A Multicenter Open-label Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With Somatostatin Receptor Positive Gastroenteropancreatic Neuroendocrine (GEP-NET) Tumors, Pheochromocytoma and Paragangliomas (PPGL)
Phase: PHASE2
Conditions: Gastroenteropancreatic Neuroendocrine Tumors, Pheochromocytoma, Paraganglioma
Sponsor: Advanced Accelerator Applications

Advanced Accelerator Applications 
Research and Development 
LUTATHERA® (lutetium Lu 177 dotatate) 
Clinical Trial Protocol CAAA601A32201 / NCT04711135
A multicenter open-label study to evaluate safety and 
dosimetry of Lutathera in adolescent patients with 
somatostatin receptor positive gastroenteropancreatic 
neuroendocrine (GEP-NET) tumors, pheochromocytoma 
and paragangliomas  
Property of Advanced Accelerator Applications, a Novartis Company 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Advanced Accelerator Applications 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-002951-39 
Version number: 
03 (Clean) 
Clinical Trial Phase: 
II 
Release date: 
14-Dec-2023 (content final)

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ................................................................................................................ 9 
Protocol summary ............................................................................................................. 11 
Protocol Amendment 03 ........................................................................................................... 16 
Protocol Amendment 02 ........................................................................................................... 18 
Protocol Amendment 01 ........................................................................................................... 19 
1 
Introduction ....................................................................................................................... 23 
1.1 
Background ........................................................................................................... 23 
1.2 
Purpose .................................................................................................................. 25 
2 
Objectives and endpoints .................................................................................................. 27 
3 
Study design ...................................................................................................................... 28 
4 
Rationale ........................................................................................................................... 30 
4.1 
Rationale for study design ..................................................................................... 30 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 32 
4.3 
Rationale for duration of follow-up ....................................................................... 33 
4.4 
Rationale for study population .............................................................................. 35 
4.5 
Risks and benefits .................................................................................................. 35 
4.5.1 
Blood sample volume ........................................................................... 37 
5 
Study Population ............................................................................................................... 37 
5.1 
Inclusion criteria .................................................................................................... 37 
5.2 
Exclusion criteria ................................................................................................... 38 
6 
Treatment .......................................................................................................................... 39 
6.1 
Study treatment ...................................................................................................... 39 
6.1.1 
Investigational drug .............................................................................. 39 
6.1.2 
Additional study treatments .................................................................. 40 
6.1.3 
Supply of study treatment ..................................................................... 41 
6.2 
Other treatment(s) .................................................................................................. 41 
6.2.1 
Concomitant therapy ............................................................................. 41 
6.2.2 
Prohibited medication ........................................................................... 41 
6.2.3 
Rescue medication ................................................................................ 42 
6.2.4 
SARS-CoV-2 vaccination ..................................................................... 42 
6.2.5 
Restriction for study participants .......................................................... 43 
6.3 
Participant numbering, treatment allocation ......................................................... 43 
6.3.1 
Participant numbering ........................................................................... 43 
6.3.2 
Treatment allocation ............................................................................. 43 

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6.4 
Treatment blinding ................................................................................................ 43 
6.5 
Dose escalation and dose modification ................................................................. 43 
6.5.1 
Dose modification ................................................................................. 43 
6.5.2 
Dose discontinuation ............................................................................. 47 
6.6 
Additional treatment guidance .............................................................................. 48 
6.6.1 
Treatment compliance ........................................................................... 48 
6.6.2 
Recommended treatment of adverse events .......................................... 48 
6.7 
Preparation and administration of Lutathera and sterile amino acid solution ....... 48 
6.7.1 
Handling of study treatment and additional treatment .......................... 49 
7 
Informed consent procedures ............................................................................................ 50 
8 
Visit schedule and assessments ......................................................................................... 51 
8.1 
Screening ............................................................................................................... 58 
8.1.1 
Screening .............................................................................................. 58 
8.1.2 
Information to be collected on screening failures ................................. 58 
8.2 
Participant demographics/other baseline characteristics ....................................... 58 
8.3 
Dosimetry .............................................................................................................. 59 
8.3.1 
Whole body planar and SPECT/CT Images ......................................... 60 
8.3.2 
Methods used to estimate absorbed radiation doses ............................. 60 
8.3.3 
Biological samples for PK and dosimetry analysis .............................. 60 
8.3.4 
Dosimetry equipment and timepoints ................................................... 61 
8.3.5 
Dosimetry and PK parameters .............................................................. 62 
8.4 
Safety assessments ................................................................................................ 62 
8.4.1 
Adverse Event Monitoring .................................................................... 62 
8.4.2 
Physical examination ............................................................................ 62 
8.4.3 
Vital signs ............................................................................................. 63 
8.4.4 
Height and Weight ................................................................................ 63 
8.4.5 
ECG ...................................................................................................... 63 
8.4.6 
Laboratory evaluations ......................................................................... 64 
8.4.7 
Urinalysis .............................................................................................. 65 
8.4.8 
Pregnancy Test ...................................................................................... 66 
8.4.9 
Safety biomarkers ................................................................................. 66 
8.4.10 
Performance score assessment .............................................................. 67 
8.4.11 
Tumor response assessment .................................................................. 67 
9 
Study discontinuation and completion .............................................................................. 67 
9.1 
Discontinuation and completion ............................................................................ 67 
9.1.1 
Study treatment discontinuation and study discontinuation ................. 67 
9.1.2 
Withdrawal of informed consent .......................................................... 69 
9.1.3 
Lost to follow-up .................................................................................. 69 
9.1.4 
Early study termination by the sponsor ................................................ 70 

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9.2 
Study completion and post-study treatment .......................................................... 70 
10 Safety monitoring and reporting ....................................................................................... 70 
10.1 
Definition of adverse events and reporting requirements ..................................... 70 
10.1.1 
Adverse events (AE) ............................................................................. 70 
10.1.2 
Serious adverse events (SAE) ............................................................... 72 
10.1.3 
Adverse Drug Reactions (ADR) ........................................................... 74 
10.1.4 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ............ 74 
10.1.5 
Adverse Events of Special Interest ....................................................... 74 
10.1.6 
SAE and AESI reporting ....................................................................... 76 
10.1.7 
Pregnancy reporting .............................................................................. 77 
10.1.8 
Reporting of study treatment errors including misuse/abuse ................ 77 
10.1.9 
Reporting rules: summary ..................................................................... 78 
10.2 
Additional Safety Monitoring ............................................................................... 78 
10.2.1 
Data and Safety Monitoring Board ....................................................... 78 
11 Data Collection and Database management ...................................................................... 79 
11.1 
Data collection ....................................................................................................... 79 
11.2 
Database management and quality control ............................................................ 79 
11.3 
Site monitoring ...................................................................................................... 79 
12 Data analysis and statistical methods ................................................................................ 80 
12.1 
Analysis sets .......................................................................................................... 81 
12.2 
Participant demographics and other baseline characteristics ................................ 81 
12.3 
Treatments ............................................................................................................. 81 
12.4 
Analysis of the primary endpoints ......................................................................... 81 
12.4.1 
Definition of primary endpoints ........................................................... 81 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 82 
12.4.3 
Handling of missing values ................................................................... 82 
12.5 
Analysis of secondary endpoints ........................................................................... 82 
12.5.1 
Comparative assessment of Dosimetry/PK in adolescents and 
adults ..................................................................................................... 82 
12.5.2 
Safety endpoints .................................................................................... 82 
 
 84 
 
 84 
 
 84 
12.7 
Interim analyses ..................................................................................................... 84 
12.8 
Sample size calculation ......................................................................................... 84 
13 Ethical considerations and administrative procedures ...................................................... 85 
13.1 
Regulatory and ethical compliance ....................................................................... 85 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................. 85 
13.3 
Publication of study protocol and results .............................................................. 85 

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13.4 
Quality Control and Quality Assurance ................................................................ 86 
13.5 
Data Protection ...................................................................................................... 87 
14 Protocol adherence ............................................................................................................ 87 
14.1 
Protocol amendments ............................................................................................ 87 
15 References ......................................................................................................................... 89 
16 Appendices ........................................................................................................................ 94 
16.1 
Appendix 1 – Requirements for contraception ...................................................... 94 
16.2 
Appendix 2 – Radioprotection Precautions for Treated with Lutathera 
lutetium Lu 177 dotatate/ lutetium (177Lu) oxodotreotide ..................................... 95 
16.3 
Appendix 3 – National Cancer Institute Common Terminology Criteria for 
Adverse Events ...................................................................................................... 95 
 

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List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 27 
Table 6-1 
Investigational drug .............................................................................. 40 
Table 6-2 
Additional Study Treatment .................................................................. 40 
Table 6-3 
Sterile 2.5% Lys-Arg solution composition ......................................... 40 
Table 6-4 
Recommended Dose Modifications of Lutathera for Adverse 
Events .................................................................................................... 44 
Table 6-5 
Administration procedure of antiemetic, amino acid solution and 
Lutathera ............................................................................................... 49 
Table 8-1 
Central readings and analysis. .............................................................. 52 
Table 8-2 
Assessment Schedule ............................................................................ 53 
Table 8-3 
Dosimetry assessments timepoints ....................................................... 61 
Table 8-4 
Laboratory assessments ........................................................................ 65 
Table 8-5 
Safety biomarker assessments .............................................................. 67 
Table 10-1 
Adverse events of special interest ......................................................... 75 
Table 10-2 
Reporting rules and timeframe ............................................................. 78 
Table 12-1 
Likelihood of observing at least one patient with acute 
toxicity for a sample size of 8 patients and incidence of acute 
toxicities  ............................................................................................... 85 
List of figures 
Figure 3-1. 
Study design .......................................................................................... 29 

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List of abbreviations 
AA 
Amino Acid 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT/ALAT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST/ASAT 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
AxMP 
Auxiliary Medicinal Product 
BALP 
Bone Alkaline Phosphatase 
BCRP 
Breast Cancer Resistance Protein 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
Cl 
Clearance 
Cr 
Creatinine 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTC 
Common Terminology Criteria 
CT 
Computed Tomography 
CTFG 
Clinical Trials Facilitation and Coordination Group 
CTIS 
Clinical Trials Information System 
CTR 
Clinical Trials Register 
CTX 
C-terminal cross-linked telopeptide of type I collagen 
DICOM 
Digital Imaging and Communications in Medicine 
DMT 
Dose Modifying Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EEA 
European Economic Area 
EMA 
European Medicines Agency 
EoT 
End of Treatment 
EoS 
End of Study 
eSource 
Electronic Source 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
FUP 
Follow-up period 
GBq 
Giga becquerel 
GCP 
Good Clinical Practice 
GEP-NETs 
Gastroenteropancreatic Neuroendocrine Tumors 
G1/2 
Grade1/2 
Gy 
Gray 
h 
Hour 
Hb 
Hemoglobin 
i.v. 
Intravenous 
IB 
Investigator’s Brochure 

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ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
ID 
Identification 
IEC 
Independent Ethics Committee 
IGF1 
Insulin-like Growth Factor 1 
IRB 
Institutional Review Board 
LAR 
Long-Acting Release (Octreotide LAR) 
LH 
Luteinizing Hormone 
177Lu 
Lutetium-177 
mCi 
Millicurie 
MCV 
Mean Cell Volume 
MDS 
Myelodysplastic Syndrome 
MedDRA 
Medical dictionary for regulatory activities  
Mg 
Milligram(s) 
M&S 
Modelling and simulation  
mL 
Milliliter(s) 
MRI 
Magnetic Resonance Imaging 
NETs 
Neuroendocrine Tumors 
NTX 
N-terminal cross-linked telopeptide of type I collagen 
PFS 
Progression-free Survival 
PK 
Pharmacokinetic(s) 
PLT 
Platelets 
PPGL 
Pheochromocytoma and paraganglioma 
PRRT 
Peptide Receptor Radionuclide Therapy 
 
 
ROI 
Region Of Interest 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SEER 
Surveillance Epidemiology and End Results Program of the US National Cancer Institute 
SmPC 
Summary of Product Characteristics 
SPECT 
Single Photon Emission Computed Tomography 
SRI 
Somatostatin Receptor Imaging 
SSTR2 
Somatostatin Subtype 2 Receptors 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAC 
Time Activity Curves 
TIAC 
Integrated Activity Coefficient 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper limit of normal 
UPCR 
Urine protein creatinine ratio 
US 
United States of America 
USPI 
United States Prescribing Information 
WBC 
White blood cell(s) 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 
WOCBP 
Women of Childbearing Potential 

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Glossary of terms 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product (e.g. any background therapy) 
Assessment 
A procedure used to generate data required by the study 
Auxiliary Medicinal 
Product (AxMP) 
Medicinal product used for the needs of a clinical trial as described in the protocol, but 
not as an investigational medicinal product (e.g., rescue medication, challenge agents, 
background treatment or medicinal products used to assess endpoints in the clinical 
trial). Concomitant therapy is not considered as AxMP. 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study participant  
Control drug 
A study drug (active) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days or weeks. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data using 
data collection systems, such as Web-based applications, interactive voice response 
systems and clinical laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed from paper source 
forms used at the point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant or at a later 
point in time as defined by the protocol  
Enrollment 
Point/time when eligibility criteria are confirmed and study treatment is prescribed  
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. concomitant 
or rescue therapy) 
Participant 
A trial participant (a patient) 
Participant number 
A unique number assigned to each participant upon signing the informed consent. This 
number is the definitive, unique identifier for the participant and should be used to 
identify the participant throughout the study for all data collected, sample labels, etc. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical 
trial database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and transferred to 
Advanced Accelerator Applications for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples. 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned completion of all 
study drug administration and/or assessments; at this time all study drug administration 
is discontinued and no further assessments are planned 
Participant number 
A unique identifier assigned to each screened participant 
Screen Failure 
A participant who did not meet one or more criteria that were required for participation in 
the study 
Screening 
Point of time when participant entry into the study at which informed consent must be 
obtained  
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-
coded data, such as paper or eSource 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the 
original site to other parts of the body 

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Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed consent by the 
first participant  
Study treatment 
Any drug or combination of drugs or intervention administered to the study participants 
as part of the required study procedures; includes investigational drug(s), control(s) or 
background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior to the 
defined study treatment completion date (if any) for any reason; may or may not also be 
the point/time of study discontinuation  
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to address 
the clinical question. The specification of the variable might include whether the 
participant experiences an intercurrent event. 
Withdrawal of study 
consent (WoC) 
Withdrawal of consent from the study occurs only when a participant does not want to 
participate in the study any longer and does not allow any further collection of personal 
data  

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Protocol summary 
Protocol number 
CAAA601A32201 
Full Title 
A multicenter open-label study to evaluate safety and dosimetry of Lutathera in 
adolescent patients with somatostatin receptor positive gastroenteropancreatic 
neuroendocrine (GEP-NET) tumors, pheochromocytoma and paragangliomas 
(PPGL) 
Brief title 
Study to evaluate safety and dosimetry of Lutathera in adolescent patients with GEP-
NETs and PPGLs  
Sponsor and Clinical 
Phase 
Sponsor: Advanced Accelerator Applications 
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
There are currently no approved therapies for GEP-NETs in the pediatric population. 
As observed in adults, the diagnosis of NETs in children is often delayed due to the 
indolent nature of the disease. It has been reported that 10% to 20% of pediatric 
patients present with metastatic disease at diagnosis (Parham 2001, Sarvida et al 
2011). While surgical intervention is favored as first-line treatment for patients with 
early-stage disease, metastatic NETs in the pediatric population, as in adults, are 
unresectable. Non-surgical treatment modalities for the pediatric population include 
those used in adults, namely, somatostatin analogues, chemotherapy, everolimus, 
and peptide receptor radionuclide therapy (PRRTs.) There is very limited published 
data on the use of Lutathera in the pediatric population with GEP-NETs (case reports 
Yesil et al 2016 and Potter et al 2018). A small number of published studies have 
reported data on the use of Lutathera in children and adolescents with 
neuroblastomas (Gains 2011, Kong 2016, Chen 2018, Gains 2020), or with 90Y-
DOTATOC in pediatric GEP-NETs (Menda 2010, Menda 2018). 
Given the lack of approved therapeutic options for the pediatric population and the 
scarcity of pediatric data, GEP-NETs in adolescents constitute an area of high unmet 
need. This clinical study aims to address this unmet need and to accelerate access of 
Lutathera as a potential treatment for adolescent patients with GEP-NETs. In this 
context, a full extrapolation of the clinical efficacy of Lutathera already established in 
adults to the adolescent population (12 to <18 years old) approach is made by 
 
 Furthermore, it is based on the 
assumption that
This full efficacy extrapolation approach for 
adolescent patients with GEP-NET is conducted based primarily on the following 4 
aspects: 
1. Similar disease characteristics, including manifestation, progression and course 
(Spunt et al 2000, Dall’Igna et al 2005, Farooqui and Chauhan 2019, Bethel et al 
1997, Fernandez et al 2015, Johnson 2014) as well as 
 
and adolescent patients with GEP-NETs to Lutathera treatment.  
2. Similar mechanism of action of Lutathera in adult and adolescent patients with 
GEP-NET, including
 
3. Similarity in 
 between adult and adolescent. 
4. Results of 
 which has established the dose for 
adolescent population based on
registration clinical studies).  
The extrapolation approach aims to provide evidence for the safe and effective use of 
Lutathera in adolescents with GEP-NETs and has been verified by the results of a 
modelling and simulation (M&S) analysis that confirmed that the Lutathera dose for 
the adolescent population 12 to <18 years old is the same as used in adults. The 
main objective of the current clinical study is to confirm the defined dose by 
assessing the safety, tolerability and dosimetry of Lutathera in adolescents with GEP-
NETs or PPGLs.  
Similarly to GEP-NETs, there are limited non-surgical treatment modalities in 
pediatric patients with progressive PPGLs. Recently, Azedra (iobenguane I 131) has 
been approved by FDA for the treatment of adult and pediatric patients 12 years and 
older with iobenguane scan positive, unresectable, locally advanced or metastatic 

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pheochromocytoma or paraganglioma who require systemic anticancer therapy. 
Increased somatostatin receptor (SSTR) expression, particularly that of SSTR2, in 
PPGLs has been demonstrated by uptake on somatostatin receptor scintigraphy 
providing the rationale for the use of PRRT with radiolabeled somatostatin analogues 
in this patient population (Reubi et al 2001, Reubi 2003). Published adult data from 
SSTR-positive PPGL patients treated with Lutathera shows clinical efficacy and 
improvement of quality of life (Satapathy 2019). Only few case reports have been 
published on the use of Lutathera in children with PPGLs (Cassano 2019, Yadav 
2019, Roll 2020, Pinato 2016), with single patients treated in each of the reports. Due 
to the rarity of pediatric data in PPGL and unmet need in this indication, this study 
includes a cohort for enrolment of adolescent patients with somatostatin receptor 
positive PPGLs. 
In conclusion, this clinical study evaluating PRRT with Lutathera in the adolescent 
population will be essential to bring a new potential therapeutic option for adolescent 
GEP-NET and PPGL patients. 
Primary Objectives  
• Evaluate organ absorbed radiation doses from PRRT with Lutathera in adolescent 
patients with SSTR-positive GEP-NETs and PPGLs as a pooled cohort  
• 
Endpoint: Target organ (e.g. kidney and bone marrow) absorbed 
radiation doses in adolescents with SSTR-positive GEP-NETs and 
PPGLs as a pooled cohort 
• Evaluate safety and tolerability of Lutathera in adolescents with SSTR-positive 
GEP-NETs and PPGLs as a pooled cohort  
• 
Endpoint: The incidence of adverse events (AEs) and laboratory 
toxicities after the 1st Lutathera administration in adolescents with 
SSTR-positive GEP-NETs and PPGLs as a pooled cohort 
Secondary 
Objectives 
• Evaluate cumulative safety of Lutathera in adolescents with SSTR-positive GEP-
NETs and PPGLs as a pooled cohort 
• 
Endpoint: The incidence of adverse events (AEs) and laboratory 
toxicities until 6 months after the last Lutathera dose (short-term follow-
up) in adolescents with SSTR-positive GEP-NETs and PPGLs as a 
pooled cohort 
• Evaluate long-term safety of Lutathera in adolescents with SSTR-positive GEP-
NETs and PPGLs as a pooled cohort  
• 
Endpoint: The incidence of adverse events (AEs) and laboratory 
abnormalities during the long-term follow-up of 5 years after the last 
Lutathera dose in adolescents with SSTR-positive GEP-NETs and 
PPGLs as a pooled cohort 
• Perform comparative assessment of dosimetry and pharmacokinetics (PK) 
between adolescent patients with GEP-NETs and PPGLs as a pooled cohort and 
adult patients using the extrapolation model developed for the clinical study. 
• 
Endpoint: Calculated organ absorbed doses and PK parameters based 
on imaging/blood radioactivity concentration data from adolescent 
patients with SSTR-positive GEP-NETs and PPGLs as a pooled cohort 
compared to the predicted distribution / organ absorbed doses 

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Study design 
This is a multicenter, open-label, single-arm study to evaluate the safety and 
dosimetry of Lutathera in adolescent patients 12 to <18 years old with somatostatin 
receptor positive GEP-NETs and PPGLs. The study will enroll at least 8 adolescent 
patients across GEP-NETs and PPGLs, including a minimum of 3 adolescents with 
GEP-NETs . 
The study schedule for each patient consists of the screening period (up to 2 weeks) 
followed by the treatment period (4 treatment administrations at 8-week intervals), 
and the follow-up period (5 years). 
During the screening period of up to 2 weeks, patient eligibility will be determined 
according to the protocol’s pre-defined inclusion and exclusion criteria. Patients who 
meet all eligibility criteria at screening can be enrolled in the study. The enrollment 
and Lutathera order must be performed immediately after all eligibility criteria are 
verified and the patient is confirmed to be eligible.  
The treatment period will consist of 4 Lutathera treatments administered at 8-week 
intervals. Lutathera administration will occur on Week 1 Day 1 of each cycle. Each 
patient will receive a total of 4 doses of Lutathera (7.4 GBq/200 mCi x 4 
administrations every 8 weeks; cumulative dose: 29.6 GBq/800 mCi). 
An infusion of sterile 2.5% Lysine - Arginine amino acid (AA) solution will be co-
administered with each Lutathera dose for renal protection according to the approved 
Lutathera local prescribing information. An antiemetic will be administered prior to 
infusion of the AA solution for prevention of infusion-related nausea and vomiting. 
The dosimetry and PK assessments will be performed during the first week after the 
1st Lutathera dose, i.e. one time during the study treatment period for each patient. 
The dosimetry analysis will allow for estimation from the 1st Lutathera administration 
of the cumulative absorbed radiation dose from 4 Lutathera doses and also for taking 
a decision on the next dose levels. In the exceptional circumstances when dosimetry 
cannot be performed in a particular patient after the first Lutathera dose, it should be 
completed as soon as feasible upon a later dose.  
In order to minimize risk for each study subject, an accelerated analysis of dosimetry 
and safety data will be performed for each patient in the study, to enable the 
Investigator to take a decision for the subsequent Lutathera doses. The results of 
dosimetry assessments (imaging and blood dosimetry) will be provided to the 
investigators for their evaluation prior to administration of subsequent therapeutic 
cycles in each patient. See Section 6.5.1 for further information on the criteria for 
evaluating the need for dose modification based on safety and dosimetry data. 
A total follow-up period of 5 years (60 months) after the last Lutathera dose will take 
place for each patient who received at least one dose of Lutathera. This follow-up 
period will be comprised of a short-term follow-up of 6 months to evaluate cumulative 
Lutathera toxicities, followed by a long-term follow up of another 54 months. 
An external Data and Safety Monitoring Board (DSMB) will also operate in the study 
to evaluate accumulating safety and dosimetry data, to ensure the safety of 
adolescents enrolled in the study, and to provide recommendations to investigators 
as well as to the clinical team in charge of conducting the study.  
Study population 
This study will enroll at least 8 adolescent patients 12 to < 18 years old with 
somatostatin receptor-positive GEP-NETs or PPGLs, including a minimum of 3 
adolescents with GEP-NETs.  
Key Inclusion 
criteria 
1. 
GEP-NET cohort: presence of metastasized or locally advanced, inoperable 
(curative intent), histologically proven, G1 or G2 (Ki-67 index ≤20%), well 
differentiated GEP-NET. 
PPGL cohort: presence of metastasized or locally advanced, inoperable 
(curative intent), histologically proven PPGL. 
2. 
Patients from 12 to < 18 years of age at the time of enrollment.  

