A Phase III Multi-center, Randomized, Open-label Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET
Phase: PHASE3
Conditions: Gastro-enteropancreatic Neuroendocrine Tumor
Sponsor: Advanced Accelerator Applications

Advanced Accelerator Applications 
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Protocol No. CAAA601A22301 
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Advanced Accelerator Applications 
Research and Development 
LUTATHERA® (lutetium Lu 177 dotatate) 
 
Clinical Trial Protocol CAAA601A22301 
 
A phase III multi-center, randomized, open-label study to 
evaluate the efficacy and safety of Lutathera in patients with 
Grade 2 and Grade 3 advanced GEP-NET 
 
 
 
Document type: 
Amended Clinical Trial Protocol 
EUDRACT number: 
2019-001562-15 
IND number 
Version number: 
77219 
2.0 
Clinical Trial Phase: 
III 
Release date: 
05 October 2022 
 
 
 
 
Property of Advanced Accelerator Applications 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Advanced Accelerator Applications 

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Table of contents 
Table of contents ........................................................................................................................ 2 
List of tables ............................................................................................................................... 5 
List of figures ............................................................................................................................. 6 
List of abbreviations ................................................................................................................... 7 
Glossary of terms ..................................................................................................................... 10 
Protocol synopsis ..................................................................................................................... 12 
Amendment rationale ............................................................................................................... 27 
1 
Introduction ....................................................................................................................... 33 
1.1 
Background ........................................................................................................... 33 
1.2 
Purpose .................................................................................................................. 36 
2 
Objectives and endpoints .................................................................................................. 37 
3 
Study design ...................................................................................................................... 39 
3.1 
Screening Phase ..................................................................................................... 40 
3.2 
Treatment Phase .................................................................................................... 40 
3.3 
Optional Treatment Extension Phase (cross-over) ................................................ 41 
3.4 
Optional Re-Treatment Phase ............................................................................... 41 
3.5 
Follow up Phase .................................................................................................... 42 
4 
Rationale ........................................................................................................................... 43 
4.1 
Rationale for study design ......................................................................................43 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 44 
4.3 
Rationale for choice of control drug ...................................................................... 45 
4.4 
Purpose and timing of interim analyses ................................................................. 46 
4.5 
Risks and benefits .................................................................................................. 46 
5 
Population ......................................................................................................................... 49 
5.1 
Inclusion criteria .................................................................................................... 49 
5.2 
Exclusion criteria ................................................................................................... 49 
5.2.1 
Eligibility Criteria for Optional Treatment Extension Phase (cross- 
over) ...................................................................................................... 51 
5.2.2 
Eligibility Criteria for Optional Re-Treatment Phase ........................... 52 
6 
Treatment .......................................................................................................................... 54 
6.1 
Study treatments .................................................................................................... 54 
6.1.1 
Investigational and control drugs .......................................................... 54 
6.2 
Other treatment(s) .................................................................................................. 58 
6.2.1 
Rescue medication ................................................................................ 58 

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6.2.2 
Other anti-cancer treatments ................................................................. 58 
6.2.3 
Prohibited medication ........................................................................... 58 
6.2.4 
SARS-CoV-2 vaccination ..................................................................... 59 
6.3 
Subject numbering, treatment assignment, randomization .................................... 60 
6.3.1 
Subject numbering ................................................................................ 60 
6.3.2 
Treatment assignment, randomization .................................................. 60 
6.4 
Treatment blinding ................................................................................................ 60 
6.5 
Dose compliance, modification and discontinuation ............................................. 60 
6.5.1 
Dose compliance ................................................................................... 60 
6.5.2 
Dose modification ................................................................................. 60 
6.5.3 
Dose discontinuation ............................................................................. 66 
6.6 
Preparation and dispensation of Lutathera ............................................................ 66 
6.6.1 
Handling of study treatment and additional treatment .......................... 68 
7 
Informed consent procedures ............................................................................................ 70 
8 
Visit schedule and assessments ......................................................................................... 72 
8.1 
Demographics and Baseline Characteristics .......................................................... 75 
8.1.1 
Diagnosis and Extent of Cancer ............................................................ 75 
8.1.2 
Ki67 ...................................................................................................... 75 
8.1.3 
Prior Antineoplastic Medications / Radiotherapy / Surgery ................. 75 
8.1.4 
SRI Tumor Uptake in Documented Lesions ......................................... 75 
8.2 
Prior/Concomitant Medications ............................................................................. 76 
8.3 
Efficacy Assessment .............................................................................................. 76 
8.3.1 
Progression Free Survival ..................................................................... 76 
8.3.2 
Objective Response Rate (ORR), Duration of Response (DOR), Time 
to Second Progression (PFS2) .............................................................. 78 
8.3.3 
Overall Survival .................................................................................... 78 
8.4 
Quality of Life ....................................................................................................... 79 
8.5 
Safety and Tolerability .......................................................................................... 79 
8.5.1 
Adverse Events ..................................................................................... 79 
8.5.2 
Laboratory Assessments ....................................................................... 79 
8.5.3 
Pregnancy Test ...................................................................................... 81 
8.5.4 
Cardiac Ejection Fraction ..................................................................... 82 
8.5.5 
ECG ...................................................................................................... 82 
8.5.6 
Physical Examination and Vital Signs .................................................. 83 
8.5.7 
Karnofsky Performance Score .............................................................. 83 
8.5.8 
Ultrasonic examination of the gallbladder (Germany only) ................. 83 
8.5.9 
SPECT/CT and whole body planar imaging (Germany only) .............. 83 

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8.5.10 
Assessments Schedule ........................................................................... 84 
8.6 
Pharmacokinetics .................................................................................................... 91 
8.6.1 Analytical method ............................................................................................................ 91 
8.7 
Biomarkers ............................................................................................................. 91 
8.8 
Imaging ................................................................................................................... 92 
9 
Study discontinuation and completion ............................................................................... 94 
9.1 
Discontinuation ....................................................................................................... 94 
9.1.1 
Discontinuation of study treatment ........................................................ 94 
9.1.2 
Withdrawal of informed consent ........................................................... 95 
9.1.3 
Lost to follow-up ................................................................................... 96 
9.1.4 
Early study termination by the sponsor ................................................. 96 
9.2 
Study completion and post-study treatment ........................................................... 96 
9.2.1 
Post-trial access to Lutathera ................................................................. 98 
10 Safety monitoring and reporting ........................................................................................ 99 
10.1 
Definition of adverse events and reporting requirements ....................................... 99 
10.1.1 
Adverse events ....................................................................................... 99 
10.1.2 
Serious adverse events ......................................................................... 102 
10.1.3 
Adverse Drug Reaction (ADR) ............................................................ 103 
10.1.4 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ........... 103 
10.1.5 
Adverse Events of Special Interest ...................................................... 103 
10.1.6 
SAE reporting ...................................................................................... 105 
10.1.7 
Pregnancy reporting ............................................................................. 106 
10.1.8 
Reporting of study treatment errors including misuse/abuse ............... 106 
10.1.9 
Annual Safety Report .......................................................................... 106 
10.2 
Additional Safety Monitoring ............................................................................... 107 
10.2.1 
Steering Committee ............................................................................. 107 
11 Data Collection and Database management ..................................................................... 108 
11.1 
Data collection ...................................................................................................... 108 
11.2 
Database management and quality control ........................................................... 108 
11.3 
Site monitoring ..................................................................................................... 108 
12 Data analysis and statistical methods ............................................................................... 110 
12.1 
Analysis sets ......................................................................................................... 110 
12.2 
Subject demographics and other baseline characteristics ..................................... 110 
12.3 
Treatments ............................................................................................................ 111 
12.4 
Analysis of the primary endpoint(s) ..................................................................... 111 
12.4.1 
Definition of primary endpoint(s) ........................................................ 111 
12.4.2 
Statistical model, hypothesis, and method of analysis ......................... 111 

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12.4.3 
Handling of missing values/censoring/discontinuations ..................... 112 
12.4.4 
Sensitivity and Supportive analyses.................................................... 112 
12.5 
Analysis of secondary endpoints ......................................................................... 113 
12.5.1 
Key secondary objectives ................................................................... 113 
12.5.2 
Other efficacy endpoints ..................................................................... 114 
12.5.3 
Safety endpoints .................................................................................. 115 
12.6 
Analysis of exploratory endpoints ....................................................................... 117 
12.6.1 
PFS2 .................................................................................................... 117 
12.6.2 
Patient reported outcomes not associated with key secondary endpoint118 
12.6.3 
Pharmacokinetics ................................................................................ 118 
12.6.4 
Re-treatment with Lutathera ............................................................... 119 
12.7 
Interim analyses ................................................................................................... 119 
12.8 
Sample size calculation ....................................................................................... 119 
12.8.1 
Primary endpoint(s) ............................................................................ 119 
13 Ethical considerations and administrative procedures .................................................... 121 
13.1 
Regulatory and ethical compliance ..................................................................... 121 
13.2 
Responsibilities of the investigator and IRB/IEC ............................................... 121 
13.3 
Publication of study protocol and results ............................................................ 121 
13.4 
Quality Control and Quality Assurance .............................................................. 122 
14 Protocol adherence .......................................................................................................... 124 
14.1 
Protocol Amendments ......................................................................................... 125 
15 References ....................................................................................................................... 126 
16 Appendices ...................................................................................................................... 135 
Appendix 1 – Precautions for Pregnancy ............................................................................... 136 
Appendix 2 – Lutathera Administration and Sterile Amino Acid Co-Infusion Scheme ........ 138 
Appendix 3 – Karnofsky Performance Scale ......................................................................... 139 
Appendix 4 – Radioprotection Precautions for Treated with Lutathera 177Lu-DOTA0-Tyr3- 
Octreotate ........................................................................................................................ 140 
Appendix 5 – Recommendations for Patients Treated with Lutathera ................................... 141 
Appendix 6 – Instructions for Shipment, Storage and Handling of 177Lu-DOTA0-Tyr3- 
Octreotate (Lutathera) Solution for Infusion ................................................................... 145 
Appendix 7 – National Cancer Institute Common Terminology Criteria for Adverse Events150 
Appendix 8 – Determination of LUTATHERA Administered Radioactivity ........................ 156 
List of tables 
Table 2-1. Study objectives and endpoints ............................................................................... 37 
Table 6-2. Composition of the Lutathera® Drug Product (per vial) ......................................... 55 

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Table 6-3. 2.5% Lys-Arg sterile solution composition* .......................................................... 57 
Table 6-4. Dose Modifications of Lutathera for Adverse Events ............................................ 61 
Table 6-5. Administration procedure of antiemetic, sterile amino acid solution and Lutathera68 
Table 8-1. Centrally Performed Assessments .......................................................................... 72 
Table 8-2. Laboratory Assessments1 ....................................................................................................................................... 80 
Table 8-3. Assessment Schedule Lutathera Arm ..................................................................... 85 
Table 8-4. Assessment Schedule Octreotide Long-Acting 60 mg Arm. .................................. 88 
Table 8-5. Octreotide long-acting PK blood collection plan .................................................... 91 
Table 10-1. Adverse events of special interest ....................................................................... 104 
 
 
List of figures 
Figure 3-1. Study Design ......................................................................................................... 39 
Figure 6-1. Lutathera Arm: schedule for administration of Lutathera, 30 mg octreotide long- 
acting, and short acting octreotide sc1 ...................................................................................................... 67 

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List of abbreviations 
 
90Y 
Yttrium-90 
111In 
Indium-111 
177Lu 
Lutetium-177 
AAA 
Advanced Accelerator Applications 
ADR 
Adverse Drug Reaction 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ALAT/ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
ASAT/AST 
Aspartate Aminotransferase 
BOR 
Best Overall Response 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
BMI 
Body Mass Index 
BW 
Body Weight 
CgA 
Chromogranin-A 
COVID-19 
Coronavirus disease 2019 
CR 
Complete Response 
CRO 
Clinical Research Organization 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DMT 
Dose Modifying Toxicity 
DOR 
Duration of Response 
DOTA 
1,4,7,10-Tetraazacyclododecane-N,N’,N’’,N’’’-tetraaacetic Acid 
DOTATATE 
 DOTA-Tyr3-octreotate 
DOTATOC 
DOTA-Tyr3-octreotide 
DTPA 
Diethylene Triamine Pentaacetic Acid 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
E-CRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EORTC 
European Organization for Research and Treatment of Cancer 
EOS 
End of Study 
EOT 
End of Treatment 
Erasmus MC 
Erasmus Medical Centre, Rotterdam, NL 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
fT4 
Free Thyroxine 
FSH 
Follicle Stimulating Hormone 
FUP 
Follow Up 
GGT or γ-GT 
Gamma-Glutamyl Transferase 
GBq 
Giga Becquerel (Bq = unit of radioactivity) 

