevated body temperature after dosing suggests infection rather than expected response to ICV dosing. Samples to be taken within 6 hours after 
completion of 177Lu-DTPA-omburtamab infusion. 
13 The ADA samples must be drawn prior to the Cycle 2 dose. The analysis can be performed from the samples drawn with the purpose of PK. 
14 Blood and CSF samples for pharmacokinetics will be drawn as per Table 5. On Day 8, blood collection only. 
15 Pregnancy testing (serum or urine) is mandatory for women of childbearing potential at screening, within one week prior to each dose, and at the EOT Visit. 
16 Non-serious AEs should be reported from the day of first IMP administration until 5 weeks after the patient’s last dose of IMP. Non-serious AEs occurring between signing the ICF 
and the first IMP administration must be recorded as medical history. Serious AEs should be reported from signing the ICF until 5 weeks after the patient’s last dose of IMP. 
Thereafter and during the follow-up period, only SAEs or Grade 3 or higher AEs at least possible related to 177Lu-DTPA-omburtamab or to the presence of the indwelling catheter 
system should be reported until end of trial. During the post-trial monitoring period, new onset of cancers, regardless of causality, should be reported. 
 


 
 
 
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Table 8: 
Schedule of Assessments – Part 2 (All Cycles) 
Dosing/Measurements/Evaluations 
Screening 
177Lu-DTPA-omburtamab 
Treatment Period1,2 
EOT  
Follow-up3 
Cycles 1 through 5 
Day -29* 
to -1 
Day 
1 of 
cycle 
Day 15 
(±1) of 
cycle 
End-of-
Cycle Visit 
(Day 29 [±1] 
of cycle) 
5 to 6 
weeks 
after last 
dose 
26, 39, and 52 (±2) 
weeks post first 
dose 
78 and 104 (±2) 
weeks post first 
dose 
Informed consent4 
X 
 
 
 
 
 
 
Eligibility check 
X 
 
 
 
 
 
 
Demographics, height, body weight 
X 
 
 
 
 
 
 
Medical, surgical, and disease history 
X 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X5 
X5 
Physical examination6 
X 
 
 
 
 
 
 
Vital signs7 
X 
X 
X 
X 
X 
X 
X 
Performance test8 
X9 
 
 
 
X 
X8 
X8 
MRI of the brain and spine10 
X9 
 
 
X10 
X 
X 
X 
Neurological examination11 
X 
X 
 
X 
X 
X 
X 
Placement of an indwelling ICV access device 
X4 
 
 
 
 
 
 
ICV access device patency/CSF flow assessment 
X 
 
 
 
 
 
 
Premedication (oral dexamethasone/IV equivalent)12 
 
X 
 
 
 
 
 
Anti-pyretic and anti-histaminergic premedication13 
 
X 
 
 
 
 
 
ICV 177Lu-DTPA-omburtamab treatment dose1 
 
X 
 
 
 
 
 
Clinical chemistry and hematology14 
X 
X 
X 
X 
X 
X 
 
CSF for cytology15, total protein, glucose, and cell 
count 
X9 
 
 
X16 
X 
X 
X 
Blood and CSF for culture 
 
X17 
 
 
 
 
 
Blood and CSF sampling for ADA 
X18 
X18 
 
 
X 
 
 
Blood and CSF sampling for pharmacokinetics 
 
X19 
 
 
 
 
 
Pregnancy testing20 
X 
X 
 
X 
X 
 
 
Adverse events21 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ADA = anti-drug antibody; AE = adverse event; CSF = cerebrospinal fluid; ctDNA = circulating tumor deoxyribonucleic acid; EOT = end of treatment; HSA = 
human serum albumin; ICF = informed consent form; ICV = intracerebroventricular; IMP = investigational medicinal product; IV = intravenous; MRI = magnetic resonance 
imaging; NCI = National Cancer Institute; SAE = serious adverse event. 
* A longer screening period (e.g., due to logistics, COVID-19 situations etc.) are allowed; however, eligibility evaluation must be re-confirmed. Screening period of >60 days with 
individual patient considerations to be discussed with the sponsor. 