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3. 
Expression of somatostatin receptors confirmed by a somatostatin receptor 
imaging (SRI) modality within 3 months prior to enrollment, with tumor 
uptake observed in the target lesions more or equal to the normal liver 
uptake. 
4. 
Performance status as determined by Karnofsky score ≥ 50 or Lansky Play-
Performance Scale score ≥ 50. 
5. 
Parent’s ability to understand and the willingness to sign a written informed 
consent document for adolescents as determined by local regulations. 
Adolescents will sign assent along with parental/legal guardian consent or 
will co-sign consent with parent/legal guardian in accordance with local 
regulation, prior to participation in the study. 
Key Exclusion 
criteria 
1. 
Laboratory parameters: 
• 
Estimated creatinine clearance calculated by the Cockroft-Gault 
method < 70 mL/min 
• 
Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L; platelets 
<75x109/L. 
• 
Total bilirubin >3 x ULN for age. 
• 
Serum albumin <3.0 g/dL unless prothrombin time is within the 
normal range. 
2. 
Established or suspected pregnancy.  
3. 
Breastfeeding female patients unless they accept to discontinue 
breastfeeding from the 1st dose until 3 months after the last administration 
of study drug. 
4. 
Female patients of child-bearing potential, unless they are using highly 
effective methods of contraception during treatment and for 7 months after 
the last dose of Lutathera (see details in the Appendix 1).  
5. 
Sexually active male patients, unless they agree to remain abstinent or be 
willing to use condoms and highly effective methods of contraception during 
treatment and for 4 months after the last Lutathera dose. 
6. 
Patients for whom in the opinion of the investigator other therapeutic options 
are considered more appropriate than the therapy offered in the study, 
based on patient and disease characteristics. 
7. 
Current spontaneous urinary incontinence. 
8. 
Other known co-existing malignancies except non-melanoma skin cancer 
and carcinoma in situ of the uterine cervix, unless definitively treated and 
proven no evidence of recurrence for 5 years. 
9. 
Hypersensitivity to the study drug active substance or to any of the 
excipients. 
10. Patients with any other significant medical, psychiatric, or surgical condition, 
currently uncontrolled by treatment, which may interfere with the completion 
of the study. 
11. Patient with known incompatibility to CT scans with I.V. contrast due to 
allergic reaction or renal insufficiency. If such a patient can be imaged with 
MRI, then the patient would not be excluded. 
12. Patients who received any investigational agent within the last 30 days. 
13. Prior therapies and procedures as detailed in Section 5.2. 
Study treatment 
Lutathera (7.4 GBq/200 mCi x 4 administrations every 8 weeks; cumulative dose: 
29.6 GBq/800 mCi), with a concomitant administration of 2.5% Lysine - Arginine 
amino acid (AA) solution 
Key safety 
assessments 
Safety assessments in the study will include physical examinations, vital signs, 
ECGs, standard clinical laboratory evaluations (hematology, blood chemistry, and 
urinalysis), safety biomarkers and adverse event monitoring. To monitor for potential 
Lutathera toxicities, safety assessments will be performed in each treatment cycle, 
with clinical laboratory samples taken regularly after each Lutathera dose. A set of 
safety biomarkers of growth and development, reproductive and endocrine function 
will be collected and analyzed for each patient. 
Dosimetry and 
pharmacokinetic 
assessments 
Patients will have whole body and organ radiation dosimetry (including the critical 
organs, i.e. bone marrow and kidney) determined following the first Lutathera 
treatment using planar imaging and blood radioactivity data. In the exceptional 

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circumstances when dosimetry cannot be done in a particular patient after the first 
dose, it should be done as soon as feasible upon a later dose. For each patient, 
dosimetry will be performed only once throughout the study. 
Dosimetry assessments will include: 
- 
Whole body planar images 
- 
SPECT/CT scan 
- 
Blood samples for radioactivity measurement  
- 
Urine sample for radioactivity measurement (all excreted urine from the start of 
Lutathera infusion until the first whole body planar imaging) 
The absorbed radiation dose in organs will be the ultimate output dosimetry 
parameter that will be provided to Investigators for each patient, and to DSMB, if 
necessary. 
Pharmacokinetic parameters such as the maximum blood concentrations (Cmax), the 
sampling time at which Cmax is reached (tmax), in addition to the area under the curve 
(AUC0-∞), systemic clearance (Cl), volume of distribution (V1 and V2) will be 
determined using model based methods. Other parameter estimates may be 
determined as deemed appropriate. 
Data analysis 
The data will be analyzed by the Sponsor and/or designated CRO.  
All statistical analyses will be descriptive in nature and will include summaries and 
graphical presentations of data. No statistical hypothesis will be tested.  
Interim analyses will be performed to evaluate dosimetry and safety when at least five 
patients (including at least two GEP-NET patients) have completed at least one cycle 
of treatment. The data from all completed treatment cycles will be presented. 
Analysis will be presented across both indications, as well as for GEP-NET and 
PPGL separately. 
The primary analysis will be conducted after at least 8 patients (including at least 3 
GEP-NET patients) have completed the first cycle (cut-off before the second dose of 
Lutathera), at which time both dosimetry and safety assessments of the first cycle will 
be complete for the assessment of the primary objective. Should the dosimetry 
assessments be done at a later cycle instead of first cycle, the primary analysis will 
be done after the dosimetry assessments are performed. All data available at the 
time of primary analysis will be collected for the assessment of the primary, 
secondary 
 objectives including the analysis of the PPGL cohort.  
A final analysis will be performed after all subjects who have received at least one 
dose of Lutathera have completed the 5 years of follow-up or have withdrawn from 
the study. 
Key words 
GEP-NET, pheochromocytoma, paraganglioma, PPGL, adolescents, pediatric, 
Lutathera, lutetium (177Lu) oxodotreotide, lutetium Lu 177 dotatate, PRRT 

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Protocol Amendment 03 
As of 14-Dec-2023, 11 patients including 4 GEP-NET and 7 PPGL patients have been enrolled 
in the study.  
Amendment rationale 
The primary purpose of Amendment 03 is to align the protocol with the amended FDA Written 
Request and PDCO positive opinion on the request for modification of the agreed PIP for 
Lutathera issued on 28-Jun-2023 and 13-Oct-2023 respectively. On 01-Dec-2023, the final 
EMA Decision/Acceptance for the modification of the agreed pediatric investigation plan for 
Lutathera (EMEA-002950-PIP01-20-M01) was received. It was agreed with both Health 
Authorities that the primary analysis of organ dosimetry, pharmacokinetic (PK) and safety data 
will be carried out across adolescent patients with GEP-NETs and PPGLs, as these parameters 
are not expected to vary substantially depending on tumor type. The main risks arising from 
treatment with Lutathera are radiation toxicities affecting either kidney function o(r bone 
marrow, which applies to both GEP-NET and PPGL. Biodistribution to organs and normal 
tissues and thus organ dosimetry and safety is not anticipated to be affected by the disease. 
Therefore, the data from both GEP-NET and PPGL patients can support the overall comparison 
between adolescents and adult GEP-NET patients during the primary analysis.  
Based on the above rationale, the study design, study objectives and endpoints are modified as 
follows: 
• The total number of patients required for the primary analysis remains the same, with at 
least 8 adolescent patients evaluable for the primary endpoints, but the primary analysis 
will be pooled across indications. Consequently, this change leads to an updated sample 
size from 8 GEP-NET patients to 8 adolescent patients across indications including a 
minimum of 3 adolescents with GEP-NET. With the enrolled number of patients, the 
updated recruitment target has already been met. 
• The co-primary and secondary objectives will be evaluated in GEP-NETs and PPGLs as a 
pooled cohort instead of GEP-NETs cohort alone, serving the same purpose to compare 
adolescent data with data from adult GEP-NET patients. 
 
 
In addition, the protocol amendment included the following changes: 
• Laboratory assessments on safety biomarkers of endocrine and gonadal function were 
added to long-term follow up visits. This implements FDA written request requirements 
that safety follow up should include monitoring for pituitary dysfunction given the 
potential risk for toxicity to the pituitary gland. 
• Added text to clarify the safety reporting requirements for Auxiliary Medicinal Products 
(AxMPs), regulatory and ethical compliance, and publication of the study protocol and 
results per EU Clinical Trial Regulation 536/2014 in view of the future study transition to 
EU CTR.  
The Amendment also includes editorial changes and text corrections made for clarification, 
where required. 

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Changes to the Protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through and red font for deletions and red underline for insertions. 
The following sections and/or tables were changed/updated: 
• Section 1, Section 2, Section 3, Section 4, Section 12.4, Section 12.5, Section 12.6, and 
Section 12.8: Updated the primary and secondary objectives of the study to use pooled 
data derived from the GEP-NET and PPGL cohorts. 
 
 
• Section 3: Updated the text to clarify that the study will enroll at least 8 adolescents across 
the GEP-NET and PPGL cohorts and a minimum of 3 adolescents in the GEP-NET 
cohort. The maximum number of 8 PPGL patients was deleted as it no longer applies. 
• Section 6.1.2 and Table 6-2: Updated the text to provide additional details regarding the 
sterile 2.5% Lys-Arg amino acid solution and clarification of anti-emetics as AxMP. 
• Table 8-2: Added an EOS visit to the assessment schedule and included a footnote to 
clarify that the last FU visit would be the EOS visit for patients who completed the long-
term FU period, and that a separate EOS should be planned for patients who discontinued 
from the study prior to completion of the long-term FU period.  
Added assessments for biomarkers of endocrine and gonadal function during the long-
term FU visit.  
Also included a footnote to clarify the collection of concomitant medications and new 
anticancer therapies administered during the FU period. 
• Section 9.1.1.1: Updated text, in line with the changes to the primary dosimetry analysis. 
• Section 10.1.1 and Section 10.1.6: Updated the text to clarify the AE reporting 
responsibility and causality assessment with regards to A(x)MPs following the EU CTR. 
• Section 10.1.2: Added text to clarify Hy’s law reporting. 
• Section 12.8: Updated text to clarify that the overall sample size calculated for the study is 
8 patients overall, across indications. 
• Section 13.1 and Section 13.3: Added wording to align with the EU CTR requirements. 
• Section 13.4: Added wording regarding the retention of records and documents, including 
signed ICFs. 
• Protocol summary was updated to reflect change to the protocol body.  
Other minor changes/corrections were made for consistency and/or clarifications. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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Protocol Amendment 02 
As of May the 8th 2023, 5 patients including 2 GEP-NET and 3 PPGL patients have been 
enrolled in the study. 
Amendment rationale 
The primary purpose of Amendment 02 is to implement interim analyses for an early evaluation 
of dosimetry and safety data when at least five patients (including at least two GEP-NET 
patients) have been treated. This formal interim analysis is introduced due to the slower than 
expected recruitment rate, and proportionally higher than expected recruitment of PPGL 
patients. The interim analysis will combine patients with GEP-NET and PPGL based on the 
consideration from clinical perspective there are no expected differences from dosimetry or 
critical organ toxicity across these two indications, which will permit an evaluation across the 
indication in order to test modelling assumptions of similar dosimetry between adolescents and 
adults. Taking the slow recruitment into account, the result of interim analysis with at least 5 
patients across these two indications could provide support for full extrapolation.  
Due to higher-than-expected screening rate of patients with PPGLs, this amendment will limit 
enrolment to a maximum of 8 PPGL patients to avoid recruitment bias between GEP-NET and 
PPGLs. 
In addition, the recommendation of the Data and Safety Monitoring Board (DSMB) regarding 
monitoring of microproteinuria during the course of study treatment is now formally 
implemented in the protocol in order to detect early signs of renal toxicity especially in light of 
treatment of patients with medical history of nephrectomy in the study. Therefore, spot urine 
test of urine protein creatinine ratio (UPCR) is added in the Assessment schedule (Table 8-2) 
before each Lutathera infusion and 3 weeks after each infusion. 
The Amendment 02 also includes editorial changes and text corrections made for clarification, 
where required. 
Changes to the Protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through and red font for deletions and red underline for insertions. 
1. Protocol summary: Data analysis section updated to reflect the implementation of interim 
analyses. Study design and Study population updated to clarify the enrollment target in 
PPGL patients. 
2. Section 1.1: updated reference and data from NETTER-1 study. 
3. Section 3: updated to add a paragraph on the interim analyses and include modified 
enrollment target in PPGL patients. 
4. Section 4.1: updated to indicate that “the investigator is advised to follow DSMB 
recommendation on dose modification”. 
5. Section 4.3: updated data from NETTER-1 study. 
6. Section 5: Added clarification on enrollment target for GEP-NET and PPGL patients. 
7. Section 6.1.1: +/-1 week visit window was added to be consistent with the footnote in 
Table 8-2. 
8. Added Section 6.2.4 “SARS-CoV-2 vaccination” to provide clarifications on the 
risk/benefit assessment in regard to SARS-CoV-2 vaccination and vaccination data 
collection. 

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9. Table 6.4: added footnote “1 No dose modification required for hematological toxicities 
Grade 3 or Grade 4 solely due to lymphopenia “in line with ongoing labeling updates. 
10. Section 8: Table 8-2 and related foot notes updated as follows: 
a. Added height measurement at week 1 of cycle 4 and at the last visit of short-term 
FUP to ensure height monitoring twice a year throughout the course of the study. 
b. Added spot urine test of urine protein creatinine ratio (UPCR). 
c. Footnote 1: AE collection related to “End of Treatment Visit” was clarified. 
11. Section 8.4.: Table 8-4 updated to include UPCR analysis as part of the Urinalysis.  
12. Section 8.4.7: wording updated to align with UPCR test addition. 
13. Section 10.1.1: clarification added to refer to section 10.1.5 for details related to adverse 
events of special interest (AESI). 
14. Section 10.1.5: wording updated to clarify that during screening only AESI meeting 
seriousness criteria should be reported to the Sponsor. 
15. Section 10.1.6: wording updated to clarify AESI reporting rules. 
16. Section 10.1.9: wording related to SAE reporting rules adjusted for consistency. 
17. Section 12: added wording related to the interim analyses and to PK modeling and 
simulation. 
18. Section 12.7: added wording related to interim analyses and removed language for 
primary and final analysis. 
19. Section 12.8: added maximum number of PPGL adolescents will be enrolled. 
20. Section 15: added a new reference. 
21. Section 16: removed Appendix 2 “Recommendations to patients treated with Lutathera” in 
Protocol Amendment 01 to align with other sponsored trial protocols. Instead this 
appendix will be attached to the Global Informed Consent Form. 
Protocol Amendment 01 
Amendment rationale 
The primary purpose of amendment 01 is to implement modifications in contraception 
requirements in line with Lutathera Investigator’s Brochure version 17 released on 09 March 
2022. The changes are not due to new data but based on Sponsor Guideline on Prevention of 
Pregnancies in Participants in Clinical Trials as well as the Clinical Trials Facilitation and 
Coordination Group (CTFG) guideline on recommendations related to contraception and 
pregnancy testing in clinical trials. According to these guidelines, for radioligand therapies, 
highly effective contraception should be used during treatment and for (5 x T ½ + 6 months) 
after treatment in women of childbearing potential, and condom should be used during 
treatment and contraception period in male patients. For Lutathera, the effective half-life is 49 
hours, and therefore, as per the calculation, the period of contraception for female patients 
should continue for 6 months and 10 days after the last dose. However, as a precautionary 
measure, the Sponsor decided to extend the highly effective contraception period from 6 months 
to 7 months for female patients. In addition, the sponsor propose to add a requirement for male 
patients to use condom with female partners of reproductive potential during treatment and for 
4 months after last Lutathera dose. This duration is based on an exposure of 5 terminal half-
lives (49 hours for Lutathera) plus 90 day (life span of spermatozoa of 60–75 days for sperm 
production + 10–14 days for transport to epididymis) (). 

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Based on its mechanism of action as a radioligand therapy, Lutathera can cause fetal harm when 
administered to a pregnant women and this information is now clarified in the Informed Consent 
Form. 
The Amendment 01 also includes the following updates: 
• Monitoring approach of women of childbearing potential (WOCBP) for pregnancy. Based 
on Sponsor Guideline on Prevention of Pregnancies in Participants in Clinical Trials, 
pregnancy testing is added monthly during treatment and during short-term follow up.  
• Integration of local protocol amendments in UK (v00-UK01, 12 Jan 2021) into the global 
amendment: 
• Contraception requirements have been updated to reflect that sexually active male 
patients must agree to remain abstinent (refrain from heterosexual intercourse) or be 
willing to use condoms and highly effective methods of contraception with female 
partners of childbearing potential, and to use condoms with pregnant female partners 
during the treatment period and for 4 months after the last Lutathera dose.  
• Female and male patients must be informed that the study treatment may potentially 
have temporary toxic effects on female and male gonads. Genetic consultation is 
recommended if the patient wishes to have children after treatment. Cryopreservation 
of sperm or eggs can be discussed as an option to patients before the treatment.  
• In alignment with Lutathera and amino acids SmPC, a recommendation has been 
added to monitor vital signs during the infusion. 
• Body temperature has been added to the vital sign measurements due to concern of 
potential hematological toxicity and resultant infection during treatment of Lutathera. 
• Specifying sterile condition of amino acid solution in order to emphasize that sterile 
solution is required for infusion. 
• Correction of an error in the Cockcroft-Gault formula for calculation of creatinine 
clearance.  
• Providing guidance to document if the participant has withdrawn his/her consent for the 
use of data in addition to a study discontinuation. 
• Adding details of data protection under Ethical Considerations and Administrative 
procedures.  
• Aligning with Lutathera USPI and updating the infusion rate from “400 mL/hr” to “up to 
400 mL/hr”. 
• Editorial changes and text corrections made for clarification, where required. 
Changes to the Protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through and red font for deletions and red underline for insertions. 
1. Protocol summary: 
a. Key Exclusion criteria #4: updated to reflect that female patients of child- bearing 
potential must use highly effective contraception during treatment and for 7 months 
(instead of 6 months) after the last Lutathera dose. 
b. Key exclusion criteria #5: use of “condoms and highly” effective methods of 
contraception “during treatment and for 4 months after the last Lutathera dose” 
inserted. 

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c. “Sterile” added before amino acid solution. 
2. Section 5.2: 
a. Exclusion criteria #4: 
i. 
Language revised as follows: using highly effective methods of contraception 
during treatment and for 7 months after the last dose of Lutathera. 
b. Exclusion criteria #5: 
i. 
Language revised as follows: use of “condoms and highly” effective methods of 
contraception. 
ii. 
Language revised as follows: “and to use condoms with” pregnant female 
partners. 
iii. 
For UK and Poland only: “6 months after the last Lutathera dose” 
updated to “4 months after the last Lutathera dose” 
3. Section 3, section 6.1.2, section 6.1.3, section 6.7 and section 10.1.5: “sterile” added 
before amino acid solution. 
4. Section 6.7: Lutathera infusion rate updated from “400” to “Up to 400” in the table 6-5. 
5. Section 7: 
a. Study treatment “may involve unknown risks to the fetus if pregnancy were to occur 
during the study” replaced by “can cause fetal harm when administered to a pregnant 
woman”. 
b. Added following paragraph: “Female and male patients must be informed that the 
study treatment may potentially have temporary toxic effects on female and 
male gonads. Genetic consultation is recommended if the patient wishes to have 
children after treatment. Cryopreservation of sperm or eggs can be discussed as 
an option to patients before the treatment.” 
6. Section 8: Table 8-2 and related foot notes updated as follows: 
a. Added “body temperature” measurement as part of the vital signs assessment. Blood 
pressure and pulse rate monitoring during Lutathera and amino acid infusion is 
recommended. 
b. Pregnancy tests split into one row for blood pregnancy tests and one row for urine 
pregnancy tests with updated timepoints in alignment with Sponsor Guideline on 
Prevention of Pregnancies in Participants in Clinical Trials. 
c. Footnote 2: AE collection related to “End of Treatment Visit” was clarified. 
d. Footnote 6: clarification about data collection related to AEs, SAEs and AESI added. 
7. Section 8.4.1: “reported” replaced by “recorded” for consistency. 
8. Section 8.4.3: language revised to include the following: 
a. “Body temperature” as part of the vital signs assessment, 
b. Blood pressure and pulse rate monitoring during Lutathera and amino acid infusion is 
recommended, 
c. Body temperature measurement can be either oral or tympanic and method should be 
maintained throughout the study. 
9. Section 8.4.6: update of the Cockcroft-Gault formula for calculation of creatinine 
clearance. 
10. Section 8.4.8: wording updated to align with Sponsor Guideline on Prevention of 
Pregnancies in Participants in Clinical Trials. 

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11. Section 9.1.2: updated wording related to withdrawal of informed consent. 
12. Section 9.1.3: slight update of the wording in line with Withdrawal of informed consent” 
section. 
13. Section 10.1.9: wording related to AE reporting rules adjusted for consistency. 
14. Section 13.5: added Data Protection section. 
15. Appendix 1: 
a. Updated to reflect that female patients of child-bearing potential must use highly 
effective contraception during treatment and “for 7 months” (instead of 6 months) 
after the last Lutathera dose. 
b. Use of “condoms and highly” effective methods of contraception “during 
treatment and for 4 months after the last Lutathera dose” inserted. 
c. For UK and Poland only, male contraception language revised as follows: “6 months 
after the last Lutathera dose” updated to “4 months after the last Lutathera 
dose”. 
16. Appendix 2: language revised as follows: 
a. Female patients of child-bearing potential must use highly effective contraception 
during treatment and “for 7 months” (instead of 6 months) after the last Lutathera 
dose. 
b. Male patients should use “condoms and highly” effective “methods” of 
contraception with female partners of reproductive potential, “and to use condoms 
with” pregnant female partners. 
c. For UK and Poland only, male contraception language revised as follows: “6 months 
after the last Lutathera dose” updated to “4 months after the last Lutathera 
dose”. 
IRBs/IECs  
A copy of this global amended protocol will be sent to Institutional Review Boards 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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1 
Introduction 
1.1 
Background 
Lutathera was FDA-approved on 26 January 2018 for the treatment of somatostatin receptor-
positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, 
and hindgut neuroendocrine tumors in adults. In the European Union, Lutathera was approved 
on 26 September 2017 for the treatment of unresectable or metastatic, progressive, well 
differentiated (G1 and G2), somatostatin receptor positive GEP-NETs in adults. 
Lutetium (177Lu) oxodotreotide (INN) or lutetium Lu 177 dotatate (USAN) has the trade name 
Lutathera® and is referred to as “lutetium (177Lu) oxodotreotide” throughout this document. 
Lutetium (177Lu) oxodotreotide is a radiolabeled somatostatin analog that has high affinity for 
SSTR2. It is comprised of the somatostatin peptide analog Octreotate, coupled to the metal-ion 
chelating moiety DOTA. It can be efficiently labelled with the beta-emitting radionuclide 
Lutetium-177 (177Lu) and binds to cells, which express somatostatin receptors (SSTR). 177Lu 
has a maximum penetration range in tissue of 2.2 mm (mean 0.67 mm), which is sufficient to 
kill targeted tumor cells with a limited effect on neighboring normal cells.  
SSTR are members of the 7-segment G-protein coupled receptor family and are expressed in 
many tissues and organs in the body (Reubi et al 2000a). Of the 5 known receptor subtypes 
(Reubi et al 2001), the SSTR2 is considered the most important subtype for neuroendocrine 
tumors (Reubi et al 2000b, Reubi et al 2000a). The SSTR2 receptor is frequently overexpressed 
in neuroendocrine tumors and is central to the mode of action of a number of pharmaceutical 
agents, including somatostatin agonists for the control of symptoms in GEP-NET patients. 
Somatostatin analogs are used as targeted delivery vehicles for radionuclides in diagnostic 
imaging or therapy. 
The biological basis for the use of peptide receptor radionuclide therapy (PRRT) in GEP-NETs 
is the receptor-mediated internalization and intracellular retention of radiolabeled somatostatin 
analogs. The SSTR2 is an attractive target for PRRT because the receptor density is higher on 
tumors than on non-tumor tissue (Reubi et al 2001, Reubi 2003), and because SSTR2 internalize 
into cells after ligand binding. After binding to SSTR2, the radiopeptide delivers tumoricidal 
radiation to the tumor tissue. 
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) constitute a heterogeneous group 
of neoplasms arising from the diffuse neuroendocrine system, known tofrequently over-express 
somatostatin subtype 2 receptors (SSTR2) (Reubi et al 2000b). GEP-NETs are recognized as 
an orphan disease by the National Cancer Institute. 
GEP-NETs are rarely seen in childhood. The estimated annual incidence of GEP-NETs in the 
pediatric population is extremely low — less than 1 per 100,000 person-years based on EU data 
from two published studies (Pastore et al., 2009; Diets et al., 2017), which is similar to estimates 
from several European cancer databases, including RARECARENet (RARECARENet, 2018), 
and ITACAN (Airtum Working Group et al., 2016). The age-adjusted annual incidence rate for 
all GEP-NETs estimated from the Surveillance, Epidemiology, and End Results Program of the 
US National Cancer Institute (SEER) using 18 cancer registries in the pediatric population was 
0.08 per 100,000 population. The rate per 100,000 population was 0 for the group aged 0 to <12 
years, and 0.21 for those aged 12 to < 17 years. The incidence increases in GEP-NET patients 
aged >17 years.  
The most commonly reported location of GEP-NETs in children is the midgut, specifically the 
appendix (SEER database). The appendiceal NET in children is usually diagnosed at stage I, 