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GCP 
Good Clinical Practice 
GEP 
Gastro-Entero-Pancreatic 
GFR 
Glomerular Filtration rate 
GI 
Gastrointestinal 
GlycoHb 
Glycosylated Haemoglobin (haemoglobin A1C) 
GMP 
Good Manufacturing Practice 
Gy 
Gray (unit of radiation exposure; equal to 100 rad) 
H 
Hours 
Hb 
Haemoglobin 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
ID 
Identification (Number) 
IEC 
Independent Ethic Committee 
irRC 
Immune-related response criteria 
I.M. 
Intramuscular 
IMP 
Investigational Medicinal Product 
IRC 
Independent Review Committee 
IRB 
Institutional Review Board 
ITT 
Intention To Treat 
I.V. 
Intravenous 
KPS 
Karnofsky Performance Score 
LAR 
Long Acting Release 
LDH 
Lactic Dehydrogenase 
LPF 
Low-Power Field (microscopic exam) 
MBq 
Mega Becquerel (Bq = unit of radioactivity) 
MCi 
MilliCurie (unit of radioactivity; 1 mCi = 37 MBq) 
MCV 
Mean Corpuscular Volume (red blood cells) 
MDS 
Myelodysplastic Syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram(s) 
Ml 
Milliliter(s) 
MM 
Millimole 
MRI 
Magnetic Resonance Imaging 
NaCl 
Sodium Chloride 
NCI 
National Cancer Institute (USA) 
NET 
Neuroendocrine Tumor 
NIH 
National Institute of Health (USA) 
NYHA 
New York Heart Association 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PAS 
Pharmacokinetic Analysis Set 
PD 
Progressive Disease or Pharmacodynamic(s) 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PFS2 
Progression Free Survival (Second Progression) 

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PI 
Principal Investigator 
PLT 
Platelets 
PPS 
Per Protocol Set 
PK 
Pharmacokinetics 
PR 
Partial Response 
PRO 
Patient Reported Outcome 
PRRT 
Peptide Receptor Radionuclide Therapy 
QoL 
Quality of Life 
QC 
Quality Control 
QMS 
Quality Management System 
QP 
Qualified Person 
RBC 
Red Blood Cells 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RVG 
Radionuclide Ventriculography 
SAE 
Serious Adverse Event 
SAF 
Safety Set (SAF) 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
S.C. 
Subcutaneous 
SD 
Stable Disease 
SOP 
Standard Operating Procedures 
SPECT 
Single photon-emission computed tomography 
Sstr2 
Somatostatin Receptor Subtype 2 
SRI 
Somatostatin Receptor Imaging 
SRS 
Somatostatin Receptor Scintigraphy 
SSAs 
Somatostatin Analogs 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TTD 
Time to deterioration 
ULN 
Upper Limit of Normal (according to local laboratory normal values) 
WBC 
White Blood Cells 
WBPI 
Whole body planar imaging 
WHO 
World Health Organization 

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Glossary of terms 
 
 
Assessment 
A procedure used to generate data required by the study. 
Biologic Samples 
A biological specimen including, for example, blood (plasma, 
serum), saliva, tissue, urine, stool, etc. taken from a study subject 
or study patient. 
Control drug 
A study treatment 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. 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol). 
GEP-NET 
Gastroenteropancreatic neuroendocrine tumors a rare type of 
tumor that can form in the pancreas or in other parts of the 
gastrointestinal tract, including the stomach, small intestine, 
colon, rectum, and appendix. Neuroendocrine tumors arising in 
the lung are not considered GEP-NETs. 
Investigational drug 
The study treatment whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.” 
Investigational treatment 
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when 
applicable). This also includes approved drugs used outside of 
their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include 
other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within 
approved indication/dosage. 
Medication number 
A unique identifier on the label of each study treatment package 
which is linked to one of the treatment groups of a study. 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment. 
Subject Number (Subject 
No.) 
A 
unique 
identifying 
number 
assigned 
to 
each 
patient/subject/healthy volunteer who enrolls in the study. 
Study Phase 
A subdivision of the study timeline; divides stages into smaller 
functional segments such as screening, treatment, follow-up, etc. 
Randomization number 
A unique treatment identification code assigned to each 
randomized patient, corresponding to a specific treatment arm 
assignment. 

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Rescue therapy 
A 
quick-relief 
or 
fast-acting 
medication 
besides 
the 
investigational drug or control that can alleviate symptoms due to 
disease or lack of efficacy of the study treatment. It acts quickly 
to stop symptoms and, the effects are not long-lasting. 
Stage related to study 
timeline 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc. 
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. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit 
or when study treatment was discontinued whichever is later. 
Study treatment 
Includes any drug or combination of drugs in any study treatment 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins. 
In specific examples, it is important to judge investigational 
treatment component relationship relative to a study treatment 
combination; study treatment in this case refers to the 
investigational and non-investigational treatments in combination. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment 
for any reason. 
Variable 
Identifier used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified 
timepoints. 
Withdrawal of consent 
Withdrawal of consent occurs only when a patient does not want 
to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
related contact. 

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Protocol synopsis 
 
 
Protocol number 
CAAA601A22301 
Full Title 
This is a multicenter, stratified, randomized, open-label comparator- 
controlled, Phase III study in patients with somatostatin receptor positive, 
well-differentiated G2 and G3, advanced GEP NETs, diagnosed within 6 
months prior to screening, comparing treatment with Lutathera (7.4 
GBq/200 mCi x 4 administrations every 8± 1 weeks; cumulative dose: 29.6 
GBq/800mCi) plus octreotide long-acting (30 mg every 8 weeks during 
Lutathera treatment and every 4 weeks after last Lutathera treatment) and 
high dose octreotide long-acting (60 mg every 4 weeks). 
Brief title 
A Phase III multi-center, randomized, open-label study to evaluate the 
efficacy and safety of Lutathera in patients with Grade 2 and Grade 3 
advanced GEP-NET. 
Sponsor and 
Clinical Phase 
Sponsored by Advanced Accelerator Applications, Phase III Study. 
Purpose and 
rationale 
The pivotal Phase III NETTER-1 study showed that Lutathera with best 
supportive care (30mg octreotide long-acting) provided a significant 
increase in PFS to patients with progressive midgut carcinoid tumors (at 
enrollment) compared to patients treated with high dose (60 mg) octreotide 
long-acting. The NETTER-1 patient population included 34.5% of patients 
with G2 NET (65.5% G1), while G3 NETs were excluded. Only patients 
progressive on SSAs were eligible (2nd line), SSA-naïve patients were 
excluded. 
The aim of the NETTER-2 study is to determine if Lutathera in combination 
with octreotide long-acting prolongs PFS in GEP-NET patients with high 
proliferation rate tumors (G2 and G3), when given as a 1st line treatment in 
comparison to treatment with high dose (60 mg) octreotide long-acting. 
SSA-naïve patients are eligible, as well as patients previously treated with 
SSAs in the absence of progression. 
Based on extensive experience with Lutathera as well as octreotide LAR in 
adult GEP NET patients, and the relevance of the molecular target in 
adolescent GEP NET patients, the study will be open to adolescents aged ≥ 
15 years and >40 kg body weight (BW); younger patients are not expected 
to present with the disease meeting the severity criteria for this trial. 
Primary 
Objective(s) 
To demonstrate that Lutathera is superior to active comparator in delaying 
the time-to-first occurrence of progression or death (PFS) as first line 
treatment. 
Key Secondary 
Objectives 
-To demonstrate the superiority of Lutathera, compared to active 
comparator, in terms of objective response 
-To demonstrate the superiority of Lutathera, compared to active 
comparator, in terms of time to deterioration in selected QoL items/scales. 

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Other Secondary 
Objectives 
-To evaluate the efficacy of Lutathera, compared to active comparator, in 
keeping the disease under control 
-To evaluate the efficacy of Lutathera, compared to active comparator, in 
terms of duration of response 
-To evaluate the safety and tolerability of Lutathera 
-To evaluate the effect of Lutathera on overall survival 
Study design 
Overall, 222 patients will be randomized (2:1 randomization ratio) to receive 
treatment with Lutathera (7.4GBq/200 mCi x 4 administrations every 8± 1 
weeks; cumulative dose: 29.6 GBq/800mCi) plus octreotide long-acting (30 
mg every 8 weeks during Lutathera treatment and every 4 weeks after last 
Lutathera treatment) or high dose octreotide long-acting (60 mg every 4 
weeks). Randomization will be stratified by Grade (G2 vs G3) and tumor 
origin (pNET vs other origin). 
The primary endpoint of the study is PFS centrally assessed (target HR=0.5; 
90% power, 1-sided α=2.5%). The primary analysis will be performed after 
99 PFS events (99 evaluable and centrally confirmed disease progressions 
or death events) have occurred. 
The study consists of a Screening Phase, a Treatment Phase, an optional 
Treatment Extension Phase (cross-over), an optional Re-treatment Phase and 
a Follow up Phase. 
Screening Phase 
The screening phase must be shortened as much as possible, in order to treat 
the patients possibly within 2 weeks after the consent signature. 
The randomization must be performed immediately after all eligibility 
criteria are verified. As Lutathera production and shipment will take circa 
12 days to be arranged, if a patient is randomized in the Lutathera arm, 
Lutathera first dose must be ordered immediately after randomization. 
The baseline CT/MRI scan should be taken possibly on the same day as 
randomization or immediately before (within 1 week) to ensure that it 
reflects the disease status closely before the therapy start. 
Treatment Phase 
During the Treatment Phase, objective tumor response will be assessed at 
W16±1, W24±1 and then every 12±1 weeks from the randomization date, 
according to RECIST 1.1 criteria (central + local assessment up to first 
progression, then only local assessment). 
Duration of the Treatment Phase: 
Before the PFS primary analysis (i.e. 99 evaluable and centrally confirmed 
disease progressions or death events), patients continue the Treatment Phase 
until progression; after the PFS primary analysis, the Treatment Phase 
duration is limited to 72 weeks. 

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At any time during the study (before or after the PFS primary analysis) any 
progressive patient (based on central imaging assessment) immediately 
ceases the Treatment Phase and proceeds to the Follow-up Phase. Patients 
who experience disease progression in the Lutathera arm after having 
received and benefitted from 4 doses/cycles as initial treatment have the 
option, if eligible, to enroll for re-treatment with Lutathera. In addition, 
patients randomized in the control arm have the option, if eligible, to enroll 
for post-progression cross-over with Lutathera. 
Optional Treatment Extension Phase (cross-over) 
In the control arm, any patient with radiological progression according to 
RECIST (based on central assessment) has the option to enroll for post- 
progression cross-over, upon signature of a new informed consent, to receive 
maximum 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles; cumulative 
dose: 29.6 GBq / 800mCi) plus 30 mg octreotide long acting every 8 weeks. 
If RECIST progression occurs after Week 72 post the primary end point 
analysis, the decision to enroll the patient in the cross-over phase will be 
based on local assessment. The time window to start Lutathera during the 
cross-over phase is within 4 years after the last patient has been randomized. 
Optional Re-treatment Phase 
Patients in the Lutathera arm with radiological progression based on 
RECIST criteria in central assessment will be offered enrollment in the 
optional re-treatment phase upon signature of a new informed consent. If 
RECIST progression occurs after Week 72 post the primary end point 
analysis, the decision to enroll the patient in re-treatment will be based on 
local assessment. 
The criteria to enter the re-treatment phase include achievement of 
stabilization of disease or radiological response to Lutathera initial treatment 
for at least 6 months after receiving the 4th Lutathera dose and good 
safety/tolerability. If a patient’s response has changed from PR/CR to SD 
within 6 months after the 4th Lutathera dose, the patient is still eligible for 
re-treatment, provided there is no documented progression within 6 months. 
Patients who received other systemic treatments for GEP-NET after 
progression (except somatostatin analogues) are not eligible for re-treatment. 
The time window to start re-treatment in this study is within 4 years after the 
last patient has been randomized. 
In the re-treatment phase, patients will initially receive 2 administrations of 
Lutathera 7.4 GBq/200 mCi at 8-week interval. Based on the physician’s 
judgment of the clinical benefit derived from the first 2 doses, up to 2 
additional doses of Lutathera may be administered. A maximum of 4 cycles 
of Lutathera is allowed during the re-treatment period. All safety and 
efficacy assessments in the re-treatment period will be performed locally 
(SRI images must also be submitted to the central images reading center 
possibly within 1 month) and following the schedule in the initial treatment 

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period. Assessments will be continued until disease progression is 
documented by investigator or until End of Study, whichever occurs first. 
Follow up Phase 
At the end of the Treatment Phase or after discontinuation for any cause 
(including disease progression), all patients will continue to be followed up 
to 3 years to continue data collection for the secondary endpoints of the 
study, such as long term safety and overall survival. Patients included in the 
optional crossover or re-treatment phase will be followed up at least 6 
months and up to 3 years (or until EoS, whatever comes first). 
During the Follow-up Phase, serious adverse events and adverse events of 
special interest (AESI) related to the study treatment as well as AESI of 
secondary hematological malignancies irrespective of causality, will be 
reported. 
Anti-tumor 
treatments 
administered 
after 
progression/discontinuation, disease status based on local CT/MRI 
assessment, and OS data will be collected every 6 months in both arms. 
End of the Study 
The End of Study is after 4 years have elapsed from the randomization of 
the last patient or 6 months after the last cross-over or re-treatment dose in 
the study, whichever occurs last. The time window to start cross-over or re- 
treatment with Lutathera in this study is within 4 years after the last patient 
has been randomized. For patients in the Lutathera arm who progress beyond 
this window, access to re-treatment with Lutathera may be granted via Post 
Study Drug Supply (PSDS) programs. 
Population 
In this study, safety and efficacy of treatment with Lutathera plus octreotide 
long-acting (30 mg) versus high dose octreotide long-acting (60 mg) is 
evaluated in patients ≥15 years with somatostatin receptor positive, well 
differentiated G2 (Ki67 index ≥10% to ≤ 20%) and G3 (Ki67 > 20% and ≤ 
55%) advanced GEP-NETs. Patients with documented RECIST progression 
to previous treatments for the current GEP-NET at any time prior to 
randomization are not eligible to participate in this study. 
Key 
Inclusion 
criteria 
Subjects eligible for inclusion in this study must meet all of the following 
criteria: 
1. Presence of metastasized or locally advanced, inoperable (curative 
intent) histologically proven, well differentiated Grade 2 or Grade 3 
gastroenteropancreatic neuroendocrine (GEP-NET) tumor diagnosed 
within 6 months prior to screening. 
2. Ki67 index ≥10 and ≤ 55%. 
3. Patients ≥15 years of age and a body weight of >40 kg at screening. 
4. Expression of somatostatin receptors on all target lesions documented by 
CT/MRI scans, assessed by any of the following somatostatin receptor 
imaging (SRI) modalities within 3 months prior to randomization: 