 
 
 
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1 The 177Lu-DTPA-omburtamab Treatment Period is divided into 5-week cycles. In Part 2, a cycle consists of a treatment dose on Day 1. The patient can receive up to 5 cycles at the 
discretion of the investigator. The infusion reservoir must be flushed with HSA and CSF after each infusion. The patient will be observed post treatment to decide if further cycles 
can be administered. 
Day 1, 15, and 29 for Cycles 2 to 5 correspond to Day 36, 50, and 64 (for Cycle 2), Day 71, 85, 99 (for Cycle 3), 106, 120, 134 (for Cycle 4), and 141, 155, and 169 (for Cycle 5). 
Adjustments to the dosing schedule will be accommodated on a patient-by-patient basis depending on the clinical condition of the patient. 
2 If the IMP is discontinued prior to completion of all scheduled visits of the cycle (i.e., up to and including Day 29), the treatment visits that fall after the date of the EOT Visit 
should be skipped, and the patient should move directly into the follow-up phase. If the IMP is discontinued after Cycle 1, an unscheduled visit (including MRI etc.) should be 
done at 13 weeks post first dose. 
3 All patients who are dosed with 177Lu-DTPA-omburtamab in Part 2 should be followed up regularly (every 13 [±2] weeks, i.e., 26, 39, and 52 weeks post first dose, then every 26 
[±2] weeks, i.e., 78 and 104 weeks post first dose, and thereafter annually) for monitoring of secondary malignancies during the trial and for at least 10 years after the end of trial, 
or until death, if sooner. 
4 Informed consent must be obtained before any trial-related procedures. If the indwelling ICV 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, unless this is placed as part of a standard of care procedure at site. If any 
procedures/tests are from before informed consent is obtained, it must be clear from source documents that this was not performed for the purpose of the present trial. In these 
cases, the procedures/tests do not need to be repeated at the Screening Visit if they were performed within the allowed timelines. The investigator is responsible for documenting 
this properly. 
5 Only anti-cancer therapy. 
6 Physical examinations to be performed at screening and as clinically indicated. 
7 Measurements of heart rate, respiratory rate, temperature, and blood pressure. On dosing days, measurements to be taken before and 30 min after the end of the IMP infusion. 
8 Lansky Scale 16 years, Karnofsky Scale ≥16 years. 
9 To be performed within 3 weeks prior to first IMP infusion. May be performed on the first dosing day but it must be before IMP administration. 
10 MRI of the brain and spine will be completed before first IMP administration and at the End-of-Cycle (Day 29) Visit for Cycles 1 and 3 only (±4 days of the actual visit date), EOT 
Visit (preferably ±4 days of the actual visit date), and each Follow-up Visit (±2 weeks of the actual visit date). MRI can be performed on a different day to the other visit 
assessments, in accordance with investigational site standards. 
11 Will be used to evaluate safety and efficacy. 
12 Beginning 24 hours before 177Lu-DTPA-omburtamab administration, divided into twice-daily doses for a total of 3 days. 
13 Given 1-2 hours prior to 177Lu-DTPA-omburtamab administration, including oral acetaminophen/paracetamol and antihistamine (e.g., diphenhydramine). 
14 In accordance with Appendix 1 and until the first follow-up visit. 
15 If CSF cytology sample is positive, it must be repeated within 4 weeks of the positive sampling. 
16 Cycles 1 and 3 only. 
17 Drawn and held for culture only if elevated body temperature after dosing suggests infection rather than expected response to ICV dosing. Samples to be taken within 6 hours after 
completion of 177Lu-DTPA-omburtamab infusion. 
18 The ADA samples must be drawn prior to dosing. Serum and CSF samples for ADA analyses will be drawn at baseline, at the start of Cycle 2 (predose), and after last treatment. 
Presence of ADA will be analyzed at a central laboratory. 
19 Blood and CSF samples for pharmacokinetics will be drawn in Cycles 1 and 2 only, as per Table 5. 
20 Pregnancy testing (serum or urine) is mandatory for women of childbearing potential at screening, prior to each dose, and at the EOT Visit. 
21 Non-serious AEs should be reported from the day of first IMP administration until 5 weeks after the patient’s last dose of IMP. Non-serious AEs occurring between signing the ICF 
and the first IMP administration must be recorded as medical history. Serious AEs should be reported from signing the ICF until 5 weeks after the patient’s last dose of IMP. 
Thereafter and during the follow-up period, only SAEs and Grade 3 or higher AEs at least related to 177Lu-DTPA-omburtamab or to the presence of the indwelling catheter system, 
should be reported. In the post-trial monitoring period, new onset of cancers, regardless of causality, should be reported. 