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the presentation with metastases is rare and survival is high. Conversely, published studies 
suggest that pancreatic NETs in the pediatric population are usually diagnosed at more 
advanced stages than NETs arising in the appendix, and their prognosis is poor (Johnson 2014). 
Pheochromocytoma and paraganglioma (PPGLs) are rare neuroendocrine tumors arising from 
the chromaffin cells of the adrenal medulla or sympathetic/parasympathetic ganglia. The 
incidence of PPGLs in pediatric patients is extremely low with only single cases recorded in 
SEER registry in 2019, corresponding to a rate lower than 0.03 per 100,000 population (SEER 
database). Similar to GEP-NET, the incidence of PPGL increases in adult patients compared to 
adolescents. 
The pathophysiology of PPGL is not substantially different in adolescents compared to adult 
patients. The symptomatology of PPGL is related to an excessive release of catecholamines 
produced by the tumor causing significant cardiovascular and gastrointestinal morbidity and 
representing the cause of hypertension in 0.5–2% of pediatric cases (Bholah 2017). A combined 
α- and β-adrenergic blockade is standard treatment for PPGL patients with pheochromocytoma 
in order to control blood pressure (Neumann 2019). While PPGLs in most patients are localized 
and can be treated by surgery, metastatic disease is diagnosed in 10% of pheochromocytomas 
and 15-35% of extra-adrenal paragangliomas (Martins 2014). Only metastases are the proof for 
a malignant PPGL, and it has been reflected in the updated WHO classification of endocrine 
tumors, which replaced the term “malignant pheochromocytoma” with “metastatic 
pheochromocytoma” (Tischler 2017). Patients with metastatic disease in non-chromaffin tissue 
have poorer prognosis and shorter overall survival than those with nonmetastatic disease 
(Jimenez 2018, Satapathy 2019). Increased SSTR expression, particularly that of SSTR2, in 
PPGLs has been demonstrated by uptake on somatostatin receptor scintigraphy providing the 
rationale for the use of Lutathera in this patient population (Reubi et al 2001, Reubi 
2003,Fishbein et al 2021). 
The approval of Lutathera was supported by two studies. The first was the Phase III NETTER-
1 study, which compared treatment with Lutathera plus best supportive care (30 mg octreotide 
long-acting) to treatment with high dose (60 mg) octreotide long-acting in patients with 
inoperable, somatostatin receptor positive, histologically proven midgut carcinoid tumors, 
progressive under octreotide long-acting therapy (Strosberg 2017). The primary endpoint 
analysis was conducted after 74 progression-free survival (PFS) events and included 229 
randomized patients. The median PFS was 8.5 months for the control arm (60 mg Octreotide 
LAR) and had not been reached for the Lutathera arm at the time of the primary endpoint 
analysis. The hazard ratio for the Lutathera arm compared to the high-dose octreotide LAR arm 
was 0.18 (95% CI: 0.11; 0.29), indicating 82% reduction in the risk of disease progression or 
death in favor of the Lutathera arm. The improvement in PFS was accompanied by a significant 
quality of life benefit (Strosberg et al, 2018). 
The second study was a single-institution, single-arm, open-label trial based on data from 1,214 
patients with somatostatin receptor-positive tumors, including GEP-NETs and PPGLs, who 
received Lutathera at the Erasmus Medical Centre in the Netherlands (Kwekkeboom 2008, 
Brabander 2017). The treatment effect observed across patients with GEP-NET in the Erasmus 
MC study was consistent with what was seen in NETTER-1 study.  
Data from the Erasmus MC study and other studies in PPGL patients (reviewed in Satapathy 
2019) demonstrated that Lutathera is an efficacious treatment option for patients with advanced 
PPGLs. Among patients with SSTR-positive tumors included in the Erasmus MC study, 38 
patients with paragangliomas were enrolled. The full efficacy analysis included 18 patients with 
paragangliomas who showed a median PFS of 50.8 months (95% CI 15.4 – n/a).  

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Lutathera demonstrated a favorable safety profile in adults. The target organs for radiation 
toxicities are bone marrow and kidneys (Bergsma 2016a, Bergsma 2016b). The kidney related 
toxicity is largely eliminated by the co-infusion of 2.5% Lysine – Arginine (Lys-Arg) amino 
acid solutions during administration of Lutathera, which reduces the radiation dose to the 
kidney by approximately 45% (Rolleman 2003). In the Erasmus MC trial, 8 patients (<1%) 
developed renal failure 3 to 36 months following Lutathera administration. 
of these 
patients either had underlying renal impairment or risk factors for renal failure (e.g., diabetes 
or hypertension) and required dialysis. Bone marrow toxicities include anemia, 
thrombocytopenia, lymphopenia and neutropenia which are usually mild, transient and 
monitorable by hematological and biochemical assessments between treatments (8 ± 1 week 
interval between doses).  
Data on Lutathera use in patients with PPGL from the Erasmus MC study and from a number 
of other recent studies (reviewed in Satapathy 2019) suggest that the safety of Lutathera in adult 
patients with PPGL is similar to safety established in GEP-NET population. During Lutathera 
treatment, the frequency of adverse events related to toxicities in radiosensitive organs do not 
seem to be dependent on the tumor type, and in PPGL patients described so far the drug 
toxicities were represented by a low number of Grade 3/4 haematotoxicities and no cases of 
significant nephrotoxicity (Satapathy 2019).  
While a wealth of adult data has been collected for Lutathera use, there is very limited published 
data on the use of Lutathera in the pediatric population, and no prospective pediatric clinical 
trials of Lutathera in GEP-NET or PPGL have been performed to date. The efficacy and safety 
of Lutathera and other PRRTs in the pediatric population have been investigated in a small 
number of studies, mostly in children with neuroblastomas (Gains 2011, Kong 2016, Chen 2018, 
Gains 2020).  
Overall, based on the available safety information from pediatric patients, there have been no 
new safety signals compared to adults that would highlight concerns of Lutathera use specific 
for the pediatric population. The safety events following Lutathera treatment in children with 
neuroblastoma consisted mostly of hematological toxicities (primarily thrombocytopenia), with 
the majority occurring in the presence of progressive bone disease or associated with prior or 
concomitant treatments (Gains 2011, Kong 2016, Chen 2018, Gains 2020). Few significant 
dose-limiting renal toxicities were reported. The types, frequency, and severity of events 
reported in the pediatric population appeared to be similar to the tolerability and safety profile 
established for the adult population. Safety data from published studies of other PPRTs in 
children and young adults with SSTR-positive tumors, including SSTR-positive NETs, also 
suggested no concerns specific for the pediatric population (Menda 2010, Menda 2018). In 
addition, based on limited safety follow-up of up to 3 years in a small number of studies, there 
were no reports of long-term safety risks, such as myelodysplastic syndrome or secondary 
malignancies in pediatric patients treated with Lutathera to date. For the detailed benefit-risk 
assessment see Section 4.5. 
1.2 
Purpose 
There are currently no approved therapies for GEP-NETs in the pediatric population. As 
observed in adults, the diagnosis of NETs in children is often delayed due to the indolent nature 
of the disease. It has been reported that 10% to 20% of pediatric patients present with metastatic 
disease at diagnosis (Parham 2001, Sarvida et al 2011). While surgical intervention is favored 
as first-line treatment for patients with early-stage disease, metastatic GEP-NETs in the 
pediatric population, as in adults, are often unresectable. Non-surgical treatment modalities for 
the pediatric population include those used in adults, namely, somatostatin analogues, 

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chemotherapy, everolimus, and PRRTs. There are reports of confirmed response in pediatric 
patients to combination therapy of chemotherapy given concomitantly with cyclophosphamide, 
vincristine, and dacarbazine (Farooqui and Chauhan 2019). There is very limited published data 
on the use of Lutathera in the pediatric population with GEP-NETs (case reports Yesil et al 
2016 and Potter et al 2018). A small number of published studies have reported data on the use 
of Lutathera in children and adolescents with neuroblastomas (Gains 2011, Kong 2016, Chen 
2018, Gains 2020), or with 90Y-DOTATOC in pediatric GEP-NETs (Menda 2010, Menda 
2018).  
Similarly to GEP-NETs, there are limited non-surgical treatment modalities in pediatric patients 
with progressive PPGLs. Recently, Azedra (iobenguane I 131) has been approved by FDA for 
the treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, 
unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require 
systemic anticancer therapy. Increased somatostatin receptor (SSTR) expression, particularly 
that of SSTR2, in PPGLs has been demonstrated by uptake on somatostatin receptor 
scintigraphy providing the rationale for the use of Lutathera in this patient population (Reubi et 
al 2001, Reubi 2003). Only few case reports have been published on the use of Lutathera in 
children with PPGLs (Cassano 2019, Yadav 2019, Roll 2020, Pinato 2016), with single patients 
treated in each of the reports. 
Given the limitations of approved therapeutic options for the GEP-NET and PPGL pediatric 
population, these diseases in adolescents constitute an area of high unmet need. This clinical 
study aims to address this unmet need and to accelerate access of Lutathera as a potential 
treatment for adolescent patients with a primary focus on GEP-NETs. Due to the rarity of 
pediatric data in PPGL and unmet need in this indication, a separate cohort will be open for 
enrolment of adolescent patients with somatostatin receptor positive PPGLs. 
For GEP-NET, a full extrapolation of the clinical efficacy of Lutathera already established in 
adults to the adolescent population (12 to <18 years old) approach is made by 
 
 
Furthermore, it is based on the assumption that
This full efficacy 
extrapolation approach for adolescent patients with GEP-NET is conducted based primarily on 
the following 4 aspects: 
1. 
Similar disease characteristics, including manifestation, progression and course (Spunt et 
al 2000, Dall’Igna et al 2005, Farooqui and Chauhan 2019, Bethel et al 1997, Fernandez 
et al 2015, Johnson 2014) as well as 
 and 
adolescent patients with GEP-NETs to Lutathera treatment.  
2. 
Similar mechanism of action of Lutathera in adult and adolescent patients with GEP-
NET, including 
 
 
3. 
Similarity in 
 between adult and adolescent. 
4. 
Results of 
 which has established the dose for 
adolescent population based on 
 registration clinical studies).  
The extrapolation approach aims to provide evidence for the safe and effective use of Lutathera 
in adolescents with GEP-NETs and has been verified by the results of a modelling and 
simulation (M&S) analysis that confirmed that the Lutathera dose for the adolescent population 
12 to <18 years old is the same as used in adults (see Section 4.2 below for results of this M&S 
analysis and dose rationale). The main objective of the current clinical study is to confirm the 

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defined dose by assessing the safety, tolerability and dosimetry of Lutathera in adolescents with 
GEP-NETs or PPGLs.  
In conclusion, this sponsored clinical study evaluating PRRT with Lutathera in the adolescent 
population will be essential to bring new potential therapeutic option for adolescent GEP-NET 
and PPGL patients. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
 
Objectives 
Endpoints 
Primary 
• 
Evaluate organ absorbed radiation 
doses from PRRT with Lutathera in 
adolescent patients with SSTR-positive 
GEP-NETs and PPGLs as a pooled 
cohort  
• 
Evaluate safety and tolerability of 
Lutathera in adolescents with SSTR-
positive GEP-NETs and PPGLs as a 
pooled cohort 
• 
Target organ (e.g. kidney and bone marrow) 
absorbed radiation doses in adolescents 
with SSTR-positive GEP-NETs and PPGLs 
as a pooled cohort 
• The incidence of adverse events (AEs) and 
laboratory toxicities after the 1st Lutathera 
administration in adolescents with SSTR-
positive GEP-NETs and PPGLs as a pooled 
cohort 
Secondary 
• 
Evaluate cumulative safety of Lutathera 
in adolescents with SSTR-positive GEP-
NETs and PPGLs as a pooled cohort 
 
• 
Evaluate long-term safety of Lutathera in 
adolescents with SSTR-positive GEP-
NETs and PPGLs as a pooled cohort  
 
• 
Perform comparative assessment of 
dosimetry and pharmacokinetics (PK) 
between adolescent patients with GEP-
NETs and PPGLs as a pooled cohort 
and adult patients using the 
extrapolation model developed for the 
clinical study 
• 
The incidence of adverse events (AEs) and 
laboratory toxicities until 6 months after the 
last Lutathera dose (short-term follow-up) in 
adolescents with SSTR-positive GEP-NETs 
and PPGLs as a pooled cohort 
• 
The incidence of adverse events (AEs) and 
laboratory abnormalities during the long-
term follow-up of 5 years after the last 
Lutathera dose in adolescents with SSTR-
positive GEP-NETs and PPGLs as a pooled 
cohort 
• 
Calculated organ absorbed doses and PK 
parameters based on imaging/blood 
radioactivity concentration data from 
adolescent with SSTR-positive GEP-NETs 
and PPGLs as a pooled cohort patients 
compared to the predicted distribution / 
organ absorbed doses 
 

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3 
Study design 
This is a multicenter, open-label, single-arm study to evaluate the safety and dosimetry of 
Lutathera in adolescent patients 12 to <18 years old with somatostatin receptor positive GEP-
NETs and PPGLs. The study will enroll at least 8 adolescent patients across GEP-NETs and 
PPGLs, including a minimum of 3 adolescents with GEP-NETs . 
The study schedule for each patient consists of the screening period (up to 2 weeks) followed 
by the treatment period (4 treatment administrations at 8-week interval), and the follow-up 
period (5 years).  
During the screening period of up to 2 weeks, patient eligibility will be determined according 
to the protocol’s pre-defined inclusion and exclusion criteria. All screening assessments should 
be performed according to Table 8-2. 
Patients who meet all eligibility criteria at screening can be enrolled in the study. The 
enrollment and Lutathera order must be performed immediately after all eligibility criteria are 
verified and the patient is confirmed to be eligible.  
There will be no study visits after screening and before the 1st Lutathera administration. 
Somatostatin receptor imaging (SRI) performed before the screening (within 3 months prior to 
enrollment) can be used for the assessment of patient eligibility. Laboratory tests completed 
before the screening can be used for the assessment of patient eligibility if performed within 2 
weeks prior to enrollment. 
The treatment period will consist of 4 Lutathera treatments administered at 8-week intervals. 
Lutathera administration will occur on Week 1 Day 1 of each cycle. Each patient will receive a 
total of 4 doses of Lutathera (7.4 GBq/200 mCi x 4 administrations every 8 weeks; cumulative 
dose: 29.6 GBq/800 mCi). 
An infusion of sterile 2.5% Lysine - Arginine amino acid (AA) solution will be co-administered 
with each Lutathera dose for renal protection according to the approved Lutathera local 
prescribing information. An antiemetic will be administered for prevention of infusion-related 
nausea and vomiting (Section 6.1.2). 

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The dosimetry and PK assessments will be performed during the first week after the 1st 
Lutathera dose as per Table 8-2 and Table 8-3, i.e. one time during the study treatment period 
for each patient. The dosimetry analysis will allow for estimation from the 1st Lutathera 
administration the cumulative absorbed radiation dose from 4 Lutathera doses and taking a 
decision on the next dose levels (see Section 6.5.1.2). In the exceptional circumstances when 
dosimetry cannot be performed in a particular patient after the first Lutathera dose, it should be 
completed as soon as feasible upon a later dose.  
Safety assessments in the study will include physical examinations, vital signs, ECGs, standard 
clinical laboratory evaluations (hematology, blood chemistry, and urinalysis), safety 
biomarkers and adverse event monitoring (see Section 8). To monitor for potential Lutathera 
toxicities, safety assessments will be performed in each treatment cycle, with clinical laboratory 
samples taken regularly after each Lutathera dose (see Table 8-2). A set of safety biomarkers 
of growth and development, reproductive and endocrine function will be collected and analyzed 
for each patient (see Section 8.4.7). 
 
 
 
Patients might need to stay overnight at the hospital or another facility for the days with 
intensive assessment schedule (e.g. for Lutathera administration, blood sampling and imaging). 
The decision on the overnight stay is up to Investigator, as appropriate according to local 
regulations, medical judgment, and the patient’s preference. 
Figure 3-1. Study design  
 
In order to minimize risk for each study subject, an accelerated analysis of dosimetry and safety 
data will be performed for each patient in the study, to enable the Investigator to take a decision 
for the subsequent Lutathera doses. The results of dosimetry assessments (imaging and blood 
dosimetry) will be provided to the investigators for their evaluation prior to administration of 
subsequent therapeutic cycles in each patient. See Section 6.5.1 for further information on the 
criteria for evaluating the need for dose modification based on safety and dosimetry data. 
A total follow-up period of 5 years (60 months) after the last Lutathera dose will take place for 
each patient who received at least one dose of Lutathera. This follow-up period will be 
comprised of a short-term follow-up of 6 months to evaluate cumulative Lutathera toxicities, 
followed by a long-term follow up of another 54 months. 
An external Data and Safety Monitoring Board (DSMB) will also operate in the study to 
evaluate accumulating safety and dosimetry data, to ensure the safety of adolescents enrolled 
in the study, and to provide recommendations to investigators as well as to the clinical team in 
charge of conducting the study (see Section 10.2.1). 

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Interim analyses was added to evaluate dosimetry and safety when at least five patients 
(including at least two GEP-NET patients) have completed at least one cycle of treatment. This 
analysis is introduced due to the slower than expected recruitment rate, and proportionally 
higher than expected recruitment of PPGL patients. The interim analysis would permit an 
evaluation across the indication in order to confirm modelling assumptions of similar dosimetry 
between adolescents and adults. The data from all completed treatment cycles will be presented. 
Analysis will be presented across both indications, as well as for GEP-NET and PPGL 
separately. 
The primary analysis to address the primary objective will be performed after at least 8 patients 
(including at least 3 GEP-NET patients) have completed the first cycle (up to cycle 2 pre-dose 
assessments) at which time both dosimetry and safety assessments of the first cycle will have 
been completed for all patients. In case the last subject has dosimetry assessments after the 2nd 
or a later dose, the data cut-off will be performed after that dose (and before the subsequent 
cycle pre-dose assessments). The primary analysis in the study will be of descriptive nature and 
no statistical hypothesis will be tested. All data available at that time from pooled cohorts will 
be used for the assessment of the primary and secondary objectives.
 
A final analysis will be performed after all subjects who have received at least one dose of 
Lutathera have completed the 5 years of follow-up or have withdrawn from the study.  
4 
Rationale 
4.1 
Rationale for study design 
Lutathera is approved in the United States for the treatment of somatostatin receptor-positive 
GEP-NETs, including foregut, midgut, and hindgut neuroendocrine tumors in adults. It is also 
approved in other regions, including EU, for the treatment of unresectable or metastatic, 
progressive, well differentiated (G1 and G2), somatostatin receptor positive GEP NETs in 
adults. There are currently no approved therapies for GEP-NETs in the pediatric population. 
As described in Section 1.2, and in line with the US and EU recommendations on extrapolation 
in the development of medicines for paediatrics (FDA General Clinical Pharmacology 
Considerations for Pediatric Studies for Drug and Biological Products, December 2014; EMA 
Reflection paper on the use of extrapolation in the development of medicines for paediatrics, 
October 2018), the development of Lutathera for adolescent patients with GEP-NETs follows 
a full efficacy extrapolation approach.  
Increased SSTR expression, particularly that of SSTR2, in PPGLs has been demonstrated by 
uptake on somatostatin receptor scintigraphy providing the rationale for the use of PRRT with 
radiolabeled somatostatin analogues in this patient population (Reubi et al 2001, Reubi 2003). 
Although Lutathera has not been approved in adults with PPGL, there is evidence of significant 
clinical benefit demonstrated by Lu177 dotatate use in this indication (Satapathy 2019). Only 
few case reports have been published on the use of Lutathera in children with PPGLs (Cassano 
2019, Yadav 2019, Roll 2020, Pinato 2016), with single patients treated in each of the reports. 
Due to the scarcity of pediatric data in PPGL and unmet need in this indication, a cohort will 
be open for enrolment of adolescent patients with somatostatin receptor positive PPGLs. 
A modelling and simulation study analysis 
 has been 
conducted to define the dose in adolescent patients based on observed Lutathera dosimetry 
values in adults, and literature based physiological values 
 from 

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adolescents. The dose assessment was based primarily on the target organs for radiation 
toxicities (kidney and bone marrow) ensuring that the selected dose gave kidney dosimetry 
values below 29 Gy and bone marrow dosimetry values below 2 Gy (see Section 4.2). Analysis 
has indicated that the full adult regimen, i.e. 4 doses of Lutathera administered every 8 weeks 
(7.4 GBq/200 mCi x 4 administrations every 8 weeks; cumulative dose: 29.6 GBq/800 mCi) is 
appropriate in the adolescent population to keep the median kidney dosimetry within the values 
outlined above. Importantly, clinical data from the pivotal adult efficacy trials have shown that 
this full adult cumulative radioactive dose from 4 administrations correlated with efficacy in 
adult population.  
In this adolescent study, dosimetry assessments will be performed in each patient after the first 
Lutathera dose (or in exceptional circumstances after a later dose in case dosimetry cannot be 
performed in a particular patient after the first Lutathera dose) to confirm dosimetry values with 
regard to reference limits (Section 6.5.1.2) and ensure continuation of safe dosing. In case that 
the resulting cumulative radiation dose exceeds the reference limits, the DSMB will evaluate 
benefit risk for the patient and give recommendation on whether dosing can continue and at 
which level (see Section 6.5.1). Although the ultimate decision on dose modification remains 
with the investigator, it is strongly recommended that the investigator follows DSMB 
recommendations. 
The co-primary objectives and endpoints have been selected to meet the main goal of the 
clinical study to validate the dose extrapolation approach for adolescent patients with GEP-
NETs or PPGLs. The clinical study will confirm the safety, tolerability and dosimetry findings 
of the adolescent dose modelled based on the original adult data. Of note, dosimetry is 
considered as a primary endpoint instead of PK parameters based on the Lutathera mechanism 
of action. 
The secondary objectives and endpoints were selected to evaluate all safety data from 
cumulative dosing, as well as long-term safety in adolescents (see the rationale for duration of 
follow-up in Section 4.3). In addition to safety analysis, a comparative assessment of dosimetry 
in adolescent patients and adults (from the NETTER-1 study) is selected as a secondary 
objective in order to evaluate the predicted organ absorbed dose and the accuracy of the model. 
The evaluation of primary and secondary objectives will be performed in GEP-NET and PPGL 
pooled cohort,
 
 
This study is designed in a non-randomized open-label fashion, which is considered appropriate 
when specifically studying a very small sample size of patients with a rare indication. Due to 
the rarity of disease, the study will be conducted at multiple centers across several countries. 
In summary, in line with the full efficacy extrapolation approach, this multicenter open-label 
clinical study will confirm the proposed Lutathera dosing strategy in adolescent patients 12 to 
<18 years old with SSTR-positive GEP-NETs or PPGLs by assessing the safety, tolerability 
and dosimetry of the dose/exposure matched Lutathera dose.
 