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[68Ga]-DOTA-TOC (e.g. Somakit-TOC®) PET/CT imaging (or MRI 
when applicable based on target lesions), [68Ga]-DOTA-TATE PET/CT 
(or MRI when applicable based on target lesions) imaging (e.g. 
NETSPOT®), Somatostatin Receptor scintigraphy (SRS) with [111In]- 
pentetreotide (Octreoscan® SPECT/CT), SRS with [99mTc]-Tektrotyd, 
[64Cu]-DOTA-TATE PET/CT imaging (or MRI when applicable based 
on target lesions). 
5. The tumor uptake observed in the target lesions must be > normal liver 
uptake. 
6. Karnofsky Performance Score (KPS) ≥60. 
7. Presence of at least 1 measurable site of disease. 
8. Patients who have provided a signed informed consent form to 
participate in the study, obtained prior to the start of any protocol related 
activities. 
Key 
Exclusion 
criteria 
Subjects meeting any of the following criteria are not eligible for inclusion 
in this study. 
1. Creatinine clearance <40 mL/min calculated by the Cockroft Gault 
method. 
2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L 
(2000/mm3); platelets <75x109/L (75x103/mm3). 
3. Total bilirubin >3 x ULN. 
4. Serum albumin <3.0 g/dL unless prothrombin time is within the normal 
range. 
5. Pregnancy or lactation. 
6. A) Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, are not allowed to 
participate in this study UNLESS they are using highly effective 
methods of contraception throughout the study treatment period 
(including cross-over and re-treatment, if applicable) and for 7 months 
after study drug discontinuation. 
B) 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 or pregnant female partners during the treatment 
period (including cross-over and re-treatment, if applicable) and for 4 
months after study drug discontinuation. In addition, male patients must 
refrain from donating sperm during this same period. 
7. Peptide receptor radionuclide therapy (PRRT) at any time prior to 
randomization in the study. 

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8. Documented RECIST progression to previous treatments for the current 
GEP-NET at any time prior to randomization. 
9. Patients for whom in the opinion of the investigator other therapeutic 
options (eg chemo-, targeted therapy) are considered more appropriate 
than the therapy offered in the study, based on patient and disease 
characteristics. 
10. Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), 
chemotherapy or other systemic therapies of GEP-NET administered for 
more than 1 month or within 12 weeks prior to randomization in the 
study. 
11. Any 
previous 
radioembolization, 
chemoembolization 
and 
radiofrequency ablation for GEP-NET. 
12. Any surgery within 12 weeks prior to randomization in the study. 
13. Known brain metastases, unless these metastases have been treated and 
stabilized for at least 24 weeks, prior to screening in the study. Patients 
with a history of brain metastases must have a head CT or MRI with 
contrast to document stable disease prior to randomization in the study. 
14. Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with 
history of congestive heart failure who do not violate this exclusion 
criterion will undergo an evaluation of their cardiac ejection fraction 
prior to randomization via echocardiography. The results from an earlier 
assessment (not exceeding 30 days prior to randomization) may 
substitute the evaluation at the discretion of the Investigator, if no 
clinical worsening is noted. The patient’s measured cardiac ejection 
fraction in these patients must be >40% before randomization. 
15. QTcF > 470 msec for females and QTcF > 450 msec for males or 
congenital long QT syndrome. 
16. Uncontrolled diabetes mellitus as defined by hemoglobin A1c value > 
7.5%. 
17. Hyperkaleamia >6.0 mmol/L (CTCAE Grade 3) which is not corrected 
prior to study enrolment. 
18. Any patient receiving treatment with short-acting octreotide, which 
cannot be interrupted for 24 h before and 24 h after the administration of 
Lutathera, or any patient receiving treatment with SSAs (eg octreotide 
long-acting), which cannot be interrupted for at least 6 weeks before the 
administration of Lutathera. 
19. Patients with any other significant medical, psychiatric, or surgical 
condition, currently uncontrolled by treatment, which may interfere with 
the completion of the study. 
20. Prior external beam radiation therapy to more than 25% of the bone 
marrow. 

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21. Current spontaneous urinary incontinence. 
22. 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. 
23. 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. 
24. Hypersensitivity to any somatostatin analogues, to the IMPs active 
substance or to any of the excipients. 
25. Patients who have participated in any therapeutic clinical study/received 
any investigational agent within the last 30 days. 
Study treatment 
In this study, approximately 222 patients with advanced G2-3 GEP-NET will 
be randomized (2:1 randomization ratio) to receive treatment with Lutathera 
(7.4 GBq or 200 mCi x 4 administrations every 8± 1 weeks; cumulative dose: 
29.6 GBq or 800 mCi) plus octreotide long-acting standard dose (30 mg 
every 8 weeks during Lutathera treatment and every 4 weeks after last 
Lutathera treatment) or octreotide long-acting high dose (60 mg every 4 
weeks). 
The 
investigational 
drug 
product 
Lutathera® 
(177Lu-DOTA0-Tyr3- 
Octreotate) will be provided by the Sponsor. The Sponsor will also provide 
the 2.5% Lys-Arg sterile amino acid solution for infusion (if it can’t be 
compounded at the hospital Pharmacy), as well as octreotide long-acting 
(Sandostatin® LAR Depot) for the entire duration of the Treatment Phase 
(and optional Treatment Extension Phase in case of cross-over) of the study. 
During the re-treatment period, Lutathera® and 2.5% Lys-Arg sterile amino 
acid solution for infusion (if it can’t be compounded at the hospital 
Pharmacy) will be provided by the Sponsor. Patients will switch to 
prescribed drugs in the follow up phase. 
Anti-emetics, SRI imaging agents, short-acting octreotide or any other 
supportive care medication will not be supplied by the Sponsor. 
Efficacy 
assessments 
During the Treatment Phase, objective tumor response will be assessed at 
W16±1, W24±1 and then every 12±1 weeks from the randomization date, 
according to RECIST 1.1 criteria (central + local assessment up to first 
progression, then only local assessment). During the Follow up Phase 
RECIST objective tumor response will be assessed locally (scans every 6 
months). 
Pharmacokinetic 
assessments 
Patients in the control arm (all countries except for China) will yield PK data 
from blood sampling performed at pre-dose with respect to the octreotide 
long-acting i.m. injection for the 2nd, 4th, 5th and 7th treatment cycle (that 
is respectively at week 4, 12, 16 and 24) for the determination of plasma 
trough levels. Data will be processed using a population based model, for 
exploratory purposes. 

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Key safety 
assessments 
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 Phase/optional Treatment Extension Phase in case of cross- 
over/optional re-treatment. During the Follow up Phase only related serious 
adverse events and related AESI other than secondary hematological 
malignancies will be recorded. AESI of secondary hematological 
malignancies will be recorded during the whole study irrespective of 
causality. 
Data analysis 
The primary efficacy and safety analyses will be performed after observing 
approximately 99 PFS events. At that time a soft database lock will ensure 
the integrity of the data and make further data entry for the continuation of 
the trial possible. 
The primary endpoint of the study is progression-free survival (PFS), 
defined as the time from the date of randomization to the date of the first 
documented progression or death due to any cause. PFS will be assessed via 
central review according to RECIST 1.1. 
The following statistical hypotheses will be tested to address the primary 
efficacy objective: 
H01 (null hypotheses): Θ1≥ 0 vs. Ha1 (alternative hypotheses): Θ1 < 0 
Where Θ1 is the log hazard ratio of PFS in the Lutathera plus Standard Dose 
octreotide long-acting (30 mg) (investigational) arm vs. High Dose 
octreotide long-acting (60 mg) (control) arm. 
The primary efficacy analysis to test this hypothesis and compare the two 
treatment groups will consist of a stratified log-rank test at an overall one- 
sided 2.5% level of significance in favor of the Lutathera plus Standard Dose 
octreotide long-acting (30 mg) arm. The stratification will be based on the 
following randomization stratification factors (grade: G2 vs. G3; and tumor 
origin: pNET vs other origin). 
Secondary objectives of the study are to compare the two treatment groups 
with respect to objective response rate, time to deterioration in selected 
EORTC QLQ-C30 and QLQ-G.I.NET21 QoL items/scales, disease control 
rate, duration of response, safety and overall survival. Objective response 
rate and time to deterioration in EORTC QLQ-C30 global health status, 
diarrhea, fatigue, and pain are identified as key secondary endpoints. 
A hierarchical testing procedure will be used to control the overall type I 
error in assessing the primary and key secondary objectives. 
Key words 
GEP-NET, PRRT, Lutathera. 

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Investigator approval signatures for: 
Clinical Trial Protocol CAAA601A22301 
 
Protocol version and release date: Version 2.0, 05 October 2022 
 
 
Investigator signature 
I have read the protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol, with applicable laws and regulations and in accordance with the ethical principles 
outlined in the Declaration of Helsinki. 
 
 
 
 
 
Investigator 
Signature 
Date 
 
 
 
 
 
Center name and address:  
 
 
 
Center name:  
 
 
 
Address:  
 

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Protocol Amendment 2.0 
 
 
Amendment rationale 
 
At the time of this amendment release, patient recruitment in the study is completed (222 patients 
randomized as of September 28th, 2022). 
The primary purpose of amendment version 2.0 is to implement modifications in contraception 
requirements in line with Lutathera Investigator’s Brochure (IB) version 17, dated 09 March 2022. 
The IB and corresponding changes in the informed consent form (ICF) were sent after the release 
to all enrolling sites and shared with IRBs/ECs as needed. 
The changes are 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 contraception requirements for male patients have been modified by specifying the 
use of condom and highly effective methods of contraception with female partners of childbearing 
potential or pregnant female partners during the treatment period (including cross-over and re- 
treatment, if applicable) and for 4 months after study drug discontinuation. 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) (EMA 
“Safety Working Party recommendations on the duration of contraception following the end of 
treatment with a genotoxic drug” dated on 27-Feb-2020). 
This protocol amendment also includes the following updates: 
• It has been clarified that based on Lutathera mechanism of action as a radioligand therapy, 
it can cause fetal harm when administered to a pregnant women. 
• Some minor updates were made to the language regarding the objective response rate 
(ORR) and disease control rate (DCR) in the objective, assessments, and statistical sections 
of the protocol. 
• According to the global Sponsor position, Lutathera should be infused slowly with an 
infusion rate up to 400 mL/hr, depending on the patient venous status, resulting in a 
duration of the infusion time of 30 ± 10 minutes. The wording “up to” was missing in the 
previous protocol version, and has been added now. 
• Sterile conditions of amino acid solution infusion have been specified in order to emphasize 
that sterile solution is required for infusion. 
• An error in the formula to calculate creatinine clearance has been noted and corrected. 

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• It has been clarified that serum chromogranin A (CgA) assessment is discontinued in Q3 
2022 in South Korea due to lab kits shortage in the country. CgA assessments performed 
before discontinuation will be included in the analyses. This discontinuation does not 
impact study primary, secondary or exploratory objectives. 
• It has been clarified that CT/MRI scan does not need to be repeated at EOT/EOS visits if 
it has been already done shortly before the visits. 
• The sentence mentioning that in case of discrepancies between the local and central tumor 
response assessment “the Investigator may request the assessment by a third evaluator for 
final adjudication” has been removed. This option is actually not foreseen in this study. 
The central review is independent, performed by two reviewers, with adjudication by a 3rd 
independent reviewer in case of discrepancy between the first two. As per process, the 
central review is not impacted by the local response assessment. 
• It has been clarified that if a patient discontinues Lutathera before confirmed disease 
progression, the patient should be followed with tumor assessments as per initial CT/MRI 
schedule until confirmed disease progression. This is done via central assessment in the 
initial Lutathera treatment, and via local assessment in the Lutathera re-treatment phase. 
• A typo related to Karnofsky Performance score (KPS) evaluation has been corrected in the 
assessment schedule. Protocol section 8.5.7 states: “KPS forms must be completed by a 
medical professional at each treatment and follow-up visit”; however, the assessment was 
not added in error in the control arm (Table 8-4) assessment schedule with the protocol 
amendment version 1.0 (typo). This typo in Table 8-4 is now corrected. 
• Added clarification on applicable processes in case of Lutathera supply disruption and/or 
quality finding. 
• Added clarification on patient management in regards to SARS-CoV-2 vaccination. 
• Added clarification on informed consent withdrawal. 
• Added clarification on study documents retention. 
• Added clarifications on SSTR uptake assessment in somatostatin receptor imaging and 
CT/MRI scans for cross-over and re-treatment eligibility visits. 
• Added clarification on management of CT/MRI scans after the second progression (PFS2) 
during the follow-up period 
• Added clarifications on allowed time window for follow-up visits and re-treatment start. 
• Added clarification on concomitant medication collection during follow-up phase. 
• Added clarifications on CT/MRI scans scheduled during cross-over/re-treatment phase. 
• Added clarification on EORTC QoL scales which are captured in the key secondary 
analysis 
• Added a footnote in the Dose modification table clarifying that lymphopenia is not a dose 
modifying toxicity. 
 
 
• 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. 