 
 
 
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Appendix 4: 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 5: Contraceptive Guidance 
Definitions 
Women of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Women of Nonchildbearing Potential: 
1. Surgically sterile: females who are permanently sterile via hysterectomy, bilateral 
salpingectomy, bilateral tubal occlusion, and/or bilateral oophorectomy by reported 
medical history and/or medical records. Surgical sterilization to have occurred a 
minimum of 3 months prior to screening. 
Fertile male: a male that is considered fertile after puberty. 
Infertile male: permanently sterile male via bilateral orchiectomy. 
Contraception Guidance 
Female Patients 
Female patients who are of nonchildbearing potential will not be required to use contraception. 
Female patients of childbearing potential must be willing to use 2 methods (1 primary and 
1 secondary method) of birth control from the time of signing the ICF until 9 weeks after the last 
dose of investigational medicinal product (IMP). Primary (non-barrier) methods of contraception 
include: 
• hormonal injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as prescribed) 
• combined hormonal patch (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• hormonal implant 
• hormonal or non-hormonal intrauterine device 
• vasectomized male partner (sterilization performed at least 90 days prior to the Screening 
Visit, with verbal confirmation of surgical success, and the sole partner for the female 
patient). 


 
 
 
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Secondary (barrier) methods of contraception include: 
• male condom with spermicide 
• female condom with spermicide 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide (as prescribed) 
• diaphragm with spermicide (as prescribed). 
Female patients of childbearing potential should refrain from donation of ova from screening 
until 9 weeks after the last dose of IMP. 
Male Patients 
Male patients will be surgically sterile for at least 90 days, with documented azoospermia, or 
when sexually active with female partners of childbearing potential will be required to use a 
male condom with spermicide from screening until 17 weeks after the last dose of IMP. Sexual 
intercourse with female partners who are pregnant or breastfeeding should be avoided unless 
condoms are used from the time of the first dose until 17 weeks after the last dose of IMP. Male 
patients are required to refrain from donation of sperm from screening until 17 weeks after the 
last dose of IMP. 
Sexual Abstinence and Same-sex Relationships 
Patients who practice true abstinence, because of the patient’s lifestyle choice (i.e., the patient 
should not become abstinent just for the purpose of trial participation), are exempt from 
contraceptive requirements. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a patient 
who is abstinent at the time of signing the ICF becomes sexually active they must agree to use 
contraception as described previously. 
For patients who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a patient who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 


 
 
 
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Appendix 6: Assessment in Pediatric Neuro-oncology (RAPNO) Criteria 
Response definitions: patients must meet ALL criteria in each response/stable disease category, or ANY criteria in the progressive disease category 
 