 

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4.2 
Rationale for dose/regimen and duration of treatment 
The modelling and simulation analysis to define the dose in the adolescent population was based 
on the clinical data from two adult clinical trials, 
 and 
approximately 50 subjects were available for analysis. As the principal Lutathera risks are 
related to renal and bone marrow toxicities, the key objective in this analysis was to investigate 
the factors influencing the absorbed dose to the kidneys and bone marrow in adults and 
extrapolate this to the adolescent population (12 to <18 years old) accounting for adolescent 
specific factors determined from the adult dosimetry model. 
The amount of 177Lu radioactivity administered to an adult patient has to achieve an optimal 
therapeutic effect of PRRT in the tumors with limited side effects to radiosensitive organs, 
namely the kidneys and bone marrow. The true threshold of the kidney-absorbed dose that 
predisposes patients to toxicity has not been accurately determined. Based on data from external 
beam radiation, commonly accepted values vary from 18 to 23 Gy (Marks et al 2010, Wessels 
et al 2008, Emami et al 1991, Emami 2013). However, there is growing evidence that PRRT 
with lutetium (177Lu) oxodotreotide is less nephrotoxic (Konijnenberg et al 2007, Bodei et al 
2008, Sundlöv et al 2017, Bergsma et al 2016b, and Löser et al 2018). As an example, results 
by Sundlöv et al 2017 support the dose limit proposed for high risk patients (concomitant risk 
factors) of 27 ± 2 Gy, while suggesting that patients without risk factors may support a higher 
kidney dosimetry value. In a study of 323 patients described by Bergsma et al 2016b, where a 
median number of four 7.4 GBq cycles of lutetium (177Lu) oxodotreotide have been 
administered, no subacute grade 3 or 4 nephrotoxicity was observed. The mean kidney absorbed 
radiation dose in this study was 20.1 ± 4.9 Gy. No correlation was observed between radiation-
absorbed dose to the kidneys and worsening creatinine clearance on long-term follow-up. A 
similar outcome was obtained also in the NETTER-1 Phase III study, in which the kidney 
absorbed radiation dose was 19.4 ± 8.7 Gy, with no clinically relevant kidney toxicity observed 
and no evidence of correlation between creatinine clearance level and kidney absorbed dose.  
For bone marrow, the commonly accepted threshold is 2 Gy (based on historical cohorts of 
patients treated with 131I (Bergsma et al 2016b), and here too the clinical relevance for PRRT 
with lutetium (177Lu) oxodotreotide has not been established. Bergsma et al 2016a described 
the hematological toxicity findings in 320 patients treated with 4 cycles of lutetium (177Lu) 
oxodotreotide (7.4 Gy each). The bone marrow dosimetry was evaluated in a subset of patients 
(obtaining a mean bone marrow absorbed dose of 2.0 ± 0.2 Gy) and no correlation was found 
between cumulative bone marrow-absorbed dose and therapy-related persistent hematologic 
disorder. Similarly, in the NETTER-1 study, in which the estimated mean bone marrow 
absorbed dose was 1.0 ± 0.8 Gy, no correlation was found between these two parameters. 
Moreover, a wide heterogeneity between authors in the methodology of bone marrow dosimetry 
(planar imaging, SPECT imaging, blood samples) makes it difficult to compare between studies.  
In view of the above, it is considered that the total doses of ≤ 29 Gy and ≤ 2 Gy of lutetium 
(177Lu) oxodotreotide, constitute appropriate thresholds for the kidney and bone marrow-
absorbed dose by subject, respectively. 
The modelling and simulation analyses were therefore conducted to estimate the projected dose 
in the adolescent population ensuring that median dosimetry estimates are ≤ 29 Gy for the 
kidney or ≤ 2 Gy for the bone for four treatment cycles. Results indicate that the covariates 
important in explaining kidney dosimetry across the adult population 
 
 These findings were also 
supported by the prior analysis of Svensson et al 2015 who indicated that patients with inferior 

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renal function were exposed to higher renal dosimetry values, and also developed hematological 
toxicity. 
Reference values taken from the literature for creatinine clearance levels in an adolescent 
population suggested limits from approximately 70 – 108 ml/min (Piepsz 2008), which are in 
line with adult values when adjusted by body surface area (Pottel 2017) indicating similar renal 
function in these two groups.  
Simulations (estimation and re-estimation, n=500) from the model 
 
 developed in adults with adjustment for adolescent renal function 
indicated that after a full adult dose of Lutathera (7.4 GBq over 4 cycles, a total of 29.6 GBq) 
median kidney dosimetry and bone marrow dosimetry would be similar to those of adults with 
values of
for kidney and
for bone marrow, i.e.
 Therefore, the full adult regimen, i.e. 4 doses of Lutathera 
administered every 8 weeks (7.4 GBq/200 mCi x 4 administrations every 8 weeks; cumulative 
dose: 29.6 GBq / 800 mCi) is appropriate to be used in this study in adolescent population 12 - 
<18 years of age. 
Data on Lutathera use in patients with PPGL from the Erasmus MC study and from a number 
of other recent studies (reviewed in Satapathy 2019) suggest that the safety of Lutathera 
administered as a full regimen (i.e. 4 cycles of 7.4 GBq each) in patients with PPGL is similar 
to safety established in GEP-NET population. During Lutathera treatment, the frequency of 
adverse events related to toxicities in radiosensitive organs do not seem to be dependent on the 
tumor type, and in PPGL patients described so far the drug toxicities were represented by a low 
number of Grade 3/4 haematotoxicities and no cases of significant nephrotoxicity (Satapathy 
2019).  
Both Erasmus MC study and other studies in PPGL patients (reviewed in Satapathy 2019) 
demonstrated that Lutathera is an efficacious treatment option for patients with advanced 
PPGLs. As the pathophysiology of PPGL is not substantially different in adolescents compared 
to adult patients, there is no evidence that adolescent patients with PPGL would exhibit different 
safety or efficacy profile after Lutathera treatment to what has been shown in adults with PPGL  
As such, extrapolation is considered to be appropriate in PPGL indication similar to GEP-NET 
indication and a full flat dose of Lutathera will be administered to adolescent patients with 
PPGL in this study. All enrolled patients will be closely monitored for safety in real-time during 
the whole treatment period and will be followed up for any long-term effects after the last dose 
(Section 4.3). Stopping rules and DMT rules will apply for both GEP-NET and PPGL cohorts, 
and DSMB will ensure safety of all adolescents enrolled in the study and evaluate accumulating 
safety and dosimetry data for both indications.  
4.3 
Rationale for duration of follow-up 
This study includes a total follow-up of 5 years (60 months) after the last Lutathera 
administration, including a 6-month short-term and a 54-month long-term follow-up periods.  
Based on Lutathera’s mechanism of action and pharmacological characteristics, the principal 
risks arising from treatment with Lutathera are potential radiation toxicities affecting bone 
marrow and kidney function (Bergsma et al 2016a, Bergsma et al 2016b, Lutathera USPI). 
Kidney related toxicity is largely eliminated by the co-infusion of 2.5% Lysine – Arginine 
amino acid solutions during administration of Lutathera, which reduces the radiation dose to 
the kidney by approximately 45% (Rolleman et al 2003, Lutathera USPI). In the NETTER-1 
study, no difference in renal long-term toxic effects between two arms was observed within the 

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period of observation (Strosberg et al 2017). In the Erasmus MC trial, 8 patients (<1%) 
developed renal failure 3 to 36 months following Lutathera administration. 
 of these 
patients had underlying renal impairment or risk factors for renal failure (e.g., diabetes or 
hypertension) and required dialysis. In the post-marketing safety surveillance of Lutathera, 43 
cases had been reported in 5,968 patients with any preferred term covered by Standardised 
MedDRA Query of “Renal dysfunction” until 19 December 2019. Time to onset was reported 
for 41% of cases and ranged from 1 to 180 days after first Lutathera treatment cycle (median 
20 days). Seventeen percent of cases were reported as resolved at the time of the last update. 
In this study, in addition to the administration of an amino acid solution for kidney protection, 
renal function will be monitored during and after the treatment with Lutathera, with the 
assessment of serum creatinine, creatinine clearance, uric acid, BUN, and urine protein after 
each dose. 
The observed effects of short-term bone marrow toxicity after Lutathera treatment are anemia, 
thrombocytopenia, leukopenia, lymphopenia and neutropenia, which are usually mild and 
transient (Strosberg at al 2017, Lutathera USPI). In the Lutathera arm of the NETTER-1 study, 
grade 3 or 4 anemia, thrombocytopenia, leukopenia, lymphopenia and neutropenia occurred in 
0%, 1%, 2%, 44% and 3% of patients, respectively (Lutathera USPI). Lymphopenia in the 
Lutathera arm was not associated with an increased rate of infections compared to the control 
arm. Overall, it is important to note that the observed lymphopenia following PRRT is not a 
major concern regarding risk of infections, since only B lymphocytes are transiently affected, 
a subtype which is not directly involved in infection defense (Sierra et al 2009). The median 
time to onset of hematological toxicities was during the 2nd - 3rd cycle of Lutathera, while the 
median time of resolution was within 6 months after the last Lutathera cycle. When 
hematological toxicity occurred, a trend towards stabilization followed by improvement in 
patients with longer follow-up was observed.  
Based on the median time to onset and the resolution time of hematological toxicities observed 
in adults in the NETTER-1 study, the short-term follow-up period in this study is 6 months after 
the last dose of Lutathera. This will allow for evaluation of cumulative toxicities after 4 cycles 
of Lutathera and for the detailed observation of resolution of hematological toxicity cases. 
As for any radiotherapy, one of the long-term safety risks of Lutathera treatment is secondary 
malignancies. In the NETTER-1 study, with a median follow-up time of 24 months, 
myelodysplastic syndrome (MDS) was reported in 3 patients (2.3%) receiving Lutathera with 
long-acting octreotide compared to no patients receiving high-dose long-acting octreotide. In 
the Erasmus MC study, 16 patients (2%) developed MDS and 4 (0.5%) developed acute 
leukemia. The median time to the development of MDS was 28 months (9 to 41 months) for 
MDS and 55 months (32 to 125 months) for acute leukemia (EU SmPC). 
Therefore, to enable a follow-up on long-term safety risks in adolescent patients treated with 
Lutathera, a follow-up period of 5 years is included in the study. During the long-term follow-
up, patient visits will occur every 6 months to collect information on adverse events, secondary 
malignancies, further anticancer treatments, as well as to draw laboratory samples for chemistry, 
hematology and safety biomarkers of growth and development, reproductive and endocrine 
function as well as bone formation. 

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4.4 
Rationale for study population 
Per Section 1.1 above, the epidemiology search has shown that the incidence of patients with 
GEP-NETs per 100,000 population is 0 for the group aged 0 to <12 years, and 0.21 for those 
aged 12 to < 17 years. The incidence of PPGLs in pediatric patients is even smaller with only 
single cases recorded in SEER registry in 2019, corresponding to a rate lower than 0.03 per 
100,000 population (SEER registry). In view of these epidemiology data, the study population 
will include adolescent patients 12 to <18 years of age.  
Patients will be included in the GEP-NET cohort if there is a presence of metastasized or locally 
advanced, inoperable (curative intent) histologically proven, well differentiated GEP-NET. 
This population was chosen in line with the indication approved for the adult population. 
For PPGL cohort, patients with metastasized or locally advanced, inoperable (curative intent), 
histologically proven PPGL will be enrolled. This population was selected based on unmet need 
and mimics adult population with PPGL that has been treated with Lutathera so far. 
As Lutathera binds to SSTR2 to deliver tumoricidal radiation to the tumor tissue, the SSTR 
expression will be confirmed before the 1st Lutathera dose by an SRI modality. 
As this is the first prospective clinical study of Lutathera in the pediatric GEP-NET and PPGL 
populations, a set of safety eligibility criteria will be implemented in the trial to exclude patients 
with significant hematological, renal and liver impairment, defined as: 
• Estimated creatinine clearance calculated by the Cockroft-Gault method < 70 mL/min 
• Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L; platelets <75x109/L 
• Total bilirubin >3 x ULN for age 
• Serum albumin <3.0 g/dL unless prothrombin time is within the normal range 
These exclusion criteria were chosen in line with the criteria used in the adult NETTER-1 study, 
except for the estimated creatinine clearance. In the NETTER-1 study, subjects were excluded 
if creatinine clearance was below 50 mL/min calculated by the Cockroft-Gault method. As a 
precaution and as this is the first study in the pediatric population, a higher creatinine threshold 
was chosen in order to reduce the risk to reach a cumulative renal absorbed dose above 29 Gy 
(assumed limit for kidney toxicity). 
4.5 
Risks and benefits 
In this pediatric study conducted in a vulnerable participant population (adolescents 12 - <18 
years of age) it will be ensured that the rights, safety and well-being of study subjects are 
protected. 
In order to minimize pain, distress, and fear in participants, this study will use facilities 
appropriate to pediatric care, and the personnel will be trained to look after children and 
supervised by experienced health care professionals. Staff will be trained to communicate with 
both parents (or legal representative) and adolescent patients. Study patients will be hosted in a 
familiar environment and their concerns will be addressed by skilled personnel. 
Appropriate eligibility criteria and specific dose-limiting toxicity definitions, as well as specific 
dose modification and stopping rules, are included in this protocol. The risk to participants in 
this trial is minimized by compliance with the eligibility criteria and study procedures, as well 
as close clinical monitoring, per the schedule in Table 8-2.  
Although this is an adolescent study, all female patients of child-bearing potential and sexually 
active males must be informed that the administration of Lutathera may involve unknown risks 

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to the fetus if pregnancy were to occur during the study, and agree that in order to participate 
in the study they must adhere to the contraception requirements outlined in the exclusion criteria 
(Section 5.2) and Appendix 1. If there is any question that the participant will not reliably 
comply, they should not be entered or continue in the study. 
As described in Section 4.1, the highest risks arising from treatment with Lutathera are radiation 
toxicities affecting bone marrow or kidney function. 
• The potential kidney related toxicities are largely eliminated by the co-infusion of 2.5% 
Lysine – Arginine amino acid solutions during administration of Lutathera, which reduces 
the radiation dose to the kidney by approximately 45% (Rolleman et al 2003, Lutathera 
USPI). In this study, in addition to AA administration for kidney protection, renal function 
will be monitored during and after the treatment with Lutathera, with the assessment of 
serum creatinine, creatinine clearance, uric acid, BUN, and urine protein after each 
Lutathera dose. 
• The potential observed effects of short-term bone marrow toxicity after Lutathera 
treatment are decreased blood cell counts (anemia, thrombocytopenia, leukopenia, 
lymphopenia and neutropenia), which are usually mild and transient. A careful monitoring 
of hematological parameters will be conducted in this study after each Lutathera dose 
allowing for a prompt identification of possible acute effects. The large interval between 
the Lutathera treatments (8 weeks) allows for a possible recovery or for a modification of 
the dose, according to the protocol-defined scheme. 
In order to minimize risk for each study subject, an accelerated analysis of dosimetry and safety 
data will be performed for each individual patient in the study, to enable the Investigator to take 
a decision for the next Lutathera dose. The results of dosimetry assessments (imaging and blood 
dosimetry) conducted in the 1st Lutathera cycle will be provided to and evaluated by 
investigators prior to administration of the next therapeutic cycle (Section 6.5.1.2).  
With regard to long term safety effects, secondary myelodysplastic syndrome and leukemia are 
potential serious adverse effects of Lutathera, similar to any radioligand therapy. All secondary 
malignancies are considered adverse events of special interest (AESI) in this study and will be 
reported during and after the treatment with Lutathera and during the long-term follow-up 
period (Section 10.1.5). 
Common adverse effects of Lutathera include vomiting and nausea which are usually mild and 
transient. In the vast majority of cases these side effects can be prevented by the use of 
antiemetics. The use of antiemetics is mandatory in this study, with the preventive 
administration given before each amino acid infusion and Lutathera treatment (Section 6.1.2).  
For the patients enrolled in the PPGL cohort, a monitoring for development of hormonal crisis 
symptoms due to potential tumor lysis and excessive catecholamine release (such as 
hypertension, pallor, sweating, palpitations) (see Section 1.1) will be performed after each 
Lutathera dose. A combined α- and β-adrenergic blockade is a standard treatment for PPGL 
patents with pheochromocytoma in order to control blood pressure (Neumann 2019), and any 
additional medications will be administered in this study by investigator if necessary per the 
medical judgment and local standards. In a study of 20 adult PPGL patients treated with 177Lu-
dotatate PRRT, hypertension flare was observed in only one patient, who had inadequate alpha- 
and beta-blockade before treatment resulting from patient nonadherence to prescribed therapy 
(Kong 2017). An appropriate adrenergic blockade, safety monitoring and patient control will 
be carried out in all adolescents with PPGL enrolled in the NETTER-P study.  

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Considering the age of participants, additional potential safety concerns in the pediatric 
population will be controlled via assessment of safety biomarkers. This includes potential 
effects of treatment with Lutathera on endocrine (hypothalamic-pituitary) function, gonadal 
function, growth and bone development that will be controlled during and after the treatment 
with Lutathera (Section 8.4.9). 
All safety effects of Lutathera will be carefully assessed in this study, and patients will be 
closely monitored. 
As this is the first study of Lutathera in adolescents with GEP-NETs and PPGLs, its efficacy 
and safety has not been established in this population yet. However, based on adult efficacy and 
similarities between adolescents and adults, it is expected that Lutathera administered in the 
study may bring therapeutic benefit to adolescents with GEP-NETs and PPGLs. This study will 
be essential to bring new potential therapeutic options for adolescent GEP-NET and PPGL 
patients. 
4.5.1 
Blood sample volume 
Blood samples for clinical safety monitoring, safety biomarkers and radioactive dosimetry will 
be collected in this study from each patient, consistent with study objectives. The schedule of 
sampling has been designed to minimize the blood sample volume for adolescent participants, 
balancing it with required safety monitoring as described in Section 4.5.  
The total blood volume taken from each patient will be in line with WHO Key 
recommendations regarding blood sampling in children involved in clinical research (Howie 
2011), and will comply with local regulations/restrictions. 
Timings of blood sample collection are outlined in the assessment schedule (Table 8-2). 
Additional unscheduled samples may be required for safety monitoring in case of adverse 
events. 
Exact blood volumes will be provided in the informed consent form (ICF) for each participant. 
Instructions for sample collection, processing, storage and shipment information are also 
available in the laboratory manual. 
5 
Study Population 
This study will enroll at least 8 adolescent patients 12 to < 18 years old with somatostatin 
receptor-positive GEP NETs or PPGLs, including a minimum of 3 GEP-NET patients. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. GEP-NET cohort: Presence of metastasized or locally advanced, inoperable (curative 
intent), histologically proven, G1 or G2 (Ki-67 index ≤20%), well differentiated GEP-
NET.  
PPGL cohort: presence of metastasized or locally advanced, inoperable (curative intent), 
histologically proven PPGL. 
2. Patients from 12 to < 18 years of age at the time of enrollment.  
3. Expression of somatostatin receptors confirmed by a somatostatin receptor imaging (SRI) 
modality within 3 months prior to enrollment, with tumor uptake observed in the target 
lesions more or equal to the normal liver uptake. 

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4. Performance status as determined by Karnofsky score ≥ 50 or Lansky Play-Performance 
Scale score ≥ 50. 
5. Parent’s ability to understand and the willingness to sign a written informed consent 
document for adolescents as determined by local regulations. Adolescents will sign assent 
along with parental/legal guardian consent or will co-sign consent with parent/legal 
guardian in accordance with local regulation, prior to participation in the study. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Laboratory parameters: 
• 
Estimated creatinine clearance calculated by the Cockroft-Gault method < 70 
mL/min 
• 
Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L; platelets <75x109/L. 
• 
Total bilirubin >3 x ULN for age. 
• 
Serum albumin <3.0 g/dL unless prothrombin time is within the normal range. 
2. Established or suspected pregnancy.  
3. Breastfeeding female patients unless they accept to discontinue breastfeeding from the 1st 
dose until 3 months after the last administration of study drug. 
4. Female patients of child-bearing potential (female pediatric patients who are menarchal or 
who become menarchal during the study), unless they are using highly effective methods 
of contraception during treatment and for 7 months after the last dose of Lutathera (see 
details in the Appendix 1). If local regulations deviate from the listed contraception 
methods to prevent pregnancy, local regulations apply and will be described in the ICF. 
5. Sexually active male patients, unless they agree to remain abstinent (refrain from 
heterosexual intercourse) or be willing to use condoms and highly effective methods of 
contraception with female partners of childbearing potential, and to use condoms with 
pregnant female partners during the treatment period and for at least 4 months after the 
last dose of Lutathera (see details in Appendix 1). In addition, male patients must refrain 
from donating sperm during this same period. 
6. Patients for whom in the opinion of the investigator other therapeutic options are 
considered more appropriate than the therapy offered in the study, based on patient and 
disease characteristics. 
7. Current spontaneous urinary incontinence. 
8. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma 
in situ of the uterine cervix, unless definitively treated and proven no evidence of 
recurrence for 5 years. 
9. Hypersensitivity to the study drug active substance or to any of the excipients. 
10. Patients with any other significant medical, psychiatric, or surgical condition, currently 
uncontrolled by treatment, which may interfere with the completion of the study. 
11. Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction 
or renal insufficiency. If such a patient can be imaged with MRI, then the patient would 
not be excluded. 
12. Patients who received any investigational agent within the last 30 days. 
13. Prior therapies and procedures: 

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• 
External beam radiation therapy to more than 25% of the bone marrow. 
• 
PRRT for GEP-NET or PPGL within 12 months prior to the first Lutathera 
administration in the study. 
• 
Long acting somatostatin analogs within 28 days or short acting octreotide within 
24 hrs prior to Lutathera administration. 
• 
Prior solid organ transplantation. 
• 
Any previous radioembolization, chemoembolization and radiofrequency ablation 
for GEP-NET and any surgery within 12 weeks prior to randomization in the study. 
• 
Corticosteroids: Patients receiving corticosteroids who have not been on a stable or 
decreasing dose of corticosteroid for at least 7 days prior to enrollment are not 
eligible. If used to modify immune adverse events related to prior therapy, ≥ 14 
days must have elapsed since last dose of corticosteroid. 
• 
Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive 
within 21 days prior to Lutathera administration (42 days for nitrosourea). 
• 
Anti-cancer systemic agents not known to be myelosuppressive within 7 days prior 
to Lutathera administration.  
• 
Antibodies, Interleukins, Interferons and Cytokines within 21 days prior to 
Lutathera administration or any toxicity related to prior antibody therapy not 
recovered to Grade ≤ 1. 
• 
Hematopoietic growth factors within 14 days prior to Lutathera administration for a 
long-acting growth factor or within 7 days prior to Lutathera administration for 
short-acting growth factor. For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended beyond the time 
during which adverse events are known to occur.  
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell 
infusion including donor lymphocyte infusion or boost infusion within 84 days 
prior to Lutathera administration. 
• 
Autologous stem cell infusion or cellular therapy within 42 days prior to Lutathera 
administration. 
6 
Treatment 
6.1 
Study treatment 
As this is a single-arm, open-label, non-randomized study, no control drug will be used in the 
study.  
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for participant numbering, prescribing/dispensing, and administration of study 
treatment are outlined in the accompanying Pharmacy Manual. 
6.1.1 
Investigational drug 
The investigational drug Lutathera® (lutetium Lu 177 dotatate/ lutetium (177Lu) oxodotreotide ) 
will be provided by the Sponsor (Table 6-1). Patients will receive a total of 4 administrations 
of Lutathera 7.4 GBq / 200 mCi every 8 ±1 weeks.  

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Table 6-1 
Investigational drug 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical Dosage 
Form 
Route of 
Administration 
Supply type 
Supplier  
Lutathera® 
Radiopharmaceutical solution 
for infusion (7.4 GBq of 
Lutathera per 30 ml vial) 
Intravenous use 
Open label; 
vials 
Sponsor  
6.1.2 
Additional study treatments 
Patients will receive a sterile 2.5% Lys-Arg amino acid solution for infusion for renal 
protection for each Lutathera administration; and an anti-emetic before each amino acid 
infusion and Lutathera administration, for prevention of infusion-related nausea and vomiting 
(Table 6-2).  
Table 6-2 
Additional Study Treatment 
Treatment Title 
Sterile 2.5% Lys-Arg solution 
Anti-emetics (ATC A04A and 
A03FA01) 
Type  
drug 
drug 
Dose Formulation 
Solution for infusion 
various 
Unit Dose Strength(s) 
25 g of L-arginine hydrochloride 
and 25 g of L-lysine hydrochloride 
various 
Dosage Level(s) 
One bag concomitantly with 
Lutathera administration 
various 
Route of Administration 
IV infusion 
various 
Use 
Reduction of renal radiation 
exposure 
Reduction of nausea/vomiting 
induced by 2.5% Lys-Arg  
Authorization status of the AxMP in 
EEA 
Yes 
Yes 
Sourcing 
Provided locally by the study site 
or by the Sponsor where 
compounded amino acid is not 
made available 
Provided locally by the study site 
Packaging and Labeling 
Will be provided in a 1-L bag. 
Each bag will be labeled as 
required per country requirement. 
As locally available 
The sterile 2.5% Lys-Arg solution must be administered intravenously with the infusion rate of 
250 ml/h. The infusion should start 30 minutes prior to the start of the Lutathera infusion and 
continue for a total of 4 hours (extension up to 6 h is allowed in case of adverse reactions that 
require infusion interruption or slowing the infusion rate). Hyperkaleamia must be corrected 
prior to sterile 2.5% Lys-Arg infusion if >6.0 mmol/L. 
The composition of the sterile 2.5% Lys-Arg solution is shown in Table 6-3 below. 
Table 6-3 
Sterile 2.5% Lys-Arg solution composition 
Component 
Quantity/1000 ml 
L-lysine HCL 
25g* 
L-arginine HCl 
 
25g** 
Sodium chloride 9 mg/mL (0.9%) solution for injection,  
or water for injection 
1 L 
*equivalent to 20.0 g lysine 
**equivalent to 20.7 g arginine 

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On the day of each Lutathera treatment, before the infusion with sterile 2.5% Lys-Arg solution 
is started, an intravenous bolus of anti-emetic must be given with sufficient lead time as per 
local prescribing information. The choice of antiemetics is at the discretion of investigator in 
accordance with institutional regulations (suggested options: Granisetron (3 mg), or 
Ondansetron (8 mg), or Tropisetron (5 mg)). Steroids must be avoided as preventive anti-emetic 
treatment because of potential somatostatin receptor down-regulation.  
In case of development of nausea and vomiting during the infusion, a repeated administration 
of antiemetics should be performed at the physician judgment. In general, investigators are 
advised to use antiemetics which are commonly prescribed in their institutions for treatment of 
nausea induced by chemotherapeutic drugs. Among such antiemetics, the use of Aprepitant 
(Emend®) should be considered. Haloperidol (Haldol®) could also be considered as an adjunct 
treatment (either i.v. or oral) in case the advised antiemetic regimens are not successful and 
patients continue to vomit, as well as Lorazepam (Ativan®). All administered antiemetics must 
be documented in the appropriate eCRF page. 
In case where the treatments previously provided for nausea and vomiting are insufficient, a 
single dose of corticosteroids can be used, as long as it is not given before initiating or within 
one hour after the end of Lutathera infusion.  
For further details on the amino acid solution and Lutathera administration, see Section 6.7 and 
Pharmacy Manual. 
6.1.3 
Supply of study treatment 
Lutathera® (lutetium Lu 177 dotatate/ lutetium (177Lu) oxodotreotide) will be supplied by the 
Sponsor.  
As Lutathera production and shipment takes approximately 12 days, Lutathera first dose must 
be ordered immediately after confirming patient eligibility and enrollment. 
The sterile 2.5% Lys-Arg solution will be provided by the Sponsor or compounded by the 
appointed Pharmacy (hospital or local pharmacy). 
Antiemetics, SRI imaging agents, somatostatin analogues or any other supportive care 
medication are not considered investigational drugs and will not be supplied by the Sponsor. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies administered after the patient 
was enrolled into the study must be recorded on the appropriate Case Report Forms, including 
somatostatin analogues, amino acid solution and antiemetic administration. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication list. If in doubt, the investigator should contact the Sponsor before enrolling a 
patient or allowing a new medication to be started. If the patient is already enrolled, contact the 
Sponsor to determine if the patient should continue participation in the study. 
6.2.2 
Prohibited medication 
Patients may not receive any other systemic therapy for the treatment of GEP-NET or PPGL 
(chemotherapeutic, biologic, or any investigational agent) other than Lutathera and 
somatostatin analogues during the study treatment period.  

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Localized therapy such as surgery or external beam irradiation may be performed on additional 
site(s), provided that it does not affect study endpoint assessment. For a major surgery, 
treatment with Lutathera must be temporarily discontinued and can be restarted after 12 weeks 
from the date of surgery.  
Somatostatin and its analogues competitively bind to somatostatin receptors. Therefore, 
administration of long-acting somatostatin analogues should be avoided within 4 weeks prior 
to the administration of Lutathera. If necessary, patients may be treated with short acting 
somatostatin analogues during the 4 weeks until 24 hours preceding Lutathera administration. 
There is some evidence that corticosteroids can induce down-regulation of SST2 receptors. 
Therefore, as a matter of caution, repeated administration of high doses of glucocorticosteroids 
should be avoided during Lutathera treatment. The use of glucocorticosteroids should also be 
avoided as preventive anti-emetic treatment. In the case where the treatments previously 
provided for nausea and vomiting are insufficient, a single dose of corticosteroids can be used, 
as long as it is not given before initiating or within one hour after the end of Lutathera infusion. 
The absence of inhibition or significant induction of the human CYP450 enzymes, the absence 
of specific interaction with P-glycoprotein (efflux transporter) as well as OAT1, OAT3, OCT2, 
OATP1B1, OATP1B3, OCT1 and BCRP transporters in preclinical studies suggest that 
Lutathera has a low probability of causing significant other drug-drug interactions.  
There is no restriction for concomitant medications during the follow-up period. 
6.2.3 
Rescue medication 
In GEP-NET cohort, subcutaneous, short-acting octreotide injections may be indicated for 
control of GEP-NET symptoms (i.e. diarrhoea and flushing) at the judgment of investigator in 
accordance with the manufacturer’s prescribing information. Short-acting octreotide for 
symptom control may be administered (at home) at investigator’s discretion and 
recommendation provided in Section 6.2.2 should be considered. Short-acting octreotide will 
not be supplied by the Sponsor. 
In the PPGL cohort, an adequate alpha- and beta-blockade should be maintained to avoid acute 
symptoms of catecholamine release (i.e. hypertension, pallor, sweating, palpitations). The 
treatment of such symptoms should be done as per standard local practice and physician 
judgment according to prescribing information (Section 4.5).  
6.2.4 
SARS-CoV-2 vaccination 
Patients are allowed to receive approved SARS-CoV-2 vaccines (inactivated, viral-vector-, or 
mRNA based Sars-CoV-2 vaccines approved by the Health Authorities in the country). The 
decision for vaccination should be done on a case-by-case basis and at the discretion of the 
treating physician, with patient consent, and in alignment with institutional guidelines, if 
available. 
Investigators are expected to evaluate potential risks/benefits in the context of individual patient 
characteristics and make an individualized decision for vaccination. Investigators should refer 
to the prescribing information for the SARS-CoV-2 vaccine planned to be used and/or follow 
local Health Authorities or institutional guidelines, if available. 
Patients should be instructed to contact their GP and/or the study site in case of side effects after 
vaccination. 
Vaccine must be reported as a prior/concomitant medication according to the protocol 
guidelines. Any AEs after vaccination must be monitored and reported in eCRF. 

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6.2.5 
Restriction for study participants 
Before leaving the clinical site after Lutathera administration, patients will be instructed about 
radioactivity protection measures. 
6.3 
Participant numbering, treatment allocation 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is screened and is retained for the participant throughout his/her 
participation in the trial. A new Participant No. will be assigned at every subsequent re-
screening. The Participant No. consists of the Center Number (Center No.) (as assigned by the 
Sponsor to the investigative site) with a sequential participant number suffixed to it, so that 
each participant’s participation is numbered uniquely across the entire database. Upon signing 
the informed consent form, the participant is assigned to the next sequential Participant No. 
available. 
6.3.2 
Treatment allocation 
No randomization will be performed in this study as this is a single-arm open-label study. All 
patients will receive Lutathera treatment, which will be allocated upon site ordering for each 
individual administration. Sites will be resupplied with amino acid solution based on 
recruitment rate. 
6.4 
Treatment blinding 
This is a single-arm open-label study: No treatment blinding will be implemented.  
6.5 
Dose escalation and dose modification 
No dose escalation is permitted in the study. For dose modification, see below. 
6.5.1 
Dose modification 
In order to minimize risk for each study subject, an accelerated analysis of dosimetry and safety 
data will be performed for each individual patient in the study, to enable the Investigator to take 
a decision for the next Lutathera dose(s).  
Dose modification recommendations for toxicities (DMT) and dose modification 
recommendations according to dosimetry results will apply as discussed in Section 6.5.1.1 and 
Section 6.5.1.2, respectively. The results of dosimetry assessments (imaging and blood 
dosimetry) and safety assessments will be provided to and evaluated by investigators prior to 
administration of next therapeutic cycle to decide on a need for dose modification based on the 
rules described below. 
Patients, whose treatment is interrupted or permanently discontinued, must be followed up at 
regular intervals. In case of treatment interruption, the frequency of follow-up visits until 
treatment is resumed is at the discretion of Investigator depending on the DMT type and 
severity. In case of permanent treatment discontinuation, patients will enter the Follow-up 
Period (see Section 9.1.1), with visits frequency as specified in the Assessment Schedule. 
In case that dosimetry results exceed reference limits in individual patient(s) (Section 4.2), 
DSMB must be consulted to evaluate benefit risk for the patient and advise on whether dosing 

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can continue and at which level (Section 6.5.1.2). The DSMB charter will include the reference 
information needed for dose decision making (including data collected from the M&S study).  
Appropriate clinical experts such as cardiologists, endocrinologists, hepatologists, 
nephrologists etc. should be consulted as deemed necessary. 
6.5.1.1 
Dose modifying toxicities (DMTs) 
Management of severe or intolerable adverse drug reactions may require temporary dose 
interruption, extending the dosing interval from 8 weeks up to 16 weeks, dose reduction, or 
discontinuation of treatment with Lutathera.  
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted to allow the patient to continue the study treatment. 
The criteria for dose modifications of Lutathera for toxicities are outlined in Table 6-4. The 
evaluation for potential DMTs will be done by Investigator based on local laboratory results 
from hematology and biochemistry tests done after each Lutathera treatment. 
If a patient requires a dose delay of > 16 consecutive weeks of Lutathera from the intended day 
of the next scheduled dose, then the patient should be discontinued from the study treatment. 
In exceptional situations, if the patient is clearly benefitting from the study treatment (i.e. stable 
disease, partial response, complete response), and in the opinion of the investigator no safety 
concerns are present, after discussion with Sponsor Medical Monitor and/or DSMB, the patient 
may remain on the study treatment.  
For each patient, a maximum of one dose reduction will be allowed after which the patient will 
be discontinued from the study.  
All dose changes must be recorded on the appropriate electronic case report form (eCRF). 
Table 6-4 
Recommended Dose Modifications of Lutathera for Adverse Events 
Adverse Reaction 
Worst Toxicity CTCAE Grade 
(unless otherwise specified) 
Dose Modification 
Thrombocytopenia  
First occurrence of: 
Grade 2 (PLT < 75 - 50 x 109/L) 
Grade 3 (PLT < 50 - 25 x 109/L) 
Grade 4 (PLT < 25 x 109/L) 
Withhold dose until 
complete or partial 
resolution (Grade 0 to 1). 
 
Resume Lutathera at 3.7 
GBq (100 mCi) in 
patients with complete or 
partial resolution. If 
reduced dose does not 
result in Grade 2, 3 or 4 
thrombocytopenia, 
administer Lutathera at 
7.4 GBq (200 mCi) for 
next dose. 
Recurrent Grade 2, 3 or 4  
Permanently discontinue 
Lutathera. 
Anemia  
First occurrence of: 
Grade 3 (Hgb < 8.0 g/dL); 
transfusion indicated 
Grade 4 (life threatening 
consequences) 
Withhold dose until 
complete or partial 
resolution (Grade 0, 1, or 
2). 
 
Resume Lutathera at 3.7 
GBq (100 mCi) in 

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Adverse Reaction 
Worst Toxicity CTCAE Grade 
(unless otherwise specified) 
Dose Modification 
patients with complete or 
partial resolution. If 
reduced dose does not 
result in Grade 3 or 4 
anemia, administer 
Lutathera at 7.4 GBq 
(200 mCi) for next dose. 
Recurrent Grade 3 or 4 
Permanently discontinue 
Lutathera. 
Neutropenia 
First occurrence of: 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Grade 4 (ANC < 0.5 x 109/L) 
Withhold dose until 
complete or partial 
resolution (Grade 0, 1, or 
2). 
 
Resume Lutathera at 3.7 
GBq (100 mCi) in 
patients with complete or 
partial resolution. If 
reduced dose does not 
result in Grade 3 or 4 
neutropenia, administer 
Lutathera at 7.4 GBq 
(200 mCi) for next dose. 
Recurrent Grade 3 or 4 
Permanently discontinue 
Lutathera. 
Renal Toxicity 
Defined as: 
First occurrence of: 
 
Creatinine clearance less than 60 
mL/min; calculate using Cockcroft 
Gault with actual body weight, or 
 
40% increase in baseline serum 
creatinine, or  
 
40% decrease in baseline 
creatinine clearance; calculate 
using Cockcroft Gault with actual 
body weight. 
Withhold dose until 
complete resolution. 
 
Resume Lutathera at 3.7 
GBq (100 mCi) in 
patients with complete 
resolution. If reduced 
dose does not result in 
renal toxicity, administer 
Lutathera at 7.4 GBq 
(200 mCi) for next dose. 
 
 
Recurrent renal toxicity as 
described above 
Permanently discontinue 
Lutathera. 
Hepatotoxicity 
Defined as:  
First occurrence of: 
 
• Bilirubinemia >3 times the 
upper limit of normal (Grade 3 
or 4), or  
 
• Hypoalbuminemia less than 30 
g/L with a decreased 
prothrombin ratio less than 
70%. 
Withhold dose until 
complete or partial 
resolution (Grade 0, 1 or 
2). 
 
Resume Lutathera at 3.7 
GBq (100 mCi) in 
patients with complete or 
partial resolution. If 
reduced Lutathera dose 
does not result in G3 or 4 
bilirubinemia, administer 
Lutathera at 7.4 GBq 
(200 mCi) for next dose. 
 
Recurrent hepatotoxicity 
Permanently discontinue 
Lutathera. 

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Adverse Reaction 
Worst Toxicity CTCAE Grade 
(unless otherwise specified) 
Dose Modification 
Any other CTCAE* Grade 3 or Grade 4 AE1 
First occurrence of: 
Grade 3 or 4 
Withhold dose until 
complete or partial 
resolution (Grade 0 to 2). 
 
Resume Lutathera at 3.7 
GBq (100 mCi) in 
patients with complete or 
partial resolution. If 
reduced dose does not 
result in Grade 3 or 4 
toxicity, administer 
Lutathera at 7.4 GBq 
(200 mCi) for next dose. 
Recurrent Grade 3 or 4  
Permanently discontinue 
Lutathera. 
1 No dose modification required for hematological toxicities Grade 3 or Grade 4 solely due to lymphopenia 
*CTCAE: Common Terminology Criteria for Adverse Events, National Cancer Institute 
In addition, 
• permanently discontinue treatment with Lutathera if hypersensitivity due to the active 
substance or any of the excipients of Lutathera is observed; 
• temporarily discontinue treatment with Lutathera, until resolution or stabilisation before 
treatment can be resumed:  
• Occurrence of an intercurrent disease (e.g. urinary tract infection); 
• Major surgery: wait 12 weeks after the date of surgery, then restart the treatment with 
Lutathera. 
If a patient experiences DMT during Lutathera therapy, subsequent treatments with Lutathera 
are permissible, provided the DMT resolves within 16 weeks following the non-tolerated 
administration. After resolution of a DMT, a patient may receive subsequent planned 
treatment(s) at 50% of the standard treatment dose, if this is felt to be safe for the patient, or the 
risk-benefit assessment is favourable. If the same DMT recurs after treatment with the reduced 
Lutathera dose, no further Lutathera treatment will be given. If the DMT event does not reoccur, 
the next treatment is at full dose, if it is considered to be safe for the patient, or the risk-benefit 
assessment is favourable.  
Dose modification recommendations for toxicities might be overruled by dose modification 
recommendations based on dosimetry, and vice versa, i.e. a dose modification should be applied 
based on toxicity grading, even if dosimetry values are within limits. 
6.5.1.2 
Dose modification based on dosimetry 
Patients will have bone marrow and kidney dosimetry (as well as that in other organs) 
determined following the first treatment using planar imaging and blood clearance (for bone 
marrow) data. In the exceptional circumstances when dosimetry cannot be done in a particular 
patient after the first dose, it should be done as soon as feasible upon a later dose.  
As discussed in Section 4.2, the dosimetry reference limits are 2 Gy and 29 Gy based on bone 
marrow and kidney dosimetry, respectively. 
Dosimetry data will be analysed by a central lab in an expedited manner, and the result of 
cumulative radiation dose will be provided to the Investigator for each patient to confirm that 

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the cumulative absorbed dose for subsequent treatments does not exceed the reference limits 
indicated above for kidney and bone marrow absorbed radiation doses.  
For each patient, the Investigator will receive the results of dosimetry analysis (cumulative 
radiation dose) before the administration of next Lutathera dose (i.e. before the 2nd Lutathera 
administration if the dosimetry is done after the 1st dose). In parallel, the Investigator will assess 
safety data for potential DMTs as described in the Section 6.5.1.1 based on local laboratory test 
results.  
In case that the resulting cumulative radiation dose is within the reference limits specified 
above, and no DMT criteria are met, the Investigator can administer full Lutathera dose for the 
next administration. DSMB does not need to be consulted in such case.  
In case that the resulting cumulative radiation dose (calculated based on dosimetry analysis) 
exceeds the reference limits specified above, the DSMB will evaluate the totality of dosimetry, 
PK and safety data (See Section 8.3 and Section 8.4 ) to assess benefit risk for the patient and 
advise on whether dosing can continue and at which level. In such cases, the Investigator will 
be informed of the DSMB recommendation (including documented justification based on all 
data reviewed) prior to the next Lutathera administration. The ultimate decision on dose 
modification in such cases will remain with the Investigator. 
The detailed guidance on dosimetry assessments will be provided in the dosimetry and imaging 
manuals. The detailed guidance for assessment of patient data and decision-making process for 
DSMB will be provided in the DSMB charter. 
6.5.1.3 
Overdose 
Lutathera overdose has a very low probability of occurring since it will be supplied as a single 
dose "ready to use product" in order to avoid any manipulation outside the production facilities. 
In addition, the infusion system methods do not allow the concurrent use of two separate 
Lutathera solution vials. No doubling of the administered radioactivity is ever allowed either in 
absolute amount or by shortening the time intervals between treatments. Treatments (amount 
of radioactivity and time of administration) will be monitored during the study and any 
unallowed treatment modification will be considered a major protocol violation. 
6.5.2 
Dose discontinuation 
The discontinuation of treatment with Lutathera is not a reason for patient’s withdrawal from 
the study (reasons for the patient’s withdrawal are discussed in Section 9). In case of a patient’s 
withdrawal from the study treatment (based on either the patient’s or the Investigator’s 
decision), patients will undergo all exams scheduled for the End of Treatment (EoT) visit (Table 
8-2) and continue into the Follow-up period.  
If the treatment discontinuation occurs because of laboratory abnormality, or any evidence of 
toxicity, the Investigator will collect additional specimens for repeat or additional analyses, at 
intervals appropriate to the abnormality. The patient will be closely followed until sufficient 
information is obtained to determine the cause or the value regresses. Appropriate remedial 
measures should be taken and the response recorded in the eCRF. 

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6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Patients will be administered the infusions of Lutathera and amino acid during the clinical trial 
visit at the site. For each single dose of Lutathera a deviation of ±10% from the scheduled dose 
is allowed. All study treatment dispensed must be recorded in the Drug Accountability Log. 
6.6.2 
Recommended treatment of adverse events 
For the treatment and prevention of nausea and vomiting with antiemetics see Section 6.1.2. 
Crises due to excessive release of hormones or bioactive substances may occur following 
treatment, therefore, observation of patients by overnight hospitalization should be considered 
in both GEP-NET and PPGL cohorts.  
Recommended treatments of patients with GEP-NET hormonal crises are: i.v. high dose 
somatostatin analogues, i.v. fluids, corticosteroids, and correction of electrolyte disturbances in 
patients with diarrhea and vomiting.  
In PPGL cohort, the treatment of symptoms related to catecholamine release should be done as 
per standard local practice and physician judgment (see Section 4.5). 
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF. 
6.7 
Preparation and administration of Lutathera and sterile amino 
acid solution 
Further to patient screening and drug ordering by the site staff, Lutathera solution is supplied 
as a ready-to-use radiopharmaceutical solution for infusion. Each dose is infused over 30 
minutes. There is no need for the patient to fast before treatment. For the detailed administration 
instructions, refer to the Pharmacy Manual. 
The total amount of administered radioactivity has to be determined by measuring the 
radioactivity in the Lutathera vial before and after administration (the procedure is provided in 
the pharmacy manual).  
All patients will receive concomitant sterile 2.5% Lys-Arg solution for kidney protection (see 
Section 6.1.2). The sterile amino acid solution and Lutathera are administered in parallel by 
peripheral vein infusion at a constant infusion rate through pumps or any other infusion system. 
The infusion with amino acids starts 30 minutes before the start of Lutathera infusion and 
continues for a total of 4 h (extension up to 6 h is allowed in case of adverse reactions that 
require interruption of infusion or slowing the infusion rate). During amino acid infusion patient 
is allowed to void. 
Infusion rates are listed in Table 6-5.  

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Table 6-5 
Administration procedure of antiemetic, amino acid solution and 
Lutathera 
Administered agents 
Start time 
(min) 
Infusion rate 
(mL/h) 
Duration 
Antiemetic: E.g. granisetron 3 mg (or 
alternative) 
with 
sufficient 
lead time 
prior to 
amino acid 
solution 
As per local 
prescribing 
information 
As per local 
prescribing 
information 
 
Sterile 2.5% Lys-Arg amino acid solution (1L) 
0 
250 
4 hours 
Lutathera with sodium chloride 9 mg/mL 
(0.9%) solution for injection 
30 
Up to 400 
30 ± 10 minutes  
In PPGL cohort, an adequate alpha- and beta-blockade should be maintained to avoid acute 
symptoms of catecholamine release. 
Following administration of Lutathera, patients should remain at the clinical site for an 
additional 4 to 5 hours in an area with suitable radiation shielding to protect others from 
unnecessary exposure (Appendix 2) time of release, patients are given written instructions 
which outline the precautions the patient must take to minimize radiation exposure to people 
around them. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Lutathera and amino acids must be received by a designated person at the study site, handled 
and stored safely and properly and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, all study treatment must be stored 
according to the instructions specified on the labels. 
Lutathera must be prepared in accordance with pharmaceutical quality requirements, and 
radiation safety regulations. Lutathera and amino acids must be administered at the 
investigational site and only in accordance with the protocol. Technical complaints are to be 
reported to the Sponsor. 
The amino acids used/unused medications will be returned to the proper local depot for 
destruction at the study completion or upon expiration or destroyed at site according to Sponsor 
decision and approval. 
Lutathera will be locally discarded according to all disposal requirements for radioactive 
materials. 
The Investigator/Pharmacist must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Monitoring of drug accountability will be 
performed by monitors during site visits or remotely and at the completion of the trial. 
It must be possible to reconcile delivery records with those of used and unused medication. Any 
discrepancies must be accounted for and explained. Appropriate forms of deliveries and returns 
must be signed and dated by the responsible person at the clinical site and maintained as records. 
The return or disposal of all study medication will be documented appropriately.For more 
details about the handling of Lutathera and amino acids refer to the pharmacy manual. 

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7 
Informed consent procedures 
Eligible adolescents may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved assent and parent(s)/guardian informed 
consent. 
If applicable, in cases where the adolescent’s representative(s) gives consent (if allowed 
according to local requirements), the adolescent must be informed about the study to the extent 
possible given his/her understanding. If the adolescent is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written assent. 
Assent and parent(s)/guardian informed consent must be obtained before conducting any study-
specific procedures (e.g. all of the procedures described in the protocol). The process of 
obtaining adolescent assent and parent(s)/guardian informed consent must be documented in 
the participant source documents. 
Sponsor will provide to investigators in a separate document a proposed assent and 
parent(s)/guardian informed consent form that complies with the ICH GCP guidelines and 
regulatory requirements and is considered appropriate for this study. Any changes to the 
proposed assent/consent form suggested by the investigator must be agreed by the 
Sponsor before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the adolescent 
assent and parent(s)/guardian informed consent and should be discussed with the adolescent 
and his/her parent/guardian during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification or an aggregate 
safety report. New information might require an update to the assent/informed consent and then 
must be discussed with the participant and his/her parent(s)/guardian. 
The following informed consents are included in this study and should be used as determined 
by local regulations: 
• Assent for adolescent 
• Parent(s)/legal guardian Informed consent form 
• Informed consent for adolescents who turn 18 years old during the study 
• As applicable, Pregnancy Outcomes Reporting Consent for female subjects or the female 
partners of any male subjects who took study treatment 
Female patients of child-bearing potential must be informed that taking the study treatment can 
cause fetal harm when administered to a pregnant woman and agree that in order to participate 
in the study they must adhere to the contraception requirements. 
Male patients must also adhere to contraception requirements and be informed that if a female 
partner becomes pregnant while he is enrolled in the study, contact with the female partner will 
be attempted to request her consent to collect pregnancy outcome information. 
Female and male patients must be informed that the study treatment may potentially have 
temporary toxic effects on female and male gonads. Genetic consultation is recommended if 
the patient wishes to have children after treatment. Cryopreservation of sperm or eggs can be 
discussed as an option to patients before the treatment.  
A copy of the approved version of all consent forms must be provided to Advanced Accelerator 
Applications after IRB/IEC approval. 

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After signing an ICF for participation in the study, each patient is given a patient card, which 
indicates the contact details of the Investigator (e.g. stamp with telephone number), the patient’s 
Subject ID, as well as the study medication name. The patient shall carry this card with him/her 
during participation in the study so that the Investigator may be contacted in case of emergency.  
Each patient also receives written instructions which outline the precautions that he/she must 
take to minimize radiation exposure to people around them. 
8 
Visit schedule and assessments 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-2). All data obtained from these assessments must be supported in the participant’s 
source documentation. Missed or rescheduled visits will not lead to automatic discontinuation.  
The screening period must be shortened as much as possible in order to enroll and treat the 
patients shortly after the informed consent signature. As Lutathera production and shipment 
will take approximately 12 days, Lutathera first dose must be ordered immediately after 
confirming patient eligibility and enrollment. There will be no study visits after screening and 
before the 1st Lutathera administration. 
The treatment period consists of 4 treatment cycles, with Lutathera administration on Week 1 
Day 1 of each cycle. The dosimetry assessments will be performed during the first week after 
the 1st Lutathera dose as per Table 8-2 and Table 8-3. In the exceptional circumstances when 
dosimetry cannot be done in a particular patient after the first dose, it should be done as soon 
as feasible upon a later dose. Patients might need to stay overnight at the hospital or another 
facility for the days with intensive assessments (e.g. for Lutathera administration, blood 
sampling and imaging). The decision on the overnight stay is up to Investigator, as appropriate 
according to medical judgment, local regulation and patient’s preference. 
The End of Treatment (EoT) visit should be performed in 8 weeks after the last Lutathera 
administration for patients who complete all 4 Lutathera doses (end of Cycle 4). Participants 
who prematurely discontinue the study treatment for any reason should be scheduled for the 
EoT/Early Termination visit as soon as possible, at which time all of the assessments listed for 
the EoT visit will be performed (refer to “EoT or early termination” column in Table 8-2). At 
this EoT visit, all adverse events and concomitant medications taken during the Treatment 
period should be reconciled and recorded on the eCRF. 
During the short-term follow-up, visits will occur every 6 weeks until 6 months after the last 
Lutathera dose, and during the long-term follow-up visit will occur every 6 months until 5 years 
after the last Lutathera dose. The last follow-up visit (5 years after the last dose of Lutathera) 
will be considered as End of Study (EoS) visit for each patient. 
The assessments listed in Table 8-1 will be performed locally and analyzed centrally. 
Procedures for centralized evaluations will be detailed in the respective manuals provided to 
each participating site. 
For the visits when several types of assessments need to be performed, the recommended 
sequence is ECG, followed by vital signs and blood samples. 

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Table 8-1 
Central readings and analysis. 
Assessment 
Central Reading/Analysis 
Study Period 
Section 
Whole body planar and 
SPECT/CT imaging for dosimetry 
assessment 
Central imaging evaluation and 
dosimetry analysis by selected 
vendors (for image analysis and 
dosimetry calculations) 
Treatment Period 
Cycle 1 Week 1* 
8.3 
Blood and urine radioactivity 
measurement for PK and 
dosimetry assessment 
Blood and urine radioactivity data will 
be used by the dosimetry vendor for 
dosimetry assessments. Blood 
radioactivity data will be used for PK 
assessments. 
Treatment Period 
Cycle 1 Week 1* 
8.3 
Safety biomarker assessment 
Blood will be collected using the 
sampling tubes provided by the 
Sponsor and shipped to a central 
laboratory.  
Treatment Period 
cycle 1, 2, 3, 4, 
Short-term and 
Long-term follow-up 
8.4.9 
*In the exceptional circumstances when dosimetry cannot be done in a particular patient after the first dose, it 
should be done as soon as feasible upon a later dose. 
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of 
providing continuing care may be implemented. When possible, phone calls and virtual contacts 
(e.g. teleconsult) should be implemented for the duration of the pandemic until it is safe for the 
participant to visit the site again. To follow is a set of general recommendations on the 
management of patients visits during COVID-19: 
• Study patients should be instructed to contact the study investigator (by telephone or 
email), if there is a change in their health status.  
• The study investigator may consider contacting patients more frequently than is required 
by the study protocol, with frequency selected according to circumstances and including 
the individual patient’s vulnerability to COVID-19 based on their medical condition. 
When contacting patients, whether by telephone or in writing, the study investigator 
should record that contact or save written correspondence to the patient medical record or 
chart so as to assure a proper source documentation for the trial. 
• Safety lab testing - The investigator should consider whether it is possible to arrange for 
the laboratory panels to be performed at a local certified laboratory for those patients who 
cannot come to the clinical site as scheduled. In exceptional cases, additional safety 
assessments might be done outside of clinical site if considered necessary to ensure the 
patient by investigator. The investigator should collect and file all local lab reports and 
normal ranges in the patient medical record or chart.  
• Scheduled or unscheduled patient study visits can be performed once feasible and 
considered safe for patients to attend the clinical appointments. 
 

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Table 8-2 
Assessment Schedule 
Visit Name 
Screeni
ng 
Treatment Period1 
End of 
Treatme
nt (EoT) 
or early 
termina- 
tion2 
Follow-up (FU) Period 
EoS
* 
Cycles / Weeks 
/ Days 
Day -14 
– 
Day -1 
Cycle 1 
Cycle 2 
Cycle 3 
 
Cycle 4 
 
Short-term Follow-
up 
Long-
term 
Follo
w-up 
Week 1 
Wee
k 3, 
5, 7 
Wee
k 1 
Wee
k 3, 
5, 7 
Wee
k 1 
Wee
k 3 
 
Wee
k 5, 
7 
Wee
k 1 
Wee
k 3 
 
Wee
k 5, 
7 
Wee
k 13 
after 
last 
dos
e 
Wee
k 19 
after 
last 
dos
e 
Wee
k 25 
after 
last 
dos
e 
Every 
6 
month
s until 
5 
years 
after 
last 
dose 
Da
y 1 
Day 
2, 
3, 4, 
8 
Parent consent 
and patient 
assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusi
on criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and 
Extent of 
Cancer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
and Prior Tx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam S 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Body Height 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Body Weight 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs3 
X 
X3a 
 
 
X3a 
 
X3a 
 
 
X3a 
 
 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Karnofsky or 
Lansky 
performance 
score 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 

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Visit Name 
Screeni
ng 
Treatment Period1 
End of 
Treatme
nt (EoT) 
or early 
termina- 
tion2 
Follow-up (FU) Period 
EoS
* 
Cycles / Weeks 
/ Days 
Day -14 
– 
Day -1 
Cycle 1 
Cycle 2 
Cycle 3 
 
Cycle 4 
 
Short-term Follow-
up 
Long-
term 
Follo
w-up 
Week 1 
Wee
k 3, 
5, 7 
Wee
k 1 
Wee
k 3, 
5, 7 
Wee
k 1 
Wee
k 3 
 
Wee
k 5, 
7 
Wee
k 1 
Wee
k 3 
 
Wee
k 5, 
7 
Wee
k 13 
after 
last 
dos
e 
Wee
k 19 
after 
last 
dos
e 
Wee
k 25 
after 
last 
dos
e 
Every 
6 
month
s until 
5 
years 
after 
last 
dose 
Da
y 1 
Day 
2, 
3, 4, 
8 
Blood chemistry 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis4 
X 4a 
X4b 
 
X 
4a,4c 
X4b 
X 
4a,4c 
X4b 
X4b 
X 4a 
X4b 
X4b 
X 4a 
X 4a 
 
 
 
 
 
Serum 
Pregnancy test 
5,S 
X 
 
 
X 5 
 
X5 
 
 
X5 
 
 
X5 
X 
 
 
 
 
 
Urine 
Pregnancy 
test5,S 
 
 
 
 
 
 
Week 3 
 
Monthly5 
 
SRI6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lutathera/Amin
o Acid 
administration 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
AE7 and 
ConMeds8 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Whole body 
planar imaging9 
 
X 
(1-3 
h) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPECT/CT 
 
 
X 
(2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Visit Name 
Screeni
ng 
Treatment Period1 
End of 
Treatme
nt (EoT) 
or early 
termina- 
tion2 
Follow-up (FU) Period 
EoS
* 
Cycles / Weeks 
/ Days 
Day -14 
– 
Day -1 
Cycle 1 
Cycle 2 
Cycle 3 
 
Cycle 4 
 
Short-term Follow-
up 
Long-
term 
Follo
w-up 
Week 1 
Wee
k 3, 
5, 7 
Wee
k 1 
Wee
k 3, 
5, 7 
Wee
k 1 
Wee
k 3 
 
Wee
k 5, 
7 
Wee
k 1 
Wee
k 3 
 
Wee
k 5, 
7 
Wee
k 13 
after 
last 
dos
e 
Wee
k 19 
after 
last 
dos
e 
Wee
k 25 
after 
last 
dos
e 
Every 
6 
month
s until 
5 
years 
after 
last 
dose 
Da
y 1 
Day 
2, 
3, 4, 
8 
imaging9, 10 
4
h) 
Urine collection 
for dosimetry9,11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling 
for dosimetry9,12 
 
X 
X 
(
D
a
y 
2,
4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers of 
Endocrine and 
Gonadal 
Function 
 
X13 
 
 
X14 
 
 
 
 
 
 
 
X15 
 
 
 
X 
X 
X 
Biomarkers of 
Growth and 
Bone 
Development 
 
X13 
 
X14 
 
 
 
 
 
 
 
X15 
 
 
 
X 
X 
X 
1. 
Lutathera treatment will be administered every 8 ±1 weeks. 
2. 
The EoT visit should be performed 8 weeks after the last Lutathera administration for patients who complete all 4 Lutathera doses (End of Cycle 4). In 
patients, who prematurely discontinue the study treatment for any reason, EoT/early termination visit should be scheduled as soon as possible. All AEs should 
be collected for 8 weeks + 30 days after last Lutathera dose. 
3. 
Blood pressure, pulse rate and body temperature will be assessed for vital signs.  
3a. Monitoring of blood pressure and pulse rate during Lutathera and amino acid infusion is recommended. 

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Visit Name 
Screeni
ng 
Treatment Period1 
End of 
Treatme
nt (EoT) 
or early 
termina- 
tion2 
Follow-up (FU) Period 
EoS
* 
Cycles / Weeks 
/ Days 
Day -14 
– 
Day -1 
Cycle 1 
Cycle 2 
Cycle 3 
 
Cycle 4 
 
Short-term Follow-
up 
Long-
term 
Follo
w-up 
Week 1 
Wee
k 3, 
5, 7 
Wee
k 1 
Wee
k 3, 
5, 7 
Wee
k 1 
Wee
k 3 
 
Wee
k 5, 
7 
Wee
k 1 
Wee
k 3 
 
Wee
k 5, 
7 
Wee
k 13 
after 
last 
dos
e 
Wee
k 19 
after 
last 
dos
e 
Wee
k 25 
after 
last 
dos
e 
Every 
6 
month
s until 
5 
years 
after 
last 
dose 
Da
y 1 
Day 
2, 
3, 4, 
8 
4. 
Urine sample will be collected during the treatment period. The urinalysis should include: 
4a: dipstick analysis 
4b: both dipstick analysis and urine protein creatinine ratio (UPCR). Urine sample must be collected before Lutathera infusion and at Week 3 of each cycle. 
4c: urine protein creatinine ratio (UPCR) which is only applied to Week 3 of each cycle.  
5. 
Serum pregnancy testing should be done: 
• 
at screening,  
• 
during treatment: 
• 
at week 3 and 7 for cycle 1 and 2 
• 
at week 7 for cycle 3 and 4  
• 
End of treatment 
Urine pregnancy tests will be done: 
• 
During treatment period: 
• 
On week 3 at cycle 3 and 4 
• 
Monthly for 7 months after last dose 
• 
During Follow-up period: monthly for 7 months after last dose. 
6. 
SRI performed within 3 months prior to enrollment can be used for patient eligibility assessment. 
7. 
For more details about data collection related to AEs, SAEs and AESI please refer to  Section 8.4.1 and Section 10.1. 
8. 
During Follow-up Phase and at the EoS visit, recording of medications use will be limited only to the medications administered for related SAEs/AESIs and/or 
for secondary hematological malignancies. In addition, all new anticancer therapies administered must be collected till EOS. 
9. 
For details and allowed windows for dosimetry assessments see Table 8-3.  
10. SPECT/CT to be done on Day 2 (24 h after Lutathera infusion)  
11. Urine collection from the start of Lutathera infusion to the 1st whole body planar imaging. If no urine is excreted from the start of Lutathera infusion until the 
first whole body planar imaging, no urine dosimetry is necessary. 

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Visit Name 
Screeni
ng 
Treatment Period1 
End of 
Treatme
nt (EoT) 
or early 
termina- 
tion2 
Follow-up (FU) Period 
EoS
* 
Cycles / Weeks 
/ Days 
Day -14 
– 
Day -1 
Cycle 1 
Cycle 2 
Cycle 3 
 
Cycle 4 
 
Short-term Follow-
up 
Long-
term 
Follo
w-up 
Week 1 
Wee
k 3, 
5, 7 
Wee
k 1 
Wee
k 3, 
5, 7 
Wee
k 1 
Wee
k 3 
 
Wee
k 5, 
7 
Wee
k 1 
Wee
k 3 
 
Wee
k 5, 
7 
Wee
k 13 
after 
last 
dos
e 
Wee
k 19 
after 
last 
dos
e 
Wee
k 25 
after 
last 
dos
e 
Every 
6 
month
s until 
5 
years 
after 
last 
dose 
Da
y 1 
Day 
2, 
3, 4, 
8 
12. Blood collection for dosimetry includes 6 radioactive blood samples at the following time points: before the start of Lutathera infusion, at the end of Lutathera 
infusion, then at 2h, 6h, 24h and 72h after the end of Lutathera infusion. 
13. On Day 1 of Cycle 1, safety biomarkers are assessed pre-dose. 
14. Safety biomarkers are taken either at Week 7 of cycle 1 or pre-dose of cycle 2. 
15. Safety Biomarkers are taken either at Week 7 of cycle 4 or at the EoT visit. 
S = assessment to be recorded in the source documentation only and not recorded in CRF page. 
* The last FU visit would be the EOS visit for patients who completed the long-term FU period; and a separate EOS visit should be planned for patients who 
discontinued from the study prior to completion of the long-term FU period.  
Variations of ± 1 week are allowed for the visits during the Treatment period (including the window for Lutathera administration visits that 
should occur in 8 weeks from the previous dose ± 1 week), and during the Short-term Follow-up. The exception is the week when dosimetry 
assessments are performed – during the dosimetry week, all visits must occur on the Days specified in the Table 8-2.  
During the Long-term Follow-up, a visit window of ± 1 month is allowed. 

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8.1 
Screening 
8.1.1 
Screening 
As described in Section 7, informed consent must be obtained before conducting any study-
specific procedures and all inclusion and exclusion criteria met before enrolment into the study 
(see Table 8-2 for list of assessments to be performed). 
The screening period occurs between patient screening visit (at which informed consent 
signature occurs) and patient enrolment (when patient eligibility is confirmed as per 
inclusion/exclusion criteria). Screening period must be shortened as much as possible.  
Somatostatin receptor imaging (SRI) performed before the screening (within 3 months prior to 
enrollment) can be used for the assessment of patient eligibility. Laboratory tests completed 
before the screening can be used for the assessment of patient eligibility if performed within 2 
weeks prior to enrollment. 
Laboratory parameters and any other applicable assessments can be re-evaluated within the 
initial screening period if the corresponding selection criteria were not met with the initial 
results. This is not considered a re-screening. If the patient is not enrolled after 2 weeks of 
screening, the patient should be screen-failed. 
It is permissible to re-screen a patient if they fail the initial screening; however, each case must 
be discussed and agreed with the Sponsor on a case-by-case basis. Rescreening should only 
occur after a subject has failed screening. In this case a new subject number will be generated 
and a specific re-screen form will be added in the eCRF, to collect the original subject number.  
8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible will 
be considered a screen failure. The reason for screen failure should be entered on the applicable 
Case Report Form. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure participants. No other data will be entered into 
the clinical database for participants who are screen failures, unless the participant experienced 
a serious adverse event during the screening period (see Section 10.1.6 for reporting details). 
Participants who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early 
termination should be captured on the appropriate disposition Case Report Form. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
The data that will be collected on patient characteristics at screening include: 
• Demography (age, sex, race, ethnicity), if local regulations allow for the collection of 
such information  
• Diagnosis and extent of cancer: patient’s cancer history, including documented primary 
location of cancer, date of diagnosis, presence of metastases with specification of the 
metastatic site(s) and tumor grading at study entry.  

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• Somatostatin receptor imaging (SRI) data obtained within 3 months prior to screening 
visit date will be collected to confirm the diagnosis and somatostatin uptake.  
• A CT/MRI assessment will be performed during the screening period to assess the status 
of the disease. 
• Prior antineoplastic medications/radiotherapy/surgery: information pertaining to any 
chemotherapy, hormonal therapy, immunotherapy, radiation, or surgery the patient has 
previously received.  
• Other medical history (e.g. important medical, surgical, and allergic conditions from the 
subject’s medical history which could have an impact on the subject’s evaluation) / 
current medical conditions (e.g., all relevant current medical conditions which are present 
at the time of signing informed consent). 
• Data from the following baseline assessments: 
• Physical examination (only abnormalities resulting from physical exam will be 
recorded in eCRF) 
• Vital signs  
• ECG 
• Height and weight measurement 
• Laboratory assessments (biochemistry, hematology, urinalysis, safety biomarkers for 
endocrine and gonadal function, growth and bone development) 
8.3 
Dosimetry 
Patients will have whole body and organ radiation dosimetry (including the critical organs, i.e. 
bone marrow and kidney) determined following the first Lutathera treatment using planar 
imaging and blood radioactivity data. In the exceptional circumstances when dosimetry cannot 
be done in a particular patient after the first dose, it should be done as soon as feasible upon a 
later dose. For each patient, dosimetry will be performed only once throughout the study. 
Dosimetry assessments will be performed as follows: 
• Whole body planar image will be acquired on Day 1 (1 to 3 hours after end of Lutathera 
infusion), 2, 3, 4 and 8 of Week 1 
• SPECT/CT scan will be acquired in 24 hours after the end of Lutathera infusion (on Day 
2) 
• Blood samples for radioactivity measurement will be collected before the start of 
Lutathera infusion, at the end of Lutathera infusion, then at 2h, 6h, 24h and 72h after the 
end of Lutathera infusion 
• All excreted urine from the start of Lutathera infusion until the first whole body planar 
imaging will be collected, its volume measured and the radioactivity concentration 
(kBq/mL) determined in order to calculate the total radioactivity excreted from the body 
from the start of Lutathera infusion to the time of the first scan. Patients should be asked 
to void before starting the infusion, so that the chances of voiding after the start of 
Lutathera before the first whole body planar imaging are minimized. If no urine is 
excreted from the start of Lutathera infusion until the first whole body planar imaging, no 
urine dosimetry is necessary. 

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8.3.1 
Whole body planar and SPECT/CT Images 
Whole body planar and SPECT/CT images will be obtained at the investigational sites and then 
provided to a selected vendor for evaluation as DICOM files, which will be made available 
through a web-exchange system or other suitable IT support (e.g. compact disks). For more 
details about the images transfer and analysis refer to the dosimetry manual provided to the 
sites. 
8.3.2 
Methods used to estimate absorbed radiation doses 
According to the Medical Internal Radiation Dose scheme (Bolch 2009, Loevinger 1988, ICRU 
1979, NCRP 1985), the radiation dose to a target organ is the sum of the self-dose from this 
organ and the cross doses from all other target organs. In order to calculate the radiation dose 
to the various target organs the amount of radioactivity present in the source organs must be 
measured. The radioactivity uptake in each organ is determined at various time points. This 
uptake defines the kinetics of the radiopharmaceutical. By integrating such time-activity curve, 
the number of decays from each source organ per injected activity dose is obtained, and this is 
the so-called time Integrated Activity Coefficient (TIAC). The TIACs from each organ will be 
processed by Olinda/EXM software for the calculation of the organ absorbed radiation doses. 
8.3.3 
Biological samples for PK and dosimetry analysis 
Radioactivity in blood and urine will be measured at the investigational sites with a properly 
calibrated gamma counting system. 
The results of the activity concentration in the blood and urine samples (if measured locally) 
and the volume of the urine excreted before the first scan will be used for PK and dosimetry 
calculations. 
a. Blood sample counting 
Whole blood samples (1 mL in heparinized tubes) will be collected from each patient at pre-
defined time points and counted in a properly calibrated gamma-counter.  
The acquired blood radioactivity data will be used for both dosimetry and PK assessments. 
b. Urine sample counting 
The majority of the infused Luthatera is excreted via the kidneys into the urine.  
The total radioactivity excreted in urine before the first image acquisition will be determined, 
as this information is needed for dosimetry evaluation. The total cumulative volume of urine 
eliminated in that interval (from the administration to the first whole body planar imaging) will 
be measured. A urine sample (1 mL) will be taken from the total volume eliminated in that 
period for radioactivity measurement by gamma-counter. If no urine is excreted from the start 
of Lutathera infusion until the first whole body planar imaging, no urine dosimetry is necessary. 

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8.3.4 
Dosimetry equipment and timepoints 
The following equipment is necessary for the data acquisition: 
1. A gamma-camera with medium energy collimator. 
2. Well counter with multichannel analyser or gamma counter to determine 177Lu 
radioactivity in blood and urine samples. 
3. A dose calibrator (activimeter) to measure the radioactivity in the reference source and 
the injected radioactivity. 
4. SPECT/CT equipment 
A detailed schedule of the dosimetry assessments is shown in the Table 8-3 below. 
Table 8-3 
Dosimetry assessments timepoints 
 
Cycle 1 / Week 1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 8 
Lutathera 
administration 
 
X (30-
min ±10 
min 
infusion) 
 
 
 
Amino acid 
administration 
X 
(4-h infusion (max 6 h)) 
 
Hours from 
end of 
Lutathera 
infusion 
Pre-dose 
 
0h 
1h 
2h 
±30 
min 
3h 
 
6h 
± 1h 
24h 
± 4h 
48h 
± 6h 
72h 
± 6h 
168h 
±6h 
Blood 
sampling for 
dosimetry 
X 
(Any time 
before 
Lutathera 
infusion) 
 
X 
 
X 
 
X 
X 
 
X 
 
Whole body 
planar 
imaging 
 
X 
(any time 
1-3 h) 
 
X 
 
X 
 
X 
 
X 
 
Urine 
collection for 
dosimetry 
 
X 
(from start of 
Lutathera 
infusion to 1st 
whole body 
planar 
imaging) 
 
SPECT/CT 
imaging 
 
 
X 
 
The intervals for dosimetry sampling and imaging in Table 8-3 are recommended and 
acceptable variations. However, if an assessment cannot be done within specified windows, it 
can be done at the closest feasible time, even if outside of the window. 
Blood sampling times for dosimetry and PK assessments have been optimized based on a 
population PK model developed in adults to provide robust estimates of individual patient 
pharmacokinetic parameter values. 

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8.3.5 
Dosimetry and PK parameters  
Lutathera bio-distribution, dosimetry and absorbed dose in critical organs will be determined 
from Time activity Curves (TACs) derived from radioactivity measured in blood and urine 
samples and in Regions of interest (ROI) for organs and tumor lesions drawn using the acquired 
planar images. Dosimetry calculations will be performed from the analyses of organs having 
significant uptake, identified visually. ROI delimiting these organs are used to determine 
relative radiotracer uptake calculated as a percentage of the injected dose. TACs are derived 
from mono-, bi-, or tri-exponential functions with best fit to time course data. By integrating 
the TACs, the Time Integrated Activity Coefficients (TIACs) are obtained. TIACs, also called 
Number of Decays, will be used to calculate the absorbed radiation dose values (Gy) in target 
organs. 
The absorbed radiation dose in organs is the ultimate output dosimetry parameter that will be 
provided to Investigators for each patient, and to DSMB, if necessary (see Section 6.5.1.2). 
Pharmacokinetic parameters such as the maximum blood concentrations (Cmax), the sampling 
time at which Cmax is reached (tmax), in addition to the area under the curve (AUC0-∞), 
systemic clearance (Cl), volume of distribution (V1 and V2) will be determined using model 
based methods. Other parameter estimates may be determined as deemed appropriate. 
8.4 
Safety assessments 
8.4.1 
Adverse Event Monitoring 
All adverse events (AEs), whether or not spontaneously reported by the patient, will be 
recorded starting from the signing of the ICF until the end of the Treatment Period. During the 
Follow-up Period only related serious adverse events (SAE) and adverse events of special 
interest (AESI) will be recorded, except for all secondary malignancies which need to be 
recorded as AESI irrespective of causality. For details on AE definitions, collection and 
reporting refer to Section 10.  
In the case where patient on-site study visits are limited due to COVID-19 pandemic, regular 
phone or virtual calls will occur for safety monitoring and discussion of the participant´s health 
status until the participant can again visit the site.  
8.4.2 
Physical examination 
A complete physical examination should be performed at screening and EoT, including an 
evaluation of the head, eyes, ears, nose, throat, neck and lymph nodes, and the cardiovascular, 
dermatological, musculo-skeletal, respiratory, GI and neurological systems. 
Before each Lutathera administration and at each visit during short and long-term follow-up 
(and at other visits if clinically indicated), a limited, symptom-directed physical examination 
should be performed at the discretion of the Investigator (see Table 8-2).  
Documentation of all physical examinations must be included in the source documentation at 
the study site. Clinically relevant findings that are present prior to signing informed consent 
must be recorded on the appropriate eCRF that captures medical history. Significant findings 
made after signing informed consent which meet the definition of an Adverse Event must be 
recorded as an adverse event. 

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8.4.3 
Vital signs 
Vital signs include blood pressure, pulse rate and body temperature. 
Blood pressure, pulse rate and body temperature will be assessed at screening, before each 
Lutathera administration, at EoT and at each visit during short and long-term follow-up (see 
Table 8-2). Blood pressure and pulse rate should be obtained in a quiet room at a comfortable 
temperature, with the patient's arm unconstrained by clothing or other material. Blood pressure 
and pulse rate measurements will be obtained after the patient has been in a sitting or supine 
position for at least 3 minutes, from the same arm (where possible), in the same position, with 
the same cuff size, using the same type of an automatic instrument with a digital readout, 
throughout the study. In addition, monitoring of vital signs (blood pressure and pulse rate) 
during the Lutathera and amino acid infusion is recommended. 
Body temperature measurement can be either oral or tympanic; the method should be 
maintained throughout the study. 
Significant findings that are present prior to baseline will be recorded in the medical history 
page, while changes during the study (including significant changes of the symptoms due to 
the underlying disease vs baseline) will be recorded on the Adverse Event page of the eCRF. 
For patients enrolled in PPGL cohort, additional measurements of blood pressure can be 
performed at Investigator discretion for the monitoring of hormone release symptoms (see 
Section 4.5). Such measurements will be recorded in eCRF as unscheduled visits. 
8.4.4 
Height and Weight 
Height will be taken at screening, week 1 of cycle 4 treatment, EoT, last visit of short-term 
FUP, and every six months during long-term FUP.  
Weight will be taken at screening, before each Lutathera administration, at the EoT, and every 
six months during long-term FUP. In addition, weight should be measured for each CrCl 
calculation (i.e. on the days when chemistry tests are taken). 
Height will be obtained in centimeters (cm) and body weight in kilograms (kg) and rounded to 
the nearest 0.1 kg. Weight will be obtained in indoor clothing, without shoes. 
8.4.5 
ECG  
Standard 12-lead ECGs will be performed at screening (baseline), immediately after each 
Lutathera/amino acid treatment procedure (following the completion of the amino acids 
infusion), and at the EoT visit (Table 8-2) to measure the ECG intervals (RR, PR, QRS, QT 
and QTcF).  
ECGs will be performed in triplicate (at least 5 minutes apart) after the patient has been in a 
sitting or supine position for at least 10 minutes, and not immediately after a meal. The 
parameters will be measured as a mean value of minimally 3 beats; the mean of each parameter 
has to be used for CRF completion. The preferred sequence of cardiovascular data collection 
at the timepoints with multiple assessments is ECG collection first, followed by vital signs, and 
blood sampling. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate.  

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The Investigator will note in the source documents (and in the eCRF) whether the ECG is 
normal or abnormal, as well as the clinical relevance of abnormal ECGs results and the different 
ECG intervals measurements, calculated using the mean value of 3 measurements for each 
parameter. Relevant ECG abnormalities at screening will be recorded in the medical history 
page, while changes during the study will be recorded on the Adverse Event page of the eCRF. 
The original ECGs on non-heat-sensitive paper or a certified copy on non-heat sensitive paper, 
appropriately signed, must be collected and archived at the study site. Each ECG tracing should 
be labeled with the study number, subject initials (where regulations permit), subject number, 
subject date of birth, ECG date, and kept in the source documents at the study site. 
8.4.6 
Laboratory evaluations 
The clinical laboratory assessments in this study include blood samples for hematology, blood 
chemistry, safety biomarkers, a urine sample for urinalysis, and a pregnancy test (Table 8-2, 
Table 8-4).  
Clinically significant abnormalities that are present prior to baseline will be recorded in the 
medical history page while any clinically relevant change from baseline onwards, will be 
recorded on the Adverse Event page of the e-CRF, possibly with a single diagnosis 
encompassing all changes possibly supporting to the single diagnosis.  
In the event of a significant laboratory abnormality, or if clinical or laboratory evidence of 
toxicity occurs, the Investigator will collect additional specimens for repeat or additional 
analyses, at intervals appropriate to the abnormality. The patient will be closely followed until 
sufficient information is obtained to determine the cause or the value regresses. Appropriate 
remedial measures should be taken and the response recorded.  
All previous safety laboratory results must be evaluated by the Investigator before each 
administration of Lutathera. 
The list of laboratory parameters described in Table 8-4 will be evaluated at the local laboratory 
of each site. Laboratory assessments will be performed according to the schedule in Table 8-2. 
The laboratory assessments after Lutathera doses (hematology, biochemistry and urinalysis, i.e. 
at Weeks 3, 5 and 7 of cycle 1 and 2 and at Weeks 5 and 7 of cycle 3 and 4) can be performed 
at another local laboratory outside of the Investigator site if considered necessary and 
convenient for the patient and investigator. In this case, the results and normal ranges should 
be provided for these tests and entered in eCRF as soon as possible to enable ongoing safety 
monitoring. 
During the COVID-19 pandemic, the investigator should consider whether it is possible to 
arrange for the laboratory tests to be performed at a local laboratory for those patients who 
cannot come to the clinical site as scheduled. The investigator should collect and file all local 
lab reports in the patient medical record or chart.  

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Table 8-4 
Laboratory assessments 
Test Category 
Test Name 
 
Hematology 
• 
WBC with differentials 
• 
Platelets 
• 
Hb 
• 
MCV 
• 
Haematocrit 
 
Blood Chemistry 
• 
BUN or urea 
• 
Serum creatinine 
• 
Creatinine Clearance1 
• 
Uric acid 
• 
Albumin 
• 
Total bilirubin 
• 
AP 
• 
AST/ASAT 
• 
ALT/ALAT 
• 
Gamma-GT 
• 
Sodium 
• 
Potassium 
• 
Magnesium 
• 
LDH 
• 
Calcium 
Urinalysis 
• 
Protein 
• 
Blood 
• 
Glucose 
• 
Leucocytes 
• 
pH 
• 
UPCR 
Pregnancy Test 
Serum / Urine pregnancy test  
1 
Creatinine clearance must be calculated using the Cockcroft-Gault formula:  
Est. Creatinine Clearance = [[140 - age (yr)]*weight (kg)]/[72*serum Cr(mg/dL)]  
(multiply by 0.85 for women) 
Or 
Est. Creatinine Clearance = [[140-age(yr)]*weight (kg)]/[0.814* serum Cr(µmol/L)] 
(multiply by 0.85 for women) 
8.4.7 
Urinalysis 
A midstream, clean-catch urine specimen will be collected for dipstick analysis of protein, 
blood, glucose, leucocytes and pH, according to the schedule in Table 8-2. If the dipstick result 
is 2+ or greater for blood, protein or leukocytes, microscopy needs to be performed. If there is 
an explanation for the positive dipstick result, e.g., menses, it should be recorded, and there is 
no need to perform microscopy. A spot urine sample should also be collected before each 
Lutathera infusion and also 3 weeks after each Lutathera infusion for UPCR test (Table 8-2). 

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8.4.8 
Pregnancy Test  
All menarchal girls and their parents/caregivers should be informed about the potential risks of 
pregnancy and the need to prevent pregnancy during the study. It is important to be sensitive 
in introducing this issue, as understanding and comprehension of puberty, sexual activity, 
pregnancy and contraception is influenced by age, as well as factors such as precocity, 
socio(educational) economic and familial background. These discussions with the patient and 
her parents/caregivers are therefore best performed by investigators familiar with the pediatric 
subject and her family and should be guided by requirements of the local regulatory authorities. 
These discussions should take into account the socio-economic, cultural factors and religious 
beliefs of the adolescent participant and her family. The investigator should also discuss the 
management of the pregnancy test results with the patient and her parents/caregivers. The 
privacy of the patient should be considered in accordance with the local law and ethics. 
All female patients should not procreate until seven months after the last Lutathera dose (see 
Appendix 1 for contraception measures). 
A pregnancy test must be performed at screening and prior to each Lutathera treatment (within 
2 weeks) for every female patient of childbearing potential. This should be continued during 
treatment and for 7 months after ending treatment. The pregnancy test must be performed as 
per schedule described in Table 8-2. During this period, monthly pregnancy serum tests can be 
changed to urine tests if there is no personal visits. The urine pregnancy testing should use a 
laboratory-based urine assay or a commercially available kit. 
If preferred by the patient, the urine pregnancy tests can be done at the clinical site. In case the 
urine pregnancy test is positive, the patient must contact the investigator immediately. A 
positive urine test needs to be confirmed with blood test. If the confirmatory blood pregnancy 
test is positive during treatment period, the participant must be discontinued from study 
treatment. 
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female pediatric patients who are menarchal or who become 
menarchal during the study.  
Additional pregnancy tests may be performed at the investigator’s discretion during the study.  
Patients becoming pregnant must be discontinued from study drug. For requirements on 
pregnancy reporting see Section 10.1.7. 
8.4.9 
Safety biomarkers 
The endocrine (pituitary) function, gonadal function, growth and development, and bone 
development function of each patient will be evaluated using the safety biomarker tests 
described in the Table 8-5. 
Samples will be collected at the time points defined in the Assessment Schedule (Table 8-2). 
A central laboratory will be used for analysis of all safety biomarker specimens. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the central laboratory manual. 

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Table 8-5 
Safety biomarker assessments 
Test Category 
Test Name 
 
Endocrine (Pituitary) function 
• 
TSH (and free Thyroxine (fT4) if TSH is abnormal)  
• 
Luteinizing hormone (LH) 
• 
Follicle-stimulating hormone (FSH) 
Gonadal function 
• 
Inhibin B in men 
• 
Estradiol in women 
• 
Testosterone in men 
Growth and development 
• 
IGF-1 
Bone development 
• 
BALP 
• 
N-terminal or C-terminal cross-linked telopeptide of type I collagen 
(NTX or CTX) 
8.4.10 
Performance score assessment 
Karnofsky performance score (KPS) evaluation must be completed by a medical professional 
at the time points defined in the Assessment Schedule (Table 8-2). If applicable and preferred 
by Investigator, KPS can be replaced by Lansky Play-Performance Scale assessment. 
8.4.11 
Tumor response assessment 
 
 
 
 CT/MRI imaging will be done at screening
 
 
 
  
9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes 
that continuation would negatively impact the participant's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Participant/guardian decision 
• Pregnancy 
• Any situation in which study participation might result in a safety risk to the participant 
including unacceptable adverse event. 

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If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. 
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2 'Withdrawal of Informed Consent' section).  
Where possible, all patients who discontinue study treatment should return for the 
EoT/Early Termination Visit assessments, and continue into the full Follow-up period as 
indicated in the Assessment Schedule. If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the 
participant/pre-designated contact as specified for lost to follow-up (Section 9.1.3). This 
contact should preferably be done according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After study treatment discontinuation, if the patient is unwilling to perform all scheduled 
assessments, then at a minimum, in abbreviated visits, the following data should be collected 
at clinic visits or via telephone/email contact: 
• Survival status 
• New / concomitant treatments, including all antineoplastic therapies 
• Adverse Events / Serious Adverse Events 
During the COVID-19 pandemic, for patients who are unable to come to the study site for their 
scheduled visit, conducting patient study visits on schedule through phone calls and virtual 
contacts (e.g. teleconsult) may be possible. As patient safety is the number one concern, 
patients may need to discontinue treatment based on the investigator’s clinical judgment or 
patient’s own decision. The investigator should document in the source notes as clearly as 
possible the decisions made around continuing or discontinuing study treatment for a patient 
and the risk-benefit for each case as it may arise. The investigator should consider if alternative 
therapeutic options exist and may be warranted based on the individual benefit-risk for the 
patient. 
In extraordinary situations due to the very short half-life of radionuclides, e.g. a sudden 
temporary supply disruption and/or a quality finding after release of the product, the 
investigator may immediately be: 
1. advised on how to manage participants in screening or on treatment; 
2. informed to withhold doses from impacted batch and not administer them to the 
participant; 
and/or 
3. asked to closely monitor participants who have received a dose from an impacted batch 
for adverse events.  

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9.1.1.1 
Replacement policy 
In general, no treated patients will be replaced, and all patients who received at least one 
Lutathera dose will be used for the primary safety analysis. However, more than 8 patients may 
be enrolled if deemed necessary, e.g. in case that a patient is not evaluable for the primary 
dosimetry analysis. 
9.1.2 
Withdrawal of informed consent 
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
• Explicitly requests to stop use of his/her data 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts). 
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is 
therefore very important to ensure accurate recording of withdrawal vs. discontinuation based 
on the protocol definitions of these terms. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her 
consent/exercise data privacy rights and record this information. The Investigator should 
clearly document if the participant has withdrawn his/her consent for the use of data in addition 
to a study discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant for the study purpose are not allowed unless safety 
findings require communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in the assessment table. 
Further details on withdrawal of consent or the exercise of participants’ data privacy rights are 
included in the corresponding consent form. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw consent (or exercise other participants’ data 
privacy rights), the Investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the participant, e.g. dates of telephone calls, registered letters, 
etc. A participant should not be considered as lost to follow-up until due diligence has been 
completed or until the end of the study. 

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9.1.4 
Early study termination by the sponsor 
The study can be terminated by the Sponsor at any time. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from DSMB after review of safety data 
• Practical reasons (including slow enrollment) 
• Discontinuation of study drug development 
In taking the decision to terminate, Sponsor will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.  
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last patient finishes their last follow-up visit and any 
assessments associated with this visit have been documented and followed-up appropriately by 
the Investigator or, in the event of an early study termination decision, the date of that decision. 
Following the end of treatment or early treatment discontinuation, patients will enter in the 
Follow-up Period unless unfeasible (e.g. consent withdrawal, patient lost to follow-up). Patient 
visits and assessments will be performed during the follow-up period as per the study schedule 
of assessments (Table 8-2) and Section 9.1.1.  
The last follow-up visit (5 years after the last dose of Lutathera) will be considered as End of 
Study (EoS) visit for each patient. 
When the study planned enrollment is met, study subjects currently on study treatment or in 
the follow-up period will continue the study as per the study schedule of assessment (Table 8-
2). 
Study Treatment will not be provided to the enrolled patients after completion of the study as 
Lutathera is administered as 4 doses and this is a full regimen. No provision of Lutathera post-
trial is considered necessary. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 

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The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
Adverse events that begin or worsen after informed consent must be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent must be 
recorded in the Medical History page of the subject’s eCRF. Adverse events (including lab 
abnormalities that constitute AEs) must be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom must be reported as a separate Adverse Event. 
The occurrence of adverse events must be sought by non-directive questioning of the 
participant at each visit during the study. Adverse events also may be detected when they are 
volunteered by the participant during or between visits or through physical examination 
findings, laboratory test findings, or other assessments.  
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with 
them, accompanied by the following information (as far as possible) (if the event is serious 
refer to Section 10.1.2; if the event is adverse event with special interest (AESI) refer to Section 
10.1.5): 
1. 
The Severity grade OR the Common Toxicity Criteria (CTC) AE grade (Appendix 3). 
a. If “severity grade” is selected, include the following: 
i. mild: usually transient in nature and generally not interfering with normal 
activities  
ii. moderate: sufficiently discomforting to interfere with normal activities 
iii. severe: prevents normal activities  
b.  If “CTCAE grade” is selected, include the following: 
i. Adverse events will be assessed and graded between 1 to 5. 
2. 
The investigator is obligated to assess the relationship between any treatment used in 
the study (study treatment, AxMPs) and each occurrence of each AE. The investigator 
will use clinical judgment to determine the relationship. A reasonable possibility of a 
relationship conveys that there are facts, evidence, and/or arguments to suggest a causal 
relationship, rather than a relationship cannot be ruled out. Alternative causes, such as 
underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study intervention administration, will be 
considered and investigated. For causality assessment, the investigator will also consult 
the IB and/or product information, for marketed products. The causality assessment is 
one of the criteria used when determining regulatory reporting requirements. 
3. 
Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported. 
4. 
Whether it constitutes a Serious Adverse Event (see Section 10.1.2 for definition of 
SAE) and which seriousness criteria have been met.  
5. 
Action taken regarding study treatment 
• Dose not changed 
• Dose reduced 

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• Drug interrupted/withdrawn 
6. 
Treatment for adverse events. All adverse events must be treated appropriately.  
7. 
Its outcome i.e., its recovery status or whether it was fatal 
If the event worsens, it should be reported a second time in the eCRF noting the start date when 
the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a lower 
grade is determined a new entry for this event should be reported in the eCRF noting the start 
date when the event improved from having been Grade 3 or Grade 4. 
Once an adverse event is detected, it must be followed until its resolution (or until it is judged 
to be permanent) or until 30 days after end of study visit. Assessments must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
For the investigational product and for non-authorized AxMPs (when applicable), information 
about adverse drug reactions and how to manage them can be found in the Investigator's 
Brochure (IB) or equivalent documentation. Information about adverse drug reactions can also 
be found in the product information for marketed products. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease.  
Reporting of AEs related to AxMP(s): 
All AEs related to any authorized auxiliary medicinal product used in this study must be 
reported to Advanced Accelerator Applications. In assessing causality, the investigators will 
use the points above. 
If a suspicion that medical occurrence could be related to study treatment (and/or interaction 
with study treatment cannot be ruled out), the reporting rules for study treatment apply.  
AxMP safety reporting requirements will only apply once the trial has been transitioned under 
EU Clinical Trial Regulation 536/2014. 
10.1.2 
Serious adverse events (SAE) 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the 
following criteria: 
• fatal 

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• life-threatening. Life-threatening in the context of a SAE refers to a reaction in which the 
participant was at risk of death at the time of the reaction; it does not refer to a reaction 
that hypothetically might have caused death if it were more severe (refer to the ICH-E2D 
Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
participant or might require intervention to prevent one of the other outcomes listed above. 
Such events should be considered as “medically significant.” Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalization or development of dependency 
or abuse (refer to the ICH-E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
Treatment-emergent elevations in AST or ALT (> 3 × ULN) in combination with total 
bilirubin > 2 × ULN or jaundice in the absence of cholestasis (defined as ALP < 2 × ULN) or 
other causes of hyperbilirubinemia can be an indicator of severe drug induced liver injury (Hy’s 
Law). The Hy’s Law criteria may be changed to increases of transaminases 2-fold above 
baseline values for subjects with elevated baseline values. For this reason, a potential Hy’s Law 
case requires expedited reporting, and will be handled as a serious unexpected adverse event 

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(assessing it as medically significant in the absence of any other seriousness criteria). It must 
be reported as an SAE to the sponsor promptly (i.e., even before all other possible causes of 
liver injury have been excluded). Reporting should include all available information, especially 
that needed for evaluating the diagnosis, severity and likelihood that the study treatment caused 
the reaction. For patient monitoring and to better understand potential etiologies, the 
investigator must initiate a close follow-up until complete resolution of the problem and 
completion of all attempts to obtain supplementary data. 
10.1.3 
Adverse Drug Reactions (ADR)  
An ADR is any noxious and unintended response to an IMP related to any dose with at least a 
reasonably possible causal relationship with the IMP. Briefly, an ADR is an AE which is 
suspected to be possibly related to IMP by either the investigator or the study sponsor. 
10.1.4 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
An ADR will be assessed to be “unexpected” if the nature, severity or frequency of the event 
is not consistent with the applicable product information available for the IMP. An ADR will 
be assessed to be “expected” if it is listed in the Investigator’s Brochure. 
A SUSAR is an adverse event regarded as serious with at least possible causal relationship to 
the drug, the nature, severity or frequency of which is not consistent with the applicable 
information available in the reference documents available for the IMP. 
10.1.5 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the Sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the Investigator to the Sponsor may 
be appropriate. Such events may require further investigation in order to characterize and 
understand them. 
These potential risks deserve special attention even if they do not fulfill any of the seriousness 
criteria. These non-serious adverse events of special interest (AESI) should be reported to the 
Sponsor using reporting procedures for SAEs. During screening, only AESI meeting 
seriousness criteria should be reported to the Sponsor. During the treatment period, all AESI 
need to be reported to the Sponsor irrespective of causality. During the follow-up period, AESI 
need to be reported only if considered related to the study treatment except for all secondary 
malignancies which need to be reported as AESI irrespective of causality. The AESI represent 
main risks of Lutathera and amino acid treatment reported in adults, as well as potential risks 
in pediatric population (Table 10-1). 

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Table 10-1 
Adverse events of special interest  
AESI categories 
Secondary malignancies  
Hematotoxicities 
Nephrotoxicities 
Endocrine disorders 
Bone development disorders 
Cardiovascular and electrolyte disorders 
Secondary malignancies: any secondary malignancies, including MDS and acute myeloid 
leukemia, should be reported in every case irrespective of causality, as AESI/SAE, until the 
end of long-term follow up period.  
Hematotoxicity: The main critical organ of Lutathera treatment is the bone marrow. 
Significant hematotoxicity, defined as Grade 2 or higher thrombocytopenia, or Grade 3 or 4 of 
any other hematotoxicity (anaemia, leuko-/lympho-/neutropenia) are considered dose-
modifying toxicities in the study and must be reported as AESI when not strictly fulfilling the 
criteria of serious adverse events. Haematological toxicities regardless of severity must be 
reported as AESI if accompanied by clinical consequences, i.e., infections in the presence of 
leuko-/neutro-/lymphopenia, hemorrhages / purpuric lesions under thrombocytopenia that is 
not explained by another coagulation disorder, dyspnea / fatigue in the presence of anaemia not 
otherwise explained by the underlying carcinoid syndrome or other co-morbidity.  
Nephrotoxicity: Since Lutathera is cleared through the kidneys and reabsorbed by the kidneys, 
the kidneys have always been considered the “critical organs”. An infusion of amino acid is 
used for kidneys protection by inhibition of tubular reabsorption of Lutathera. Pursuant to these 
risk minimization efforts and in addition to the criteria of dose-modifying toxicities and criteria 
of inclusion (at baseline and before subsequent treatments) pertinent to renal function 
measurements, renal and urinary tract toxicities are considered AESI. Investigators must report 
as AESI renal toxicities including renal failure (ranging from significantly reduced measured 
or estimated creatinine clearance to clinically overt renal failure other than that of obvious non-
IMP-induced origin), suspected radiation nephropathy of any type, such as radiation-induced 
thrombotic microangiopathy (manifested with, e.g., proteinuria, hypertension, edema, anaemia, 
decrease serum haptoglobin), or general symptoms and signs of acute radiation toxicity (e.g., 
increased frequency and urgency of urination, nocturia, dysuria, bladder spasm, bladder 
obstruction, genitourinary ulceration or necrosis).  
Endocrine (hypothalamic-pituitary and growth) disorders: Since the potential effect of the 
Lutathera treatment on the pituitary-gonadal and pituitary-thyroid axes is not well described in 
the adolescent population, the endocrine effects will be closely monitored via specific 
biomarkers. Any suspected endocrine toxicity should be considered AESI regardless of 
severity. 
Effects on bone development: Radiation exposure has a potential effect on the overall quantity 
and quality of bone by interfering with the trabecular architecture through increased osteoclast 
activity and decreased osteoblast activity. Biomarkers of bone metabolism help to detect the 
metabolic imbalance and identify bone toxicities. Any suspected bone toxicity should be 
considered AESI regardless of severity. 

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Cardiovascular and electrolyte disorders:  
All clinically significant changes in blood pressure, heart rate, electrocardiogram and 
electrolyte parameters must be reported as AESI if they occur within reasonable propinquity 
of Lutathera or sterile amino acid solution administration in the judgment of the Investigator. 
Likewise, clinically manifest consequences of hypo-/hypertension, arrhythmias, cardiac 
conduction disturbances, electrolyte disorders and other cardiac pathologies evidenced by 
objective findings / changes on electrocardiogram or echocardiography should also be 
considered for AESI reporting. 
10.1.6 
SAE and AESI reporting 
SAE reporting: 
To ensure subject safety, after the patient signed the informed consent and before the patient 
received a study drug, only SAE potentially related to any study procedure must be reported. 
After the first dose of study drug(s), all SAEs regardless of suspected causality and until 30 
days after the EoT visit must be reported to the Sponsor within 24 hours of learning of its 
occurrence. Afterwards, any SAEs experienced during the Follow-up period should only be 
reported to the Sponsor if the investigator suspects a causal relationship to study treatment.  
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
Information about all SAEs is collected and recorded on the SAE Form; all applicable sections 
of the form must be completed in order to provide a clinically thorough report. The investigator 
must assess and record the relationship of each SAE to each specific study treatment (if there 
is more than one study treatment), complete the SAE Report Form in English, and submit the 
completed form within 24 hours to the Sponsor. 
Follow-up information is submitted in the same way as the original SAE Report. Each 
reoccurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, and whether the patient 
continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, the Sponsor may urgently 
require further information from the investigator for health authority reporting. The Sponsor 
may need to issue an Investigator Notification (IN) to inform all investigators involved in any 
study with the same study treatment that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 and EU Clinical Trial Regulation 536/2014 (once transitioned under EU CTR) 
or as per national regulatory requirements in participating countries. 

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All SAEs related to any authorized auxiliary medicinal product (whether authorized or not) 
used in this study must be reported to Advanced Accelerator Applications within 24 hours of 
the site becoming aware of it. In assessing causality, the investigators will use the points above. 
If a suspicion that medical occurrence could be related to study treatment (and/or interaction 
with study treatment) cannot be ruled out, the reporting rules for study treatment apply. AxMP 
safety reporting requirements will only apply once the trial has been transitioned under EU 
Clinical Trial Regulation 536/2014. 
AESI reporting: 
During screening, only AESI meeting seriousness criteria should be reported. During the 
treatment period, all AESI need to be reported to the Sponsor irrespective of causality within 
24 hours. During the follow-up period, AESI need to be reported only if considered related to 
the study treatment except for all secondary malignancies which need to be reported as AESI 
irrespective of causality. 
For all reportable AESI irrespective of their seriousness, SAE form will be completed and 
submitted to the sponsor within 24 hours.  
10.1.7 
Pregnancy reporting 
For the requirements on pregnancy tests see Section 8.4.8, and for the requirements on 
contraception see Appendix 1. 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 
signing the informed consent must be reported to Sponsor using a pregnancy reporting form 
within 24 hours of learning of its occurrence until the end of follow-up period. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. The newborn should be followed-up until one year 
after he/she was due to be born. Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the Lutathera treatment and any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
Pregnancy outcomes should also be collected for the female partners of any males who received 
Lutathera in this study until the end of follow-up period. Consent to report information 
regarding these pregnancy outcomes should be obtained from the female partner. 
10.1.8 
Reporting of study treatment errors including misuse/abuse 
Neither overdose nor drug abuse/misuse are expected to be a concern with Lutathera, because 
it is administered by a trained clinician with appropriate prior training and provided as a single-
dose, ready-to-use product containing a predefined amount of radioactivity.  
Any AE/SAE/AESI in connection with radiation overdose must be reported as per the general 
reporting rules. 

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10.1.9 
Reporting rules: summary 
The below table summarize all reporting rules and timeframes for safety data reporting (SAE 
form) to sponsor global safety database described in the above sections: 
Table 10-2 
Reporting rules and timeframe  
Event 
During 
Screening 
During Treatment 
period 
During Follow-up 
period 
Reporting 
timeframe 
Non-serious AEs 
Not reported 
Not reported 
Not reported 
Not applicable 
SAEs 
Only SAEs 
potentially 
related to any 
study procedure 
All SAEs, regardless of 
causality, until 8 weeks 
+ 30 days after last 
dose 
SAEs to be reported 
only if the 
investigator suspects 
a causal relationship 
to study treatment 
Within 24 hours of 
awareness 
AESI 
Only if SAE, 
see above 
All AESI irrespective of 
causality 
AESI to be reported 
only if considered 
related to the study 
treatment except for 
all secondary 
malignancies which 
need to be reported 
as AESI irrespective 
of causality 
Within 24 hours of 
awareness 
Pregnancy 
To be reported 
To be reported 
To be reported 
within 24 hours of 
awareness 
10.2 
Additional Safety Monitoring 
10.2.1 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be commissioned by the 
Sponsor to evaluate accumulating safety and dosimetry data in patients enrolled in the study, 
to ensure the safety of the patients in the study, and to provide recommendations to 
investigators and to the clinical teams in charge of conducting the study. 
The DSMB will comprise one or several experts in the field of oncology, pediatrics and nuclear 
medicine. All DSMB members will disclose their financial interests to the sponsor. The DSMB 
will function independently of all other individuals associated with the conduct of this clinical 
trial, including the site investigators participating in the study. The DSMB will assess at defined 
intervals the progress of the clinical trial, including safety and dosimetry data for individual 
patients if applicable, and recommend to the sponsor whether to continue, modify, or terminate 
a trial. In addition, the DSMB might take decisions for treatment continuation of individual 
patients. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DSMB reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DSMB. 

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11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Sponsor personnel (and/or designated CRO) will review the data entered by investigational 
staff for completeness and accuracy. Electronic data queries stating the nature of the problem 
and requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using 
the World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by the Sponsor. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Sponsor 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Sponsor employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits.  
Continuous remote monitoring of each site’s data may be performed by the Sponsor or a 
delegated CRO. Additionally, a central analytics organization may analyze data & identify 

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risks & trends for site operational parameters and provide reports to Sponsor clinical teams to 
assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Sponsor monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
The data will be analyzed by the Sponsor and/or designated CRO.  
All statistical analyses will be descriptive in nature and will include summaries and graphical 
presentations of data. No statistical hypothesis will be tested.  
Missing data will not be replaced in this study. 
Interim analyses will be performed to evaluate dosimetry and safety when at least five patients 
(including at least two GEP-NET patients) have completed at least one cycle. The data from 
all completed treatment cycles will be presented. Analysis will be presented across both 
indications, as well as for GEP-NET and PPGL separately.  
The primary analysis will be conducted after at least 8 patients (including at least 3 GEP-NET 
patients) have completed the first cycle (cut-off before the second dose of Lutathera), at which 
time both dosimetry and safety assessments of the first cycle will be complete for the 
assessment of the primary objective. Should the dosimetry assessments be done at a further 
cycle instead of first cycle, the primary analysis will be done after the dosimetry assessments 
are performed. All data available at the time of primary analysis will be used for the assessment 
of the primary and secondary objectives, including analysis of the GEP-NETs and PPGLs as a 
pooled cohort 
 
  
A final analysis will be performed after all subjects who have received at least one dose of 
Lutathera have completed the 5 years of follow-up or have withdrawn from the study. 
Any data analysis carried out independently by the investigator should be submitted to Sponsor 
before publication or presentation.  

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12.1 
Analysis sets 
The full analysis set (FAS) will include all participants that received at least one dose of 
Lutathera and will thus be equivalent to the safety analysis set (SAF).  
The Dosimetry and PK analysis set will include all participants with at least one available valid 
(i.e. not flagged for exclusion) dosimetry measurement, who received at least one dose of 
Lutathera and have no protocol deviations that have an impact on dosimetry data.  
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for all participants for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term for all participants. 
12.3 
Treatments 
The FAS will be used for the analyses below.  
The cumulative dose (MBq) will be summarized by means of descriptive statistics. The number 
of subjects who have dose reductions, permanent discontinuations or interruptions, and the 
reasons will also be summarized. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system for all participants. 
12.4 
Analysis of the primary endpoints 
The primary aims of the study are to evaluate organ radiation doses as well as safety and 
tolerability of Lutathera in adolescent patients with SSTR-positive GEP-NETs and PPGL as a 
pooled cohort.  
12.4.1 
Definition of primary endpoints 
Dosimetry 
The analysis of dosimetry primary endpoint will consist of descriptive summaries and graphical 
presentations of the derived parameters. The Lutathera dosimetry and absorbed dose in critical 
organs (e.g. kidney, bone marrow) will be determined from Time activity Curves (TACs). 
Regions of interest (ROI) will be drawn around the organs of interest in the acquired images 
and relative radiotracer uptake will be calculated as a percentage (or fraction) of the injected 
dose per gram of tissue at each timepoint. Blood data will be also collected by measuring (by 
gamma-counter) the radioactivity of the blood samples withdrawn at the different time points. 
Tissue activity curves (ACs) will be generated by fitting mono or multi- exponential equations 
to the organ uptake and blood data.  
By integrating such time-activity curve, the Time Integrated Activity Coefficients (TIACs) will 
be obtained. The TIACs from each organ will be processed by Olinda/EXM software for the 
calculation of the organ absorbed radiation doses. 

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Safety 
Adverse events and laboratory toxicities occurring during the first cycle of treatment are also 
considered primary endpoints and the results for GEP-NETs and PPGLs as pooled cohort will 
be summarized descriptively as defined in Section 12.5.2 to evaluate the acute toxicities 
induced by a single full-dose Lutathera infusion (7.4 GBq).  
12.4.2 
Statistical model, hypothesis, and method of analysis 
All analyses will be reported descriptively. No statistical hypothesis testing will be performed. 
12.4.3 
Handling of missing values  
Missing data will not be replaced. 
The censoring rules will be described in the Statistical Analysis Plan (SAP). 
12.5 
Analysis of secondary endpoints 
12.5.1 
Comparative assessment of Dosimetry/PK in adolescents and adults 
Pharmacokinetic and the dosimetry data will be collected from the adolescent population and 
assessed in the context of previously derived adult data. Adolescent pharmacokinetic 
parameters including (Cmax and AUC0-24) will be compared to those parameters derived from 
the adult population, to ensure that adolescent values lie within those estimates determined 
from the adult population. In a similar manner the individual derived dosimetry data from the 
adolescent patients will be compared to the adult values to ensure that estimates lie within the 
intervals derived from the adult population. Other methods may also be applied if deemed 
valuable in the assessment of the adolescent data. 
Model based assessments of the individual dosimetry values in light of the individual 
adolescent creatinine clearance and dose may also be undertaken for comparative purposes. 
All adolescent dosimetry and pharmacokinetic data will be pooled and analyzed collectively to 
ensure covariate effects including age and weight are of limited value in dosimetry prediction. 
In this way it can be ensured that the pediatric population is adequately characterised by the 
adult population. 
A difference in biodistribution between patients with GEP-NET and PPGL is generally not 
anticipated, as disease normally does not affect the uptake in organs and normal tissues and 
thus estimates of absorbed dose. The review of the preliminary dosimetry and safety data 
already obtained from this study shows a good concordance between adolescent and adult 
dosimetry patients in line with this hypothesis. 
12.5.2 
Safety endpoints 
For all safety analyses, the FAS will be used. All listings and tables will be presented for all 
GEP-NET and PPGL participants as a pooled cohort. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries) and long-term safety assessments which will be summarized separately. 
In addition, a separate summary for death including on treatment and post treatment deaths will 

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be provided. In particular, summary tables for adverse events (AEs) will summarize only on-
treatment events, with a start date during the on-treatment period (treatment-emergent AEs). 
The on-treatment period lasts from the date of first administration of study treatment to 56 days 
after the date of the last actual administration of Lutathera. 
Adverse events 
All information obtained on adverse events will be displayed by participant. 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of treatment but 
increased in severity based on preferred term) will be summarized in the following ways: 
• by primary system organ class and preferred term. 
• by primary system organ class, preferred term and maximum severity. 
Separate summaries will be provided for study medication related adverse events, death, 
serious adverse events, other significant adverse events leading to discontinuation, and adverse 
events leading to dose adjustment. 
The number (and proportion) of participants with adverse events of special interest as defined 
in Section 10.1.5 will also be summarized. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Vital signs 
All vital signs data will be listed by participant, and visit/time and if ranges are available, 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by visit/time. 
12-lead ECG 
1. 
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each 
participant during the study. ECG data will be read and interpreted locally. 
2. 
Categorical Analysis of QT/QTc interval data based on the number of participants 
meeting or exceeding predefined limits in terms of absolute QT/QTc intervals or changes 
from baseline will be presented. In addition, a listing of these participants will be 
produced.  
All ECG data will be listed by treatment group, participant and visit/time, abnormalities will 
be flagged. Summary statistics will be provided by visit/time. 
Clinical laboratory evaluations 
All laboratory data including safety biomarkers will be listed by participant, and visit/time and 
if normal ranges are available abnormalities will be flagged. Summary statistics will be 
provided by treatment and visit/time. Shift tables using the low/normal/high/ (low and high) 
classification will be used to compare baseline to the worst on-treatment value. 

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12.7 
Interim analyses 
For the interim analysis, population pharmacokinetics (PK) and dosimetry models developed 
based on adult patients will be used to support justification of adolescent population dose by 
pooling both GEP-NET and PPGL cohort data. Population PK model will be used to derive 
adolescent PK metrics (i.e. AUC, Caverage), and assess the similarity of exposure in adolescent 
population as compared to adult PK. Influence of patient baseline characteristics 
 
 on the PK will also be explored. Adult 
and 
bone marrow will be used to assess the similarity of E-R relationship between dose and 
dosimetry for adolescent as compared to that for adults. Dosimetry data pooling from GEP-
NET and PPGL cohorts, in relation to the adolescent specific creatinine clearance values and 
other baseline characteristics 
will be explored to confirm that a dose of 
7.4 GBq over four cycles would give a median dosimetry value for kidney less than 29 Gy and 
a median dosimetry value for bone marrow less than 2 Gy. 
12.8 
Sample size calculation 
No formal sample size or power calculations were made in the context of this safety study. The 
overall sample size of 8 patients (with a minimum of 3 GEP-NET patients) is 
deemed sufficient to confirm similar organ dosimetry results in the adolescent population 
compared to the ones in adults.   
Modelling and simulation analysis shows that a mean (standard deviation) of the absorbed dose 
in the kidney of approximately 18 Gy (SD 8) is expected in the adolescent population (Section 
4.2). Assuming a standard deviation of 8, a sample size of 8 patients will produce a two-sided 
95% confidence interval with a distance from the mean to the limits that is equal to 6.688.  
Additionally, a sample size of 8 patients produces an adequate probability of observing acute 
toxicities (See Table 12-1). Indeed, in the phase III NETTER-1 study grade 3/4 adverse drug 
reactions related to Lutathera treatment were observed in 30% of patients. The probability to 
detect similar events assuming a true incidence rate of 30% in this study population is 94.2% 
with 8 patients. 

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Table 12-1 
Likelihood of observing at least one patient with acute toxicity for a 
sample size of 8 patients and incidence of acute toxicities   
Sample size 
Acute toxicities true incidence rate, % 
10% 
20% 
30% 
40% 
50% 
8 
57.0 
83.2 
94.2 
98.3 
99.6 
13 
  Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC or European Clinical 
Trial Regulation 536/2014, US CFR 21), and with the ethical principles laid down in the 
Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, participant recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
participants. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Sponsor monitors, auditors, Sponsor Quality Assurance representatives, 
designated agents of The Sponsor, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must 
inform The Sponsor immediately that this request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT or CTIS public website. In addition, after study completion (defined as 
last patient last visit) and finalization of the study report the results of this trial will be submitted 
for publication and posted in a publicly accessible database of clinical trial results, such as the 
Sponsor clinical trial results website and all required Health Authority websites (e.g. 
Clinicaltrials.gov, EudraCT, CTIS public website etc). 
The Sponsor follows the ICMJE authorship guidelines (www.icmje.org). Authors (including 
Sponsor associates who may qualify for authorship), must therefore satisfy all of the following 
ICMJE authorship criteria:  
1. 
Substantial contributions to conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; AND  
2. 
Drafting the work or revising it critically for important intellectual content; AND 
3. 
Final approval of the version to be published; AND 
4. 
Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.  

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The key principles that will be followed for Advanced Accelerator Applications-sponsored, 
research-related publications are:  
• Advanced Accelerator Applications supports the publication of study results for its 
innovative medicines in a timely manner, whatever their outcome. Advanced Accelerator 
Applications policy is not to withhold, veto or suppress data. However, due consideration 
must be given to the rights of Advanced Accelerator Applications to protect confidential 
and/or patentable information, and to the protection of personal information, in particular 
patient privacy. 
• Review by Advanced Accelerator Applications of draft publications by clinical 
investigators in advance of submission/presentation of publication is designed to:  
• 
Confirm the accuracy of the data 
• 
Verify that proprietary information is not being inadvertently disclosed 
• 
Secure intellectual property rights, as needed 
• 
Provide any relevant supplementary information  
• Publication of partial data (unless planned in the protocol) is discouraged. As a matter of 
scientific rigor and fairness to all investigators involved in a clinical study, and in 
accordance with the Joint Position on the Publication of Clinical Trial Results in the 
Scientific Literature, issued by the International Federation of Pharmaceutical 
Manufacturers and Associations (IFPMA), European Federation of Pharmaceutical 
Industries and Associations (EFPIA), Japan Pharmaceutical Manufacturers Association 
(JPMA), and Pharmaceutical Research and Manufacturers of America (PhRMA), it is 
Advanced Accelerator Applications policy for multicenter clinical studies that: 
• The first publication in a journal, or a presentation at a congress, be based on consolidated 
data from all centers, analyzed as stipulated by the protocol and agreed upon by 
investigators before trial initiation.  
• Multicenter trials are designed to take full account of data accumulated from all centers 
(sample sized, powered with appropriate error rates), and Advanced Accelerator 
Applications discourages presenting or publishing data gathered from a single, or small 
group of centers, unless agreed to by study investigators (e.g., Study Steering Committee) 
and Advanced Accelerator Applications. Center specific analyses have greater variability 
and lead to exaggerated observed-treatment effects that are inherently less reliable. Valid 
conclusions regarding the primary endpoint of a clinical trial can only be based on the 
analyses predefined by the protocol.  
• Study results should be published according to the contracted protocol agreements.  
13.4 
Quality Control and Quality Assurance 
The Sponsor maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and The Sponsor systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of 
the clinical trial. The clinical audit process uses a knowledge/risk-based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Sponsor processes. 

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Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for at least 15 years after study completion 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. 
13.5 
Data Protection 
Participants will be assigned a unique identifier by Sponsor. Any participant records or datasets 
that are transferred to Sponsor will contain the identifier only: participant’s name or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for his/her data to be used as 
described in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Sponsor has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Sponsor and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Sponsor and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
Due to the ongoing COVID-19 pandemic during the conduction of this study, protocol 
deviations related to COVID-19 in the given time period will be documented as applicable and 
an explanation will be provided in the clinical study report (CSR) that this was attributed to the 
coronavirus outbreak. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Sponsor, health authorities where required, and the IRB/IEC prior to 
implementation. 

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Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Sponsor should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 

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15 
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16 
Appendices 
16.1 
Appendix 1 – Requirements for contraception 
Based on its mechanism of action, Lutathera can cause fetal harm when administered to a 
pregnant woman. Female patients of child-bearing potential, defined as all female patients 
physiologically capable of becoming pregnant (i.e. female adolescent patients who are 
menarchal or who become menarchal during the study), cannot participate in this study, unless 
they are using highly effective methods of contraception during treatment and for 7 months 
after the last dose of Lutathera according to Lutathera Investigator’s Brochure version 17. If 
local regulations deviate from the listed contraception methods to prevent pregnancy, local 
regulations apply and will be described in the ICF. 
Female patients of child-bearing potential, who are or might become sexually active, must be 
informed of the need to prevent pregnancy during the study. 
According to CTFG guidance, highly effective contraception methods those methods that can 
achieve a failure rate of less than 1% per year when used consistently and correctly. Such 
methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
• oral 
• intravaginal 
• transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
• oral 
• injectable 
• implantable 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomised partner. Vasectomised partner is a highly effective birth control method 
provided that partner is the sole sexual partner of the WOCBP trial participant and that 
the vasectomised partner has received medical assessment of the surgical success. 
• Total sexual abstinence. Sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. 
In case of use of oral contraception female patients should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 
Female patients are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. 
age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks 

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ago. In the case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow-up hormone level assessment is she considered not of child-bearing 
potential. 
Sexually active male patients must agree with following requirements:  
• remain abstinent (refrain from heterosexual intercourse) or be willing to use condoms and 
highly effective methods of contraception with female partners of childbearing potential, 
and to use condoms with pregnant female partners (see above) during the treatment 
period and for at least 4 months after the last dose of Lutathera. 
• refrain from donating sperm during this same period. 
The decision on the contraceptive method should be reviewed with each patient at least every 
3 months to evaluate the individual need and compatibility of the method chosen. 
For requirements on pregnancy tests in the study see Section 8.4.8, and for requirements on 
pregnancy reporting see Section 10.1.7. 
16.2 
Appendix 2 – Radioprotection Precautions for Treated with 
Lutathera lutetium Lu 177 dotatate/ lutetium (177Lu) oxodotreotide 
Based on radiation exposure calculations employing whole body clearance data (Wehrmann C 
et al, 2007) and exposure rates at one meter at 24 h (7.5 ± 3.6 µSv/h, Dpt. of Nucl. Med. 
Erasmus MC Rotterdam), patients may be treated on an outpatient basis for an administration 
of 7.4 GBq of Lutathera. As a precaution, it is recommended that patients be kept in radiation 
isolation for a period of 4 – 5 hours following administration, and be allowed to urinate during 
that time, and before release. This precaution is deemed prudent because this is the route of 
Lutathera elimination (approximately 50% of Lutathera eliminated by urination within the first 
6 hours; Kwekkeboom et al, 2001). At the time of release, the patient is given written 
instructions which summarize the precautions to take, in order to keep the exposure to others 
below regulatory limits. 
16.3 
Appendix 3 – National Cancer Institute Common Terminology 
Criteria for Adverse Events 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) will be 
used for assessing the severity of adverse events and laboratory toxicities in this study. For the 
actual 
CTCAE 
guide, 
please 
refer 
to 
the 
following 
website: 
[://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_refere
nce_8.5x11.pdf]