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1. Protocol synopsis, Data Analysis: Removed reference to QLQ-G.I.NET21 for the key 
secondary endpoints 
2. Protocol summary, Section 5.2, Appendix 1, Appendix 5: 
a. Exclusion criterion #6a: 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. Exclusion criterion #6b: updated to reflect the use of “condoms and highly” 
effective methods of contraception by male patients during treatment and for 4 
months (instead of 6 months) after the last Lutathera dose. 
3. Objectives and endpoints, Section 2 
a. Updated definitions for Objective response rate (ORR) and Disease control rate 
(DCR) 
4. “Sterile” added before “amino acid solution” in all relevant instances where the solution 
is cited in the Protocol. 
5. Sections 3.2 and 3.4: added a clarification that if a patient discontinues Lutathera before 
confirmed disease progression, the patient should be followed with tumor assessments as 
per initial CT/MRI schedule until confirmed disease progression. 
6. Sections 3.5, 8.3.1, 8.5.2, 8.5.10 updated to clarify that the allowed time window for 
follow-up visits is 6 months ± 1 month. 
7. Section 4: Added a new section (4.6) on rationale for public health emergency mitigation 
procedures under. 
8. Updated Sections 4.2 and 5.2.2 to clarify that a window of -2 weeks is allowed for the 
confirmation of 6 months of SD/PR/CR response. 
9. Updated Section 5.2.1, Section 5.2.2, Table 8-3 and Table 8-4 to clarify that post 
progression Cross-Over/Re-treatment Eligibility CT/MRI scan doesn’t need to be repeated 
if performed within the previous 12 weeks. Both Cross-Over/Re-treatment Eligibility SRI 
and CT/MRI scans need to be submitted to the central imaging center for a second review: 
there is no central ‘real time’ assessment of the Cross-Over and Re-treatment Eligibility 
SRI uptake; however, the images should be submitted to the central imaging center 
possibly within 1 month. 
10. Added Section 6.2.4 “SARS-CoV-2 vaccination” to provide clarifications on the 
risk/benefit assessment in regards to SARS-CoV-2 vaccination and vaccination data 
collection. 
11. Table 6.4: added footnote “1 No dose modification required for hematological toxicities 
Grade 3 or Grade 4 solely due to lymphopenia “ 
12. Table 6.5: added “up to” to the infusion rate of Lutathera (i.e. “up to 400 ml/hr”). 
13. Section 7: Study treatment “may involve unknown risks to the fetus if pregnancy were to 
occur during the study” has been replaced by “Lutathera can cause fetal harm when 
administered to a pregnant woman”. 
14. Section 8.2, 8.5.1, Table 8-3 and Table 8-4, updated to clarify that during the Follow-up 
Phase concomitant medications must be collected only if administered for related 
SAEs/AESI and/or for secondary hematological malignancies (in addition to anticancer 
medications). 
15. Section 8.3.1 updated to clarify that for progressive patients participating in cross-over or 
re-treatment, CT/MRI scans performed after the cross-over or re-treatment eligibility will 
follow the visits schedule counted from the 1st Lutathera dose. 
16. Section 8.3.2 updated to clarify that after the first progression is confirmed centrally and 
the second progression is confirmed locally (i.e. after PFS2 event), the sites which do not 

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routinely perform 6-monthly follow up CT/MRI scans for progressive GEP-NET patients 
can omit this examination at the subsequent patient’s visits (no protocol deviation). 
17. Section 8.3.2: Updated definition for Objective response rate (ORR) 
18. Table 8-3: a footnote added to clarify that “For patients who entered the Lutathera re- 
treatment phase, since there are no procedures requiring in-person patient’s attendance, 
the following visits can be performed by phone: Visits W32, 40, 44, 52, 56, 64 and 68 
following Lutathera re-treatment (for Germany only: visits W56, 64 and 68).” 
19. Table 8-4: Added Karnofsky Performance score (KPS) evaluation during the 3-years 
follow up phase for control arm. 
20. Section 8.5.2. Creatinine clearance formula has been corrected 
Est. Creatinine Clearance = [[140-age(yr)]*weight (kg)]/[48816 0.814* serum Cr(mmol 
umol/L)] (multiply by 0.85 for women) 
21. Section 8.5.5: 
­ The sentence related to ECG entry in eCRF has been removed, since no ECG 
parameters are entered in eCRF (only clinical significance is entered). 
­ The sentence related to ECG local review has been updated to clarify the process 
to document clinical significance of ECG findings. 
22. Sections 8.7 and 12.5.3 and Table 8-2, Table 8-3, Table 8-4 updated to clarify that CgA 
assessment is discontinued in Q3 2022 in South Korea due to lab kits shortage (assessments 
performed before discontinuation will be included in the analyses). 
23. Section 8.8: The sentence saying that “the Investigator may request the assessment by a 
third evaluator for final adjudication.” has been removed. 
24. Section 9.1.1 has been updated to describe applicable procedures in case of 
sudden temporary Lutathera supply disruption and/or a quality finding after the product 
release. 
25. Section 9.1.2 has been updated to include clarifications on withdrawal of 
consent/opposition to use of data and/or biological samples. 
26. Section 9.2, Table 8-3 and Table 8-4: clarified that at the EOT, a CT/MRI scan is required 
only if not taken in the previous 12 weeks. If no post-baseline scan is available, a scan is 
needed at EOT. At the EOS, a CT/MRI scan is required only if a scan was not taken in the 
previous 6 months. 
27. Section 12.1: Added definitions for cross-over and re-treatment sets 
28. Section 12.4.3: Fixed formatting for this section 
29. Analysis of secondary endpoints, Section 12.5 
a. Updated definition of ORR as well as highlighted that the key secondary endpoint 
is calculated per central review 
b. Section 12.5.1: Emphasized that further details for best sensitivity and 
supplementary analyses for the key secondary endpoints will be provided in the 
SAP. 
c. Section 12.5.1: Removed reference to QLQ-G.I.NET21 for the key secondary 
endpoints 
d. Section 12.5.2: Updated definition of Disease Control Rate (DCR) 
30. Section 13.4 has been updated to include clarifications on study documents verification 
and retention. 
 
 
A detailed description of each modification is provided in the separate document ‘TABLE OF 
CHANGES’. 

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This amendment is classified as substantial by Sponsor. 
 
 
All protocol changes have been reviewed and approved by the Study Steering Committee. 
 
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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Protocol Amendment 1.0 
 
Amendment rationale 
At the time of this amendment release, patient recruitment in the study is ongoing. A total of 123 
patients have been randomized in the study as of September 23rd, 2021. The amendment does not 
affect the primary and key secondary endpoints of the study. 
The protocol has been amended for the following reasons: 
Addition of Re-treatment phase: 
The main purpose of this protocol amendment is to introduce optional re-treatment with 
additional doses of Lutathera for patients treated in the Lutathera arm upon disease 
progression. Once patients experience disease progression, they may receive any 
subsequent antineoplastic treatment. Based on a meta-analysis (Strosberg et al., 2021) 
including patients with progressive GEP-NETs (n=560) who received re-treatment with 
Lutathera (one to six doses during re-treatment, majority of patients received 200 mCi per 
administration), median PFS was 12.52 months (available in 414 patients), median OS was 
26.78 months from the start of re-treatment (available in 194 patients), and DCR was 71% 
(available in 347 patients) supporting the clinical benefit of re-treatment. The safety profile 
of Lutathera re-treatment was similar to initial treatment. Hematologic grade 3/4 AEs were 
reported in 9% of patients who received PRRT re-treatment. Notably, AML and MDS 
occurred in <1% of patients who received re-treatment with Lutathera, comparable to the 
incidence observed with initial PRRT (2% in the studies included in the meta-analysis). 
These data indicate that re-treatment with Lutathera may be considered as a treatment 
approach to maximize benefit without compromising on safety upon careful assessment of 
clinical status of each individual patient. 
Based on this body of evidence, the patient candidates for re-treatment with Lutathera in 
this protocol amendment, are patients with centrally documented tumor progression in 
Lutathera arm (if RECIST progression occurs after Week 72 post the primary end point 
analysis, the decision to enroll the patient in re-treatment will be based on local 
assessment), who have completed the 4 doses/cycles of Lutathera during the treatment 
phase, had CR/PR/SD as best response for at least 6 months after the 4th Lutathera dose, 
and had tolerated the treatment (according to criteria defined in Section 5.2.2). An SSTR 
uptake must be documented in target lesions by SRI before starting re-treatment. 
Patients will be offered to receive initially two Lutathera doses in re-treatment period 
(Section 4.3). Based on the physician judgment of clinical benefit derived from the first 2 
doses, patients may receive up to 2 additional doses of Lutathera (criteria for additional 
doses are listed in Section 3.4). A maximum of 4 doses of Lutathera is allowed during the 
re-treatment period. 
All safety and efficacy assessments in the re-treatment period will be performed as per the 
schedule in initial treatment period (Table 8-2) and will be continued until disease 
progression is documented by investigator. 

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A descriptive analysis will be performed in all patients who received Lutathera re-treatment 
(Section 12.6.4). Safety will be presented in a similar manner to that in Section 12.5.3. All 
efficacy analyses for ORR, DoR, PFS, PFS2, and OS will be descriptive. Definitions for 
ORR, DoR, and PFS (as per local assessment) are the same definitions in Section 12.5.2 
except that the baseline will be based on the tumor assessment which demonstrated 
progression thus allowing re-treatment with Lutathera. Definitions for OS and PFS2 are 
the same to that in Section 12.5.2 and Section 12.6.1, respectively. 
The assessment of Lutathera re-treatment has been added as an exploratory objective in the 
study: To explore the safety and efficacy (ORR, PFS, PFS2, DoR, OS) of re-treatment with 
Lutathera in progressive patients in Lutathera arm. The following exploratory endpoints 
have been added: 
- 
Safety (Re-treatment): Rate of adverse events and laboratory toxicities during re- 
treatment with Lutathera. 
- 
ORR (Re-treatment): Rate of complete and partial responses after receiving re- 
treatment with Lutathera (CR, PR) (locally assessed according to RECIST 1.1). 
- 
PFS (Re-treatment): Time from the 1st dose of re-treatment with Lutathera to objective 
tumor progression (locally assessed according to RECIST 1.1) or to death due to any 
cause. 
- 
PFS2 (Re-treatment): Time from randomization to the objective tumor progression 
(locally assessed according to RECIST 1.1) or to death due to any cause after receiving 
re-treatment with Lutathera. 
- 
DOR (Re-treatment): Time from initially meeting the criteria for response (CR or PR) 
after receiving re-treatment with Lutathera until the time of progression according to 
RECIST 1.1 (locally assessed) or death due to underlying disease only. 
- 
OS (Re-treatment): Time from the randomization date until the day of death due to any 
cause in patients who have received re-treatment with Lutathera. 
 
 
Other Protocol changes 
•  Dose modification rules have been updated, to clarify that toxicities meeting DMT criteria 
which are resolved before the next scheduled dose will not trigger a dose reduction (Section 
6.5.2.1). The dose modification rules in the initial protocol reflected Lutathera label DMT 
guidance. However, patients in NETTER-2 have higher grade tumors (G2 and G3) as 
compared to the patients in the approved label (G1 and G2); therefore, the administration 
of a full dose (200 mCi/7.4 GBq) if a toxicity is resolved, even if this toxicity met DMT 
criteria, is considered to maximize the potential treatment effects. Therefore, in view of the 
higher GEP-NET severity in the NETTER-2 study, and in order to maintain a positive 
benefit/risk ratio, the protocol has been amended in Section 6.5.2.1. There are no changes 
to requirements for dose interruption if a toxicity is not resolved, nor to requirements for 
treatment discontinuation (Section 6.5.2, Section 6.5.3). 

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• Inclusion and exclusion criteria have been modified for clarity and consistency 
o Inclusion criterion 4: amended to include all available SSTR-directed imaging 
agents and modalities to evaluate baseline expression of somatostatin receptors on 
target lesions. The following imaging agents and modalities were added: [99mTc]- 
Tektrotyd, [64Cu]-DOTA-TATE PET/CT; in addition, option of PET/MRI has 
been added to all PET imaging modalities (when applicable based on target 
lesions). 
o Inclusion criterion 5: amended to delete the second part of the sentence “The tumor 
uptake observed in the target lesions must be > normal liver uptake observed on 
planar imaging” (removed as not applicable in all SRI methods). 
o Exclusion criterion 6: amended to specify in exclusion criteria the contraception 
methods and sperm donation recommendation during the study for sexually active 
male patients, separately from requirements for female patients (important details 
were listed in the Appendix 1 but missing in the exclusion criteria). In addition, 
Appendix 1 was updated to align with CTFG guidelines for contraception (v1.1, 
Sep 2020). 
o Exclusion criterion 10: amended to specify in exclusion criteria that only systemic 
therapies for the studied disease (GEP-NET) are excluded (if administered for more 
than 1 month or within 12 weeks prior to randomization). 
o Exclusion criterion 11: amended to specify in exclusion criteria that only previous 
radioembolization, chemoembolization and radiofrequency ablation for the studied 
disease (GEP-NET) are excluded. 
o Exclusion criterion 13: amended to clarify that MRI is acceptable for assessment of 
brain metastasis, in addition to CT. 
o Exclusion criterion 14: amended to clarify that congestive heart failure history can 
be assessed via echocardiography only (gated equilibrium radionuclide 
ventriculography is not required). 
o Exclusion criterion 16: amended as the definition of uncontrolled diabetes (“fasting 
blood glucose > 2 ULN”) was non-standard; the revised definition is “hemoglobin 
A1c > 7.5%” (NICE guideline on Type 2 diabetes in adults: management, 2015). 
o Exclusion criterion 18: amended to delete the second part of Exclusion Criterion 
18, which is irrelevant in this study as the tumor uptake on target lesions must be 
greater than the liver uptake in all patients in this study (typo correction) (as 
described in inclusion criteria 5): “Any patient receiving treatment with short- 
acting octreotide, which cannot be interrupted for 24 h before and 24 h after the 
administration of Lutathera, or any patient receiving treatment with SSAs (eg 
octreotide long-acting), which cannot be interrupted for at least 6 weeks before the 
administration of Lutathera, unless the tumor uptake on target lesions observed by 
study permitted somatostatin receptor imaging (SRI) modalities during continued 
long acting SSA treatment is greater than the liver uptake observed by planar 
imaging.” 
o Exclusion criterion 24: amended to exclude patients with hypersensitivity to the 
IMPs active substance or to any of the excipients. 

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• Included list of possible Octreotide Drug-Drug-Interactions (DDI) in Section 6.2.3, 
according to the Octreotide label. 
• Clarified requirements for contraception (Section 8.5.3 and Appendix 1). 
• Added Section 9.2.1 to clarify that for patients who are eligible to Lutathera re-treatment 
beyond the EoSs window a may receive post-trial access (PTA) to Lutathera. PTA to 
Lutathera may be granted via Post Study Drug Supply (PSDS) programs, based on local 
regulation in a non-trial setting. The PSDS must comply with local laws and regulations in 
the participating trial countries. 
• Added clarifications on safety reporting procedures in Section 10. 
o During the treatment phase, all SAEs and AESI need to be reported to the Sponsor 
irrespective of causality. During the follow-up phase, SAEs and AESI need to be 
reported only if considered related to the study treatment except for all secondary 
hematological malignancies which need to be reported as AESI irrespective of 
causality. 
o  Clarified the 4 categories of AESI (Hematotoxicity; Secondary hematological 
malignancies; Nephrotoxicity; Cardiovascular and electrolyte disorders) (Table 10- 
1), and removed the table with AESI by treatment type, as AESI must be reported 
for both arms. 
o Clarified that serious adverse events (SAEs) must be reported immediately, without 
undue delay and under no circumstances later than 24 hours following knowledge. 
o Clarified that progression of GEP-NET (including fatal outcomes), if documented 
by use of appropriate method, should not be reported as a serious adverse event, 
except if the investigator considers that progression of malignancy is related to 
study treatment. 
 
• Explained methods of providing continuing care to the patients during COVID-19 
pandemic (Sections 8, 8.2, 8.5.1, 8.5.2, 9.1.1, 10.1.1, 10.1.2, 14). 
 
• Updated definition of EoS in Section 9.2: End of Study (EOS) is after 4 years have elapsed 
from the randomization of the last patient, or 6 months after the last dose of crossed over/re- 
treatment patient, which occurs last. 
 
• Section 12 has been updated as follows: 
• Corrected the PFS definition throughout the document to align with currently approved 
Section 12.4.1 that define the PFS as follows: “The primary endpoint of the study is 
progression-free survival (PFS), defined as the time from the date of randomization to 
the date of the first documented progression or death due to any cause.” 
• Added statistical hypothesis information in the protocol synopsis for the data analysis 
sub-section. 
• Updated language for PFS2 endpoint in the Objectives and Endpoints section to 
improve clarity. 

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• Updated definition for DOR throughout protocol as follows (addition in bold/italic): 
“DOR: The Duration of Response (DOR) is defined as the time from initially meeting 
the criteria for response (CR or PR) until the time of progression according to RECIST 
1.1 or to death due to underlying disease only” 
• Updated language at the beginning of Section 12 to further highlight the primary 
objective and the timing of analyses throughout the study. 
• Re-structured Section 12.5 with the following updates: 
o Separated key secondary endpoints into its own sub-section 
o Highlighted that TTD for key secondary endpoints was for EORTC QLQ- 
G.I.NET21 questionnaire, EORTC QLQ-C30 questionnaire: global health 
status (TTD)-diarrhea (TTD)-fatigue, (TTD)-pain (TTD). 
o Moved pharmacokinetics and patient related outcomes section (for PRO 
assessments that are not part of key secondary endpoints) to Section 12.6. 
• Added subsections to Section 12.6 including the addition of the sub-section for re- 
treatment of Lutathera. 
 
• This protocol amendment specifies the procedures required locally only for particular 
countries, based on local requirements (the following procedures have already been 
implemented via local amendments and are included in the global protocol via this 
amendment): 
o Only for Germany and UK: 
 Additional pregnancy tests added in the assessment schedule (Table 8-2) 
o Only for Germany: 
 Added a section outlining that, according to the Octreotide label, ultrasonic 
examination of the gallbladder should be performed before and at six- 
monthly intervals during Octreotide LAR treatment in order to detect and 
prevent possible cholecystitis and biliary duct dilatation risks for the 
patients is recommended (Section 8.5.8). 
 SPECT/CT and whole body planar imaging (local assessment only) added 
to the assessment schedule (Section 8.5.9 and Table 8-2). The assessments 
should be performed after each Lutathera injection, as per local standards. 
The dosimetry results will be collected in eCRF. 
o Only for China: 
 Octreotide PK assessment will not be done in patients enrolled in China 
(Section 8.6). 
 
• Updated Appendix 1 – Precautions for pregnancy to align with CTFG recommendations 
(CTFG 2020). 
 
• Updated Appendix 2 to clarify that the detailed methods of administration of Lutathera and 
amino acids are described in the pharmacy manual. 

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• Updated Appendix 5 – Recommendations for Patients Treated with Lutathera to align with 
latest approved recommendations. 
 
 
A detailed description of each modification is provided in the separate document ‘TABLE OF 
CHANGES’). 
 
 
This amendment is classified as substantial by Sponsor. 
 
 
All protocol changes have been reviewed and approved by the Study Steering Committee. 
 
 
 
IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities (HA). 
This amended protocol requires IRB/IEC/HA approval prior to implementation. 
The Informed Consent has been updated according to the protocol amendment changes. 

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1 
Introduction 
1.1 Background 
Neuroendocrine tumors (NET) are rare malignant neoplasms that can arise throughout the body, 
and account for approximately 1% of all human tumors. NETs have been classified according to 
their embryonic origin as foregut, midgut, or hindgut NETs. The World Health Organization 
(WHO) staging system classifies gastroenteropancreatic NET (GEP-NET) based on primary tumor 
localization, size, mitotic activity, invasiveness, and functional status (Klöppel, 2011). Despite 
certain common morphological and immunohistochemical features, there is significant 
heterogeneity in the prognosis and treatment strategies according to the primary site, histological 
differentiation (poorly or well-differentiated) and stage. Histologic differentiation and proliferative 
activity are the strongest predictors of survival. In terms of site of origin, the majority (50-70%) 
of NETs diagnosed in Western countries are gastrointestinal NETs (Modlin, Lye, & Kidd, 2003). 
Of 270 NETs originating in the midgut or hindgut, 62% (5- year survival rate (YSR), 95.2%) were 
Grade 1, 32% (5-YSR 82.0%) were Grade 2, and 6% (5-YSR, 51.4%) were Grade 3 NETs (Jann, 
et al., 2011). 50-70% of NETs of unknown origin have been reported to be well-differentiated 
(Catena, et al., 2011) and have a similar behavior and prognosis to midgut NETs (Kirshbom, 
Kherani, Onaitis, Feldman, & Tyler, 1998). 
Surgical resection of the primary and metastatic lesions remains the mainstay of treatment, and the 
only way to obtain a cure. However, resection is often not possible as NETs are frequently detected 
in a more advanced tumor stage (Yao, et al., 2008). 
In patients with inoperable NET, the treatment goal is to prolong survival, improve and maintain 
quality of life, to control tumor growth, and to control secretory symptoms (if the tumor is 
functional). Somatostatin analogs (SSAs) octreotide long-acting 30 mg (Sandostatin® LAR®) or 
lanreotide ATG 120 mg (lanreotide ATG, SOMATULINE® DEPOT or SOMATULINE® 
AUTOGEL®) have become the mainstay of treatment in patients with low- or intermediate-grade 
GEP-NET. 
In the PROMID study, 42 patients with metastatic midgut NET who received octreotide long- 
acting 30 mg/month had more than double the time to tumor progression compared with 43 patients 
who received placebo (14.3 versus 6.0 months, respectively; P=0.000072). Overall, 67% of 
patients treated with octreotide long-acting achieved stable disease compared with 37% of patients 
who received placebo (Rinke, et al., 2009). In the CLARINET study, patients with G1-2 midgut 
and pancreatic NET treated with lanreotide 120 mg/month had significant prolongation of 
progression free survival (PFS) when compared to placebo (median PFS not reached vs. 18.0 
months, P<0.001; HR for progression or death with lanreotide vs. placebo, 0.47; 95% CI 0.30 to 
0.73) (Caplin, et al., 2014). 
Where approved, the dose for octreotide long-acting for the treatment of advanced midgut NET is 
30 mg/month. Higher doses of octreotide up to 120 mg per month have been used for symptom 
control in patients no longer responding adequately to standard doses. Higher doses have also been 
used for tumor control though controlled studies are lacking (Broder, Beenhouwer, Strosberg, 
Neary, & Cherepanov, 2015). Three studies have investigated the antiproliferative efficacy of 
high-dose treatment with either octreotide long-acting (up to 160 mg every 2 weeks) or lanreotide 
(up to 15 mg/d), showing disease stabilization in 37-75% of advanced midgut carcinoid and/or 
metastatic GEP-NET patients (Eriksson, Renstrup, Imam, & Oberg, 1997; Faiss, et al., 1999; 
Welin, et al., 2004). 

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Furthermore, retrospective analyses suggest that higher doses of octreotide may delay the time to 
tumor progression / other types of intervention (Lau, Abdel-Rahman, & Cheung, 2018; Chadha, 
et al., 2009). In a small (n=28) sequential study, increased frequency of dosing of somatostatin 
analogs resulted in delayed time to tumor progression and time to biochemical progression 
(Ferolla, et al., 2012). 
In patients whose disease has progressed, mTOR therapy (everolimus), tyrosine kinase inhibitors 
(sunitinib) and peptide radionuclide receptor therapy (PRRT) provide treatment options (Yao, et 
al., 2010; Yao, et al., 2011; Pavel, et al., 2011; Yao, et al., 2016; Kwekkeboom & Krenning, 
Peptide Receptor Radionuclide Therapy in the Treatment of Neuroendocrine Tumors., 2016). 
Currently there is no broadly accepted standard chemotherapy for the treatment of NET. A 
combination of streptozotocin and 5-flourouracil or doxorubicin is frequently used in patients with 
well-differentiated pancreatic NET (PNET), with inoperable progressive liver metastasis, but there 
is no robust evidence to support the use of chemotherapy in patients with NETs of other origin 
(Pavel, et al., 2012). 
Within the group of neuroendocrine neoplasm (NEN) G3, the distinction between NET G3 and 
neuroendocrine carcinomas (NEC) G3 is clinically meaningful. NET G3 and NEC are 
characterized by significant differences in Ki67 index (tumors with a Ki67 index between 20 and 
55% are less aggressive than tumors with a Ki67 index above 55%). While platinum-based 
chemotherapy is effective in NEC, it seems to have limited value in NET G3. Treatments 
established for NET G2 such as temozolomide based chemotherapy or PRRT may be considered 
for the treatment of NET G3 (Rinke 2017). 
Tumor-targeted peptide receptor radionuclide therapy (PRRT) has been under clinical evaluation 
since 1992 for tumors expressing somatostatin receptors. The biological basis for radionuclide 
receptor imaging and receptor targeted radionuclide therapy is the receptor-mediated 
internalization and intracellular retention of radiolabelled somatostatin analogues. Sst2 receptors 
are an attractive target for PRRT because the receptor density is higher on tumor than on non- 
tumor tissue (Reubi, Waser, Schaer, & Laissue, 2001; Reubi J. C., 2003), and because sst2 
receptors internalize into cells after ligand binding. Consequently, the radioactivity delivered by 
the radiolabelled peptide is captured in the target cell after binding to the sst2 receptor (Reubi, et 
al., 2000). 
177Lu-DOTA0-Tyr3-Octreotate (177Lu-Dotatate, Lutathera®) consists of a somatostatin peptide 
analogue, coupled to the metal-ion chelating moiety, DOTA, and radiolabelled with 177Lu. 177Lu- 
DOTA0-Tyr3-Octreotate binds with high-affinity to somatostatin receptors and retains its binding 
properties and physiological functions when complexed with 177Lu. 177Lu emits low to 
intermediate-energy beta-particles with an Emax of 0.5 MeV, and which have a tissue penetration 
range of up to 2 mm. The relatively short penetration range of 177Lu betas leaves more of the 
radiation dose in the tumor with less loss to the surrounding tissues. 
There is rapid urinary clearance of radiolabelled 177Lu-DOTA0-Tyr3-Octreotate from the 
circulation, which gives this radiopharmaceutical a major advantage over other approaches, such 
as cell targeted radiolabelled antibodies. 
Because of 177Lu-DOTA0-Tyr3-Octreotate mechanism of action, there is some radioactivity 
retention in the kidneys, however concomitant administration of the amino acids lysine and 
arginine reduces renal uptake of radioactivity without altering tumor uptake (Kwekkeboom, et al., 
2001; Strosberg, et al., 2017). This phenomenon of protection mediated by co-infusion of a lysine 

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and arginine solution occurs by “blocking” the mechanism for renal tubular uptake of proteins or 
peptides (Hammond, et al., 1993; Rolleman, Valkema, Jong, Kooij, & Krenning, 2003). The co- 
administration of 2.5% lysine and arginine (Lys-Arg) amino acid solution yields about 33% 
inhibition of renal uptake of radioactivity at 24 hours and is better tolerable compared to the 
commercial amino acid solutions, specifically in terms of nausea and vomiting, due to the higher 
osmolality of the more complex formulated commercial AA solutions (Rolleman, Valkema, Jong, 
Kooij, & Krenning, 2003; Kwekkeboom, et al., 2008). 
Common side effects of Lutathera include lymphopenia, increased GGT, AST and/or ALT, 
vomiting, nausea, hyperglycemia and hypokalemia. Serious side effects of Lutathera include 
myelosuppression, secondary myelodysplastic syndrome and leukemia, renal toxicity, 
hepatotoxicity, neuroendocrine hormonal crises and infertility. 
Lutathera (lutetium (177Lu) oxodotreotide) was approved in Europe on September 26, 2017 for the 
treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2) GEP-NETs 
and in the USA on 26 January 2018 for the treatment of somatostatin receptor positive GEP-NETs. 
The approval of Lutathera was supported by two studies: 
­ The first was the Phase III NETTER-1 study sponsored by Advanced Accelerator Applications. 
This was multicenter, stratified, open, randomized, comparator-controlled, parallel-group 
study, comparing treatment with 177Lu-DOTA0-Tyr3-Octreotate (Lutathera, lutetium Lu 177 
dotatate) 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 
(Strosberg, et al., 2017; Strosberg, et al., 2018). A significant improvement in PFS, the primary 
endpoint, was demonstrated. There were 21 confirmed events (disease progressions according 
to RECIST 1.1 centrally assessed or deaths without confirmed progression) in the Lutathera 
arm and 70 events in the octreotide long-acting 60 mg arm. The median PFS for the control 
arm was 8.5 months while the median PFS for the Lutathera arm had not yet been reached. 
The improvement in median PFS in the Lutathera arm was statistically significant with a 
hazard ratio of 0.18 (95% CI, 0.11 - 0.29), demonstrating a risk reduction of 79% in the 
likelihood of having a progression or death event when treated with Lutathera versus 60mg 
octreotide long-acting. 
­ The second study was based on data from 1,214 patients with somatostatin receptor-positive 
tumors, including GEP-NETS, who received Lutathera at the Erasmus Medical Centre in the 
Netherlands (Kwekkeboom, et al., 2008; Brabander, et al., Long-Term Efficacy, Survival, and 
Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and 
Bronchial Neuroendocrine Tumors., 2017a). Complete or partial tumor remission was reported 
in 39% of patients. 
On June 02, 2016 and 15 December, 2016 Advanced Accelerator Applications obtained marketing 
approval from the FDA for NETSPOT™ (68Ga-Dotatate) and from the European Commission for 
Somakit-TOC™ (68Ga-Dotatoc), the diagnostic companions of Lutathera. 
Neuroendocrine tumors (NET) are rarely seen in childhood. The incidence in children and 
adolescents is low at 2.8 per million persons under the age of 30 years. Despite their low incidence, 
NETs represent the most frequent tumor of the gastrointestinal tract in children (Howell & 
O'Dorisio, 2012). Currently all treatments approved for GEP-NETs are for adults only. 

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1.2 Purpose 
The pivotal Phase III NETTER-1 study showed that Lutathera with best supportive care (30mg 
octreotide long-acting) provided a significant increase in PFS to patients with progressive midgut 
carcinoid tumors (at enrollment) compared to patients treated with high dose (60 mg) octreotide 
long-acting. The NETTER-1 patient population included 34.5% of patients with G2 NET (65.5% 
G1), while G3 NETs were excluded. Only patients progressive on SSAs were eligible (2nd line), 
SSA-naïve patients were excluded. 
The aim of the NETTER-2 study is to determine if Lutathera in combination with octreotide long- 
acting prolongs PFS in GEP-NET patients with high proliferation rate tumors (G2 and G3), when 
given as a 1st line treatment in comparison to treatment with high dose (60 mg) octreotide long- 
acting. SSA-naïve patients are eligible, as well as patients previously treated with SSAs in the 
absence of progression. Based on extensive experience with Lutathera as well as octreotide LAR 
in adult GEP-NET patients, and the relevance of the molecular target in adolescent GEP-NET 
patients, the study will be open to adolescents aged ≥ 15 years and >40 kg body weight (BW); 
younger patients are not expected to present with the disease meeting the severity criteria for this 
trial. Due to the rarity of the disease, and specifically GEP-NETs with the severity assessed in this 
study, no minimum number of adolescent patients is required. The study has been open to 
adolescents to ensure that access is not unnecessarily denied. 
In addition, in the NETTER-2 study, any progressive patient in the high dose octreotide long acting 
arm has the option, if eligible, to enroll for post-progression cross-over with Lutathera. 
Furthermore, patients who experience disease progression in the Lutathera arm after having 
received and benefitted from 4 doses/cycles in an initial treatment have the option, if eligible 
according to criteria described in Section 5.2.2, to enroll for re-treatment phase with Lutathera. 
The purpose of the NETTER-2 study is to evaluate the efficacy and safety of Lutathera in patients 
≥15 years of age with Grade 2 and 3 advanced GEP-NET (Ki67 index of ≥ 10 and ≤ 55%), 
considered being a candidate for treatment with high dose octreotide long-acting. 

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2 
Objectives and endpoints 
 
The study primary, secondary, explorative objectives and endpoints are described in Table 2-1. 
 
Table 2-1. Study objectives and endpoints 
 
Primary Objective 
Endpoint for primary objective 
To demonstrate that Lutathera is superior 
to active comparator in delaying the time- 
to-first occurrence of progression or death 
(PFS) as first line treatment 
PFS: Time from randomization to the first line 
progression (centrally assessed according to 
RECIST 1.1) or death due to any cause. 
Key Secondary Objectives 
Endpoints for key secondary objectives 
-To demonstrate the superiority of 
Lutathera, compared to active comparator, 
in terms of objective response 
-ORR: Rate of patients with best overall 
response of partial response (PR) or complete 
response (CR) (centrally assessed according to 
RECIST 1.1) 
-To demonstrate the superiority of 
Lutathera, compared to active comparator, 
in terms of time to deterioration in selected 
QoL items/scales 
-Time to decline (TTD) by 10 points from 
baseline in the following scores measured by 
the EORTC QLQ-G.I.NET21 questionnaire and 
EORTC QLQ-C30 questionnaire: global health 
status, diarrhea, fatigue, and pain. 
Other Secondary Objectives 
Endpoints for other secondary objectives 
-To evaluate the efficacy of Lutathera, 
compared to active comparator, in keeping 
the disease under control 
-DCR: Rate of patients with best overall 
response of partial response (PR), complete 
response (CR) or stable disease (SD) (centrally 
assessed according to RECIST 1.1) 
-To evaluate the efficacy of Lutathera, 
compared to active comparator, in terms of 
duration of response 
-DOR: The Duration of Response (DOR) is 
defined as the time from initially meeting the 
criteria for response (CR or PR) until the time 
of progression according to RECIST 1.1 or 
death due to underlying disease only. 
-To evaluate the safety and tolerability of 
Lutathera 
-Safety: Rate of adverse events and laboratory 
toxicities (scored according to CTCAE grade). 
-To evaluate the effect of Lutathera on 
overall survival 
-OS: Time from the randomization date until 
the day of death due to any cause. 
Exploratory Objectives 
Endpoints for exploratory objectives 
-To explore the effect of Lutathera on Time 
to Second Progression (PFS2) 
-PFS2: Time from randomization to objective 
tumor progression on next line treatment or 

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death due to any cause (PFS2), assessed locally 
according to RECIST 1.1. 
-To explore Health related quality of life 
(QoL) as measured by the EORTC QLQ- 
G.I.NET21, EORTC QLQ-C30, EQ-5D-5L 
questionnaires 
-TTD for Items/Scales not included among key 
secondary endpoints. Change from baseline in 
the total score for health status from the EQ-5D 
questionnaire. 
-To explore PK of octreotide long-acting at 
the high dose of 60 mg 
-Steady-state trough plasma concentration of 
octreotide. 
-To explore the safety and efficacy (ORR, 
PFS, PFS2, DoR, OS) of re-treatment with 
Lutathera in progressive patients in 
Lutathera arm 
- Safety (Re-treatment): Rate of adverse events 
and laboratory toxicities during re-treatment 
with Lutathera. 
- ORR (Re-treatment): Rate of patients with 
best overall response of partial response (PR) or 
complete response (CR) after receiving re- 
treatment with Lutathera (locally assessed 
according to RECIST 1.1). 
- PFS (Re-treatment): Time from the 1st dose of 
re-treatment with Lutathera to objective tumor 
progression (locally assessed according to 
RECIST 1.1) or to death due to any cause. 
- PFS2 (Re-treatment): Time from 
randomization to the objective tumor 
progression (locally assessed according to 
RECIST 1.1) or to death due to any cause after 
receiving re-treatment with Lutathera. 
- DOR (Re-treatment): Time from initially 
meeting the criteria for response (CR or PR) 
after receiving re-treatment with Lutathera until 
the time of progression according to RECIST 
1.1 (locally assessed) or death due to 
underlying disease only. 
- OS (Re-treatment): Time from the 
randomization date until the day of death due to 
any cause in patients who have received re- 
treatment with Lutathera. 

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The primary endpoint of the study is PFS centrally assessed (target HR=0.5; 90% power, 1-sided 
α=2.5%). The primary analysis will be performed after 99 PFS events (99 evaluable and centrally 
confirmed disease progressions or death events) have occurred. 
 
The study consists of a Screening Phase, a Treatment Phase, an optional Treatment Extension 
Phase (cross-over) / an optional Re-treatment Phase and a Follow up Phase. 
 
3.1 Screening Phase 
The screening phase should be shortened as much as possible, in order to treat the patients possibly 
within 2 weeks after the consent signature. 
The randomization should be performed as soon as possible, after all eligibility criteria are verified. 
Patients under octreotide long-acting before study entry should have their last dose carefully 
programmed during the screening phase (in case of randomization in the Lutathera arm a washout 
period of 6 weeks from octreotide long-acting must be observed prior to Lutathera injection). 
As Lutathera production and shipment will take circa 12 days to be arranged, if a patient is 
randomized in the Lutathera arm, Lutathera first dose should be ordered within 24h after 
randomization. 
The baseline CT/MRI scan should be taken possibly on the same day as randomization or 
immediately before (within 1 week) to ensure that it reflects the disease status closely before the 
therapy start. 
 
3.2 Treatment Phase 
During the Treatment Phase, patients will be followed according to the assessments schedule in 
Table 8-3, and Table 8-4. Objective tumor response will be assessed at W16±1, W24±1 and then 
every 12±1 weeks from the randomization date, according to RECIST 1.1 criteria (central + local 
assessment up to first progression, then only local assessment). 
Duration of the Treatment Phase: 
• 
Before the PFS primary analysis: 
The Treatment Phase is not fixed and the patients who are randomized should continue to 
receive the study treatments until progression or death (patients randomized in the Lutathera 
arm, will continue octreotide long-acting 30 mg injections after the completion of the 4 
Lutathera treatments until progression or death; patients randomized in the octreotide long- 
acting arm will continue octreotide long-acting 60 mg injections until progression or death). 
• 
After the PFS primary analysis: 
The Treatment Phase becomes fixed and will stop at week 72 (patients randomized in the 
Lutathera arm, will continue octreotide long-acting 30 mg injections after the completion of 
the 4 Lutathera treatments until week 72 or earlier in case of progression or death; patients 
randomized in the octreotide long-acting arm will continue octreotide long-acting 60 mg 
injections until week 72 or earlier in case of progression or death). 

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In other words, before the PFS primary analysis (i.e. 99 evaluable and centrally confirmed disease 
progressions or death events), patients continue the Treatment Phase until progression; after the 
PFS primary analysis, the Treatment Phase duration is limited to 72 weeks. 
 
At any time during the study (before or after the PFS primary analysis) any progressive patient 
(based on central imaging assessment) immediately ceases the Treatment Phase and proceeds to 
the Follow-up Phase (Table 8-3 and Table 8-4). If a patient discontinues Lutathera before centrally 
confirmed disease progression, the patient should be followed with tumor assessments as per initial 
CT/MRI schedule until centrally confirmed disease progression. 
 
In addition, patients randomized in the control arm have the option, if eligible, to enroll for post- 
progression cross-over with Lutathera, see Table 8-4). Control arm patients who cross-over after 
progression will be allowed to complete the Lutathera treatments after week 72 or to cross-over 
during the Follow-up Phase, in case of late progression. Furthermore, patients who experience 
disease progression in the Lutathera arm have the option, if eligible, to enroll for re-treatment 
phase with Lutathera, see Table 8-3. 
Patients included in the optional crossover or re-treatment phase will be followed up at least 6 
months and up to 3 years (or until EoS, whatever comes first). 
 
3.3 Optional Treatment Extension Phase (cross-over) 
In the control arm, any RECIST progressive patient (based on central assessment) has the option 
to enroll for post-progression cross-over, upon signature of a new consent, to receive maximum 4 
cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles; cumulative dose: 29.6 GBq / 800mCi) plus 30 
mg octreotide long acting every 8 weeks. 
If RECIST progression occurs after Week 72 post the primary end point analysis, the decision to 
enroll the patient in cross-over will be based on local assessment. 
The cross-over phase will last until the completion of four Lutathera administrations after which 
patients will undergo EOT visit (at Week 28), and proceed to the follow up phase. 
After cross-over phase is complete, patients will be followed up for 3 years or until EoS, whichever 
occurs first (and at least 6 months after the last Lutathera dose administered during cross-over). 
The time window to start cross-over treatment with Lutathera in this study is 4 years after last 
patient randomized. 
 
3.4 Optional Re-Treatment Phase 
In the Lutathera arm, patients with radiological progression based on RECIST criteria as per 
central assessment have the option to enroll for post-progression re-treatment, upon signature of a 
new informed consent, to receive 2 to 4 additional cycles of 7.4 GBq/200 mCi of Lutathera. If 
RECIST progression occurs after Week 72 post the primary end point analysis, the decision to 
enroll the patient in re-treatment will be based on local assessment. 
Patients who have received Lutathera in Optional Treatment Extension Phase (cross-over) are not 
eligible for re-treatment with Lutathera. 
For enrolment in the optional re-treatment phase, patients must undergo SSTR imaging and meet 
all requirements listed in Section 5.2.2. 

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After enrolment into re-treatment phase, patients will initially receive 2 administrations of 
Lutathera 7.4 GBq/200 mCi at 8-week interval. After that, the Investigator should determine if: 
• The patient shows evidence of disease stabilization or response (i.e. absence of radiological 
progression, or assessed by clinical benefit). 
• Has shown good tolerance to Lutathera re-treatment. 
If the investigator considers this treatment option in the best interest of the participant and if the 
participant meets these criteria and agrees to continue with further treatment with Lutathera, the 
Investigator may administer up to 2 additional administrations of Lutathera 7.4 GBq/200 mCi at 
8-week interval. A maximum of 4 administrations of Lutathera is allowed during the re-treatment 
period. 
All safety and efficacy assessments in the re-treatment period will be performed locally and 
following the schedule in initial treatment period (expression of somatostatin receptors on all target 
lesions will be evaluated locally before re-treatment; there is no central ‘real time’ assessment of 
the SRI images, however the images should be submitted to the central imaging center possibly 
within 1 month for a second review). 
During the re-treatment phase, the administration of SSAs is at investigator’s discretion. 
The re-treatment phase will last until locally confirmed disease progression or until EoS, 
whichever occurs first. If a patient discontinues Lutathera before locally confirmed disease 
progression in re-treatment, the patient should be followed with tumor assessments as per initial 
CT/MRI schedule until locally confirmed disease progression. After re-treatment phase is 
complete, patients will be followed up for 3 years or until EoS, whichever occurs first (and at least 
6 months after the last re-treatment dose in the study). 
The time window to start re-treatment in this study is within 4 years after the last patient 
randomized. 
For patients in Lutathera arm who are eligible for re-treatment beyond this window, Lutathera 
access for re-treatment may be granted via Post Study Drug Supply (PSDS) programs, based on 
local regulation (see Section 9.2.1). 
 
 
3.5 Follow up Phase 
At the end of the Treatment Phase (or the optional Treatment Extension Phase in case of cross- 
over, or the optional Re-treatment Phase) or after discontinuation for any cause (including disease 
progression), all patients will continue to be followed up at least every 6 months and up to 3 years 
(or until EoS, whatever comes first) to continue data collection for the secondary endpoints of the 
study, such as long term safety and overall survival. 
During the Follow-up Phase, SAEs and adverse events of special interest (AESI) other than 
secondary hematological malignancies, related to the study treatment and AESI of secondary 
hematological malignancies irrespective of causality, will be reported. Anti-tumor treatments 
administered after progression/discontinuation, disease status based on local CT/MRI assessment, 
and OS data will be collected every 6 months (± 1 month) in both arms (see schedule of 
assessments in Table 8-3, and Table 8-4). 

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4 
Rationale 
4.1 Rationale for study design 
This study is justified by the markedly longer PFS and significantly higher response rate in 2nd line 
G1 and G2 midgut NETs demonstrated in the Lutathera arm of the Phase III NETTER-1 pivotal 
study (Strosberg, et al., 2017). 
The WHO 2010 classification distinguishes G3 NETs (usually ≤55% Ki67) from G3 NECs 
(usually > 55%), recognizing the NET-specific features of G3-NETs (continuum between G2 and 
G3 NET) (Rindi 2010, Rindi 2014). 
While the Erasmus MC Phase I-II study and the NETTER-1 studies have proven the safety and 
efficacy of Lutathera in well differentiated Grade 1 and 2 GEP-NETs (Kwekkeboom, et al., 2008; 
Strosberg, et al., 2017), Grade 3 GEP-NETs still represent high unmet medical need for several 
reasons: 
­ Historically, most studies have excluded G3 NET (~20% of all NETs); 
­ The number of patients diagnosed at G3 NET stage continues to increase (Dasari, et al., 
2017); 
­ There is no universally accepted standard of care for the treatments of G3 NETs. ESMO 
(Oberg, Knigge, Kwekkeboom, Perren, & Group, 2012), ENET (Perren, et al., 2017), 
NANETS (Kunz, et al., 2013) and NET NCCN (Kulke, et al., 2015) guidelines outline 
chemotherapy as primary treatment; however physicians’ practice may vary (SSA and/or 
chemotherapy used in 1st and 2nd line). 
­ Based on experts’ considerations and from the NORDIC NEC study, a Ki-67 cutoff 
between 50% and 60% has been proposed as the minimum level that should be considered 
to use platinum-based chemotherapy. Therefore, it appears reasonable to manage well- 
differentiated G 3 and G 2 NET patients similarly (Vélayoudom-Céphise, et al., 2013; 
Heetfeld, et al., 2015). In addition, prognosis and response rate of well-differentiated G3 
NET seem to be close to well differentiated G 1/2 NET with a worse overall survival 
(Coriat, Walter, Terris, Couvelard, & Ruszniewski, 2016). 
- Efficacy of current 1st line treatments appear to be modest with low ORR with limited 
evidence of PFS/OS benefit (Coriat, Walter, Terris, Couvelard, & Ruszniewski, 2016). In 
addition, in non-pancreatic NET G-3, no chemotherapy regimen should be considered as a 
standard of first-line care, considering the very small amount of data available. 
Therefore, in the current NETTER-2 study an advanced GEP-NET patient population of G2 with 
Ki67 ≥ 10% and G3 with Ki67 ≤ 55% has been included to evaluate a potential new treatment 
option for these patients. 
In accordance with the recently finalized guidance for industry on considerations for the inclusion 
of adolescent patients in adult oncology clinical trials and the consensus expert opinion presented 
by the European multi-stakeholder platform ACCELERATE to include adolescents in adult 
oncology clinical trials when the histology and biologic behavior of the cancer under investigation 
is the same in, or the molecular target of the drug is relevant to, cancers in both adult and adolescent 
patients (FDA guidance), this study will include adolescents ≥15 years and >40 kg BW. Even 
though the number of adolescents ≥15 years fulfilling the inclusion criteria for this study is very 
small, the high unmet medical need in this population is justifying their enrollment. It is not 

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expected that adolescents below the age of 15 years will present with the disease meeting the 
inclusion criteria for this study. 
Due to the radioactive nature of Lutathera and its method of infusion, and similarly to the 
NETTER-1 trial design, it is not possible to implement a fully double-blinded design for this study, 
however a central, blinded, real-time IRC (Independent Review Committee) assessment is 
implemented to ensure an independent evaluation of the tumor response according to RECIST 1.1 
criteria. 
Randomization will be stratified by Grade (G2 vs G3) and tumor origin (pNET vs other origin), 
preventing imbalance between treatment groups for known factors that influence prognosis. 
For this trial a 2:1 randomization design is chosen to allow patients to have a higher chance of 
getting the treatment which is anticipated to be more effective. For the same reason and to 
minimize the possible higher drop-out rate in the control arm, patients will be offered to cross- 
over to Lutathera after centrally confirmed RECIST progression (or locally confirmed if it occurs 
after Week 72 post the primary end point analysis). 
Patients randomized in the Lutathera arm will also be offered optional re-treatment with additional 
2-4 Lutathera doses/cycles after centrally confirmed RECIST progression (or locally confirmed if 
it occurs after Week 72 post the primary end point analysis), based on the physician judgment of 
potential clinical benefit. Overall, therapeutic options in patients who progress after PRRT 
treatment are limited. Based on a meta-analysis (Strosberg et al., 2021) including patients with 
progressive GEP-NETs (n=560) who received re-treatment with Lutathera (one to six doses during 
re-treatment, majority of patients received 200 mCi per administration), the clinical benefit of re- 
treatment was supported by a median PFS of 12.52 months (available in 414 patients), median OS 
of 26.78 months from the start of re-treatment (available in 194 patients), and DCR of 71% 
(available in 347 patients). The safety profile of Lutathera re-treatment was similar to initial 
treatment. These data indicate that re-treatment with Lutathera may be considered as a treatment 
approach to maximize benefit without compromising on safety and with a careful assessment of 
clinical status of each individual patient. 
 
 
4.2 Rationale for dose/regimen and duration of treatment 
The Lutathera arm dose/regimen of the NETTER-2 study is identical to the established regimen 
used in the Erasmus MC Phase I/II study (Kwekkeboom, et al., 2008) and in the Phase III 
NETTER-1 pivotal study (Strosberg, et al., 2017) with Lutathera cumulative dose of 29.6 GBq 
(800 mCi), divided into 4 administrations every 8±1 weeks, plus octreotide long-acting (30 mg) 
every 4 weeks. 
Lutathera was approved in Europe for the treatment of unresectable or metastatic, progressive, 
well differentiated (G1 and G2) GEP-NETs and in the USA for the treatment of somatostatin 
receptor positive GEP-NETs based on the results of the pivotal Phase III NETTER-1 study and 
data from 1,214 patients with somatostatin receptor-positive tumors, including GEP-NETS, who 
received Lutathera at the Erasmus Medical Centre in the Netherlands. 
Treatment with Lutathera resulted in markedly longer progression-free survival and a significantly 
higher response rate than high-dose octreotide long-acting among patients with advanced midgut 
neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim 

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analysis; confirmation will be required in the planned final analysis. Clinically significant 
myelosuppression occurred in less than 10% of patients in the Lutathera group. The PFS- 
prolongation was similar in the two Ki67 strata (≤2% and 3-20%) suggesting a potential benefit 
for patients with advanced G2 and 3 GEP-NET to be included in the NETTER-2 study. 
Optional re-treatment with additional doses of Lutathera will be offered to patients treated in the 
Lutathera arm upon disease progression, based on recent published data on re-treatment in GEP- 
NETs (Strosberg et al., 2021). The candidate patients for re-treatment with Lutathera in this 
protocol, are patients with centrally documented tumor progression in Lutathera arm, who have 
completed the 4 doses/cycles of Lutathera during the treatment phase, had CR/PR/SD as best 
response for at least 6 months (-2 weeks window is allowed) after the 4th Lutathera dose, and had 
tolerated the treatment (according to criteria defined in Section 5.2.2). Patients will be offered to 
receive initially two Lutathera doses in re-treatment period (Section 4.3). Based on the physician 
judgment of clinical benefit derived from the first 2 doses, patients may receive up to 2 additional 
doses of Lutathera (criteria for additional doses are listed in Section 4.3). A maximum of 4 doses 
of Lutathera is allowed during the re-treatment period. The dose level assessed in the re-treatment 
portion of this study will be the same as the approved level of 7.4 GBq per cycle, based on the 
published meta-analysis data that showed that majority of patients received this dose (Strosberg et 
al., 2021). 
 
 
4.3 Rationale for choice of control drug 
The control arm dose/regimen of the NETTER-2 study is identical to the dose/regimen used in the 
NETTER-1 study (octreotide long-acting (60 mg) every 4 weeks). 
The clinical experience with octreotide is extensive, but there is currently a lack of data in the use 
of somatostatin analogues in G3 GEP-NET patients. 
Patients in the comparator arm of the present NETTER-2 study will receive 60 mg octreotide long- 
acting at 4-weeks intervals. The dose is supported by findings of Broder et al. (2015), who 
performed a systematic review of the literature to analyze the anti-proliferative benefit of 
somatostatin analogs. They confirmed that doses of >30 mg octreotide long-acting are commonly 
used by clinical experts for symptom and tumor progression control in NET patients. This dose 
(60 mg) was also tested in comparator arm of the pivotal Phase III NETTER-1 study (Strosberg, 
et al., 2017). In current clinical practice, it is likely that even a higher percentage of patients receive 
>30 mg of Octreotide LAR (Anthony & Vinik, 2011; Joseph, et al., 2010; Wolin, 2012; Broder, 
Beenhouwer, Strosberg, Neary, & Cherepanov, 2015). The 4-week interval injections of 60 mg 
octreotide long-acting is a higher dose than the 4-week interval injections with 20 mg or 30 mg, 
which is presently the registered dose for Sandostatin® LAR Depot. With this treatment, the 
majority of symptomatic patients show an improvement in QoL, and most patients obtain 
temporary stable disease based on CT scans (Faiss, et al., 1999; Faiss, et al., 2003; Rinke, et al., 
2009; Ludlam & Anthony, 2011; Anthony & Vinik, 2011; Wolin, 2012; Broder, Beenhouwer, 
Strosberg, Neary, & Cherepanov, 2015). 
Furthermore, according to the Phase III NETTER-1 study results, patients with metastatic midgut 
tumors progressive after standard dose (30 mg) SSAs treated in the control arm of the study with 
high dose (60 mg) octreotide long-acting had a median time free from relapse of 8.4 months 

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(Strosberg, et al., 2017) without notable side effects, confirming that this regimen has anti-tumor 
benefit and is well tolerated. 
In a clinical study published by Astruc et al. (Astruc, et al., 2005), in which healthy subjects were 
treated with 20 mg and 60 mg of Octreotide LAR, the PK data showed that the plasma exposure 
was dose-proportional and the treatment was well tolerated at both doses. 
Available pharmacokinetic (PK) data in children at 40 mg Octreotide LAR show that the plasma 
exposure, corrected for the dose, is similar in adults and young patients. Moreover, Octreotide 
LAR was well tolerated in children at 40 mg. It should be noted that the same dose was given to 
<12 and >12 years old patients. 
Therefore, in accordance with available PK data and in line with FDA guidance for inclusion of 
adolescents in the adult oncology trials and the consensus expert opinion presented by the 
European multi-stakeholder platform ACCELERATE it is considered acceptable to include 
adolescents in the NETTER-2 study at the same fixed dose administered in adults, considering a 
population ≥ 15 y and > 40 kg. 
Based on currently available data of high dose somatostatin analogues, the use as a comparator in 
this study, at 60 mg dosage, is justified considering the high unmet medical need in a population 
not candidate for chemo or targeted therapy in the investigator opinion. 
 
4.4 Purpose and timing of interim analyses 
At the time of the PFS primary analysis, an estimate of overall survival will be calculated in terms 
of hazard ratio (point estimate) and 95% confidence interval. 
 
4.5 Risks and benefits 
Neuroendocrine tumors (NETs) represent a small proportion of cancers but are increasing in 
incidence due to incidental diagnosis. Prognosis for grade 1 and localized NETs has steadily 
improved, however patients with distant and/or grade 3 NETs continue to fare poorly (Sackstein, 
O'Neil, Neugut, Chabot, & Fojo, 2018). 
Patient management poses a significant challenge because of the heterogeneous clinical 
presentations and varying degrees of aggressiveness. 
Randomization will be stratified by tumor origin (pNET vs other origin) and Grade (G2 vs G3), 
preventing imbalance between treatment groups for known factors that influence prognosis. 
The population of G2 and G3 GEP-NET patients included in the NETTER-2 study is not candidate 
for chemo or targeted therapy in the investigator opinion. G3 GEP-NET patients with Ki67 ≤ 55 
are a category of G3 neuroendocrine neoplasm (NEN) where tumors retain their well-differentiated 
characteristics, continue to express somatostatin receptors, but have a higher proliferation rate then 
the majority of GEP-NETs (Rindi, et al., 2018). Aggressive G2 GEP-NETs patients with Ki67 
range 10% to 20% share with G3 GEP-NETs the greater likelihood of poor prognosis, and limited 
treatment options. Despite advances in medical therapy for these tumors, there is still a high unmet 
medical need to control tumor growth, especially for G3 GEP-NETs (~10-20% of all NETs), which 
historically have been excluded from most studies (Sorbye, et al., 2019; Coriat, Walter, Terris, 
Couvelard, & Ruszniewski, 2016; Dasari, et al., 2017). 
The most important risk mitigating factor for GEP-NET patients who are considered for treatment 
with Lutathera, is the ability to use receptor scintigraphy imaging to select those patients who are 

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most likely to respond to PRRT, and to exclude patients who would not benefit from the treatment 
because their tumors do not express high enough levels of the somatostatin receptor. 
Based on the results achieved in other PRRT studies using 177Lu-dotatate (Strosberg 2017; 2018 
Brabander 2016), the major expected benefits to patients treated with Lutathera include the high 
probability of extending progression free survival, increasing overall survival and increasing time 
to deterioration of quality of life. 
For this trial a 2:1 randomization design is chosen to allow patients to have a higher chance of 
getting the treatment which is anticipated to be more effective. For the same reason and to 
minimize the possible higher drop-out rate in the control arm, patients will be offered to cross- 
over to Lutathera after centrally confirmed RECIST progression (or locally confirmed if it occurs 
after Week 72 post the primary end point analysis). 
The highest risks arising from treatment with Lutathera are radiation toxicities affecting either 
bone marrow or kidney function (Bergsma, et al., 2016a; Bergsma, et al., 2016b). 
Kidney function risks are largely eliminated by the co-infusion of 2.5% Lys-Arg solutions during 
administration of Lutathera, which reduces the radiation dose to the kidney by approximately 45% 
(Rolleman, Valkema, Jong, Kooij, & Krenning, 2003). In the NETTER-1 trial no evidence of renal 
toxicities occurred within the period of observation (Strosberg, et al., 2017). 
Bone marrow toxicity may occur in two forms: 1) acute toxicity that occurs after administration 
of Lutathera, during the treatment period; and 2) delayed toxicity that occurs in 1.5 to 2% of 
patients. The potential observed effects of short-term bone marrow toxicity are anemia, 
thrombocytopenia, and neutropenia which are usually mild and transient. In the NETTER-1 trial, 
grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9% of 
patients (Strosberg, et al., 2017). Where hematological toxicity occurs, a trend towards 
stabilization followed by improvement in patients with longer follow-up is observed. It is 
important to note that the lymphocyte toxicity observed following PRRT is not a major concern 
regarding risk of infections, since only B lymphocytes are affected, a subtype which is not directly 
involved in infection defense (Sierra, et al., 2009). 
There is evidence that males may be at risk of decreased spermatogenesis following PRRT with 
177Lu-dotatate. In a study by (Teunissen, et al., 2009), a significant decrease of mean serum inhibin 
B levels was observed in male patients (N=35) treated with 177Lu-dotatate. It has been 
demonstrated that serum inhibin B levels are positively correlated with spermatogenic status and 
sperm count (Pierik, Vreeburg, Stijnen, De Jong, & Weber, 1998). The study (Teunissen, et al., 
2009) also found recovery to almost pretreatment levels after 24 months. The potential long-term 
genetic damage to spermatogenic cells has not been studied. 
Women and men should not procreate until six months after the end of their last treatment with 
Lutathera. However, due to additional exposure from CT scans taken during the study, women in 
both arms should also not procreate during the whole treatment period of the study. Women of 
child bearing potential and sexually active males must be informed that taking the study treatment 
may involve unknown risks 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 and in Appendix 1. If there is any question that the subject will not reliably 
comply, they should not be entered or continue in the study. 

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Based on the FDA guidance for inclusion of adolescents in the adult oncology trials and the 
consensus expert opinion presented by the European multi-stakeholder platform ACCELERATE 
it is recommended that adolescents can receive the same dose administered in adults if there is no 
relevant effect of body size on pharmacokinetics, which is the case for both, Lutathera and 
octreotide long-acting. Based on the similar clinical presentation of the disease under evaluation 
in adolescents, the following inclusion criteria have been chosen for this study: ≥15 years old and 
>40 kg BW (aligned with the BW recommendation from the FDA guidance). 
With regards to re-treatment with Lutathera, the results of a meta-analysis of patients with 
progressive GEP-NETs who received re-treatment with peptide receptor radionuclide therapy 
(PRRT), are supportive of administration of additional Lutathera doses after progression on initial 
treatment. It was shown that the safety profile of Lutathera re-treatment was similar to initial 
treatment (Strosberg et al., 2021). In this meta-analysis, additional treatment courses with 
Lutathera ranged from one to six doses, and majority of patients received 200 mCi per 
administration. Hematologic grade 3/4 AEs were reported in 9% of patients who received PRRT 
re-treatment. Notably, AML and MDS occurred in <1% of patients who received re-treatment with 
Lutathera, comparable to the incidence observed with initial PRRT. Re-treatment with Lutathera 
provided encouraging median PFS. This data indicates that re-treatment with Lutathera can be 
offered to patients to maximize benefit without compromising on safety and with a careful 
assessment of clinical status of each individual patient. 
Dose modifying toxicity rules have been implemented in this study taking into account the higher 
GEP-NET severity in the NETTER-2 study compared to the approved indication. The 
administration of a full Lutathera dose (200 mCi/7.4 GBq) if a toxicity is resolved will maximize 
the potential treatment effects and maintain a positive benefit/risk ratio. 
To ensure the safety of the subjects in this trial, appropriate eligibility criteria and study 
procedures, as well as close clinical monitoring, following dose modifying toxicity rules, and 
Steering Committee study oversight are included in this protocol. 
In light of all the above-mentioned elements, the benefit-risk balance of Lutathera within the 
overall clinical context defined in the clinical trial appears to weight in favor of patient’s benefit. 
 
4.6 
Rationale for public health emergency mitigation procedures 
In the event of a public health emergency as declared by local or regional authorities (i.e. 
pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure 
participant safety and trial integrity and are listed in relevant sections of the study protocol. 
Notification of the public health emergency should be discussed with Sponsor prior to 
implementation of mitigation procedures and permitted/approved by local or regional health 
authorities and ethics committees as appropriate. 

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5 
Population 
In this study, safety and efficacy of treatment with Lutathera plus octreotide long-acting (30 mg) 
versus high dose octreotide long-acting (60 mg) is evaluated in patients ≥15 years old with 
somatostatin receptor positive, well differentiated G2 (Ki67 index ≥10%) and G3 (Ki67 ≤ 55%) 
advanced GEP-NETs. Patients with documented RECIST progression to previous treatments for 
the current GEP-NET at any time prior to randomization are not eligible to participate in this study. 
 
 
5.1 Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Presence of metastasized or locally advanced, inoperable (curative intent) histologically 
proven, well differentiated Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine (GEP- 
NET) tumor diagnosed within 6 months prior to screening. 
2. Ki67 index ≥10 and ≤ 55%. 
3. Patients ≥15 years of age and a body weight of >40 kg at screening. 
4. Expression of somatostatin receptors on all target lesions documented by CT/MRI scans, 
assessed by any of the following somatostatin receptor imaging (SRI) modalities within 3 
months prior to randomization: [68Ga]-DOTA-TOC (e.g. Somakit-TOC®) PET/CT (or MRI 
when applicable based on target lesions) imaging, [68Ga]-DOTA-TATE PET/CT (or MRI 
when applicable based on target lesions) imaging (e.g. NETSPOT®), Somatostatin Receptor 
scintigraphy (SRS) with [111In]-pentetreotide (Octreoscan® SPECT/CT), SRS with [99mTc]- 
Tektrotyd, [64Cu]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) 
imaging. 
5. The tumor uptake observed in the target lesions must be > normal liver uptake. 
6. Karnofsky Performance Score (KPS) ≥60. 
7. Presence of at least 1 measurable site of disease. 
8. Patients who have provided a signed informed consent form to participate in the study, 
obtained prior to the start of any protocol related activities 
 
5.2 Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
 
1. Creatinine clearance <40 mL/min calculated by the Cockroft Gault method. 
2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L (2000/mm3); platelets <75x109/L 
(75x103/mm3). 
3. Total bilirubin >3 x ULN. 
4. Serum albumin <3.0 g/dL unless prothrombin time is within the normal range. 
5. Pregnancy or lactation. 

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6. A) Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, are not allowed to participate in this study UNLESS they are using highly 
effective methods of contraception throughout the study treatment period (including cross-over 
and re-treatment, if applicable) and for 7 months after study drug discontinuation. Highly 
effective contraception methods include: 
• 
True abstinence when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of exposure to IMP, and withdrawal are not 
acceptable methods of contraception. 
• 
Male or female sterilization 
• 
Combination of any two of the following (a+b or a+c or b+c): 
a. Use of oral, injected, or implanted hormonal methods of contraception. In case of use of 
oral contraception, women should be stable on the same pill for a minimum of 3 months before 
taking study treatment. 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/vaginal suppository. Post-menopausal women are 
allowed to participate in this study. Women 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) confirmed 
by a high follicle stimulating hormone (FSH) level, or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to 
screening. 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. 
B) 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 or pregnant female partners during 
the treatment period (including cross-over and re-treatment, if applicable) and for 4 months 
after study drug discontinuation. In addition, male patients must refrain from donating sperm 
during this same period. 
7. Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study. 
8. Documented RECIST progression to previous treatments for the current GEP-NET at any time 
prior to randomization. 
9. Patients for whom in the opinion of the investigator other therapeutic options (eg chemo-, 
targeted therapy) are considered more appropriate than the therapy offered in the study, based 
on patient and disease characteristics. 
10. Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), chemotherapy or other 
systemic therapies of GEP-NET administered for more than 1 month or within 12 weeks prior 
to randomization in the study. 
11. Any previous radioembolization, chemoembolization and radiofrequency ablation for GEP- 
NET. 

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12. Any surgery within 12 weeks prior to randomization in the study. 
13. Known brain metastases, unless these metastases have been treated and stabilized for at least 
24 weeks, prior to screening in the study. Patients with a history of brain metastases must have 
a head CT or MRI with contrast to document stable disease prior to randomization in the study. 
14. Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history of congestive 
heart failure who do not violate this exclusion criterion will undergo an evaluation of their 
cardiac ejection fraction prior to randomization via echocardiography. The results from an 
earlier assessment (not exceeding 30 days prior to randomization) may substitute the 
evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient’s 
measured cardiac ejection fraction in these patients must be >40% before randomization. 
15. QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QT 
syndrome. 
16. Uncontrolled diabetes mellitus as defined by hemoglobin A1c value > 7.5%. 
17. Hyperkaleamia >6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to study 
enrolment. 
18. Any patient receiving treatment with short-acting octreotide, which cannot be interrupted for 
24 h before and 24 h after the administration of Lutathera, or any patient receiving treatment 
with SSAs (eg octreotide long-acting), which cannot be interrupted for at least 6 weeks before 
the administration of Lutathera. 
19. Patients with any other significant medical, psychiatric, or surgical condition, currently 
uncontrolled