Complete Response (CR) 
Partial Response (PR) 
Stable Disease 
Progressive Disease (PD) 
Criteria 
Must meet ALL criteria 
Must meet ALL criteria 
Must meet ALL criteria 
Must meet ANY criteria 
MRI-brain 
Complete disappearance of all 
disease (enhancing and non-
enhancing, measurable and 
nonmeasurable) for a minimum 
of 4 weeks; no new lesions 
≥50% decrease (compared with 
baseline) in the sum of the 
products of perpendicular 
diameters of all (up to 4) 
measurable lesions sustained for 
at least 4 weeks; no progression 
of nonmeasurable disease 
Does not meet criteria for 
CR, PR, or PD 
≥25% increase (compared with smallest 
measurement at any timepoint) in the sum of the 
products of perpendicular diameters of all 
measurable lesions; significant progression of 
nonmeasurable disease not attributed to prior 
therapy; any new tumor (any new lesions 
suspected to be treatment related should be 
confirmed by biopsy) 
MRI-spine 
Complete disappearance of all 
disease (enhancing and non-
enhancing, measurable and 
nonmeasurable) for a minimum 
of 4 weeks; no new lesions 
≥50% decrease (compared with 
baseline) in the sum of the 
products of perpendicular 
diameters of all measurable 
lesions sustained for at least 
4 weeks; no progression of 
nonmeasurable disease. If 
negative at baseline, must remain 
negative 
Does not meet criteria for 
CR, PR, or PD 
≥25% increase (compared with smallest tumor 
measurement at any timepoint) in the sum of the 
products of perpendicular diameters of all (up to 
4) measurable lesions; significant progression of 
nonmeasurable disease not attributed to prior 
therapy; any new tumor (any new lesions 
suspected to be treatment related should be 
confirmed by biopsy) 
CSF cytology 
If tumor cells are present at 
baseline, must be negative × 2 
(sampling at least 2 weeks 
apart) 
If absent (negative) at baseline, 
must remain absent. If present at 
baseline, can be present or absent 
If absent at baseline, must 
remain absent. If present at 
baseline, can be present or 
absent 
Previously absent tumor cells in CSF now 
present (positive) 
Neurologic exama 
Stable or improving 
Stable or improving 
Stable or improving 
Clinical deterioration not attributable to other 
causes 
Steroid use 
Off steroids or physiologic 
replacement doses only 
Stable or less than baseline dose 
Stable or less than baseline 
dose 
 
Extra-CNS 
disease 
If positive at any timepoint, 
must be re-evaluated and have 
no evidence of disease 
No new sites of disease 
No new sites of disease 
New sites of disease 
Serum or CSF 
AFP, βhCG (if 
obtained, eg, 
germ cell tumors) 
Must be within normal range 
for age 
 
 
A previously negative (normal) assessment 
becomes positive 
Abbreviations: βhCG=beta human chorionic gonadotropin; AFP=alpha-fetoprotein; CNS=central nervous system; CSF=cerebrospinal fluid; MRI=magnetic resonance imaging. 
a If it is unclear that the patient has disease progression, it may be a reasonable option to keep the patient on study until subsequent assessments (e.g., MRI, CSF cytology) confirm 
progression. If subsequent testing confirms progression, the date of progression should be backdated to the onset of neurologic deterioration. 
Adapted from Warren et al. 201810. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761545/ 


 
 
 
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Appendix 7: Intracerebroventricular Access Device/CSF Flow Assessment 
The following is an example of intracerebroventricular access device (e.g., Ommaya)/CSF flow 
assessment. Local assessment may be used in case this fulfils similar requirements. 
CSF CISTERNOGRAM: 
Evaluate CSF circulation 
INDICATIONS: 
Determine patency and flow from indwelling intracerebroventricular access 
device (e.g., Ommaya) 
PATIENT PREPARATION: 
None 
Radiopharmaceutical: 
Indium (In) 111 Diethylenetriamine Pentaacetic Acid (111In-DTPA) 
Dose: 
0.5 mCi for cisternal infusion via indwelling intracerebroventricular access 
device (e.g., Ommaya) 
Instrument: 
Dual-detector gamma camera 
Isotope Energy Peak: 
111In-DTPA: Medium Energy General Purpose (MEGP) 173, 247 keV 
Energy Window Width: 
20% 
 
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 should be recorded at 4, 6, and 24 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. Single-photon emission computed tomography (SPECT) images (optional) may be 
recorded in a 128 × 128 matrix for 30 seconds per 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 (after infusion of the 
radiopharmaceutical), and spread over the convexities by 24 hours. 
Only patients with sufficient flow should be dosed. Efforts to correct CSF flow can be 
installed and if sufficient flow is established, the patient should be dosed (see exclusion 
criterion # 1. 
 


Signature Page for CLIN-000019 v8.0
Signature Page for CLIN-000019 v8.0
Approval
Charlotte Lybek Lind
Clinical
25-Feb-2022 12:22:41 GMT+0000
Approval
Maria Düring
Biometrics
25-Feb-2022 12:38:17 GMT+0000
Approval
Lone Nørgård Troelsen
Medical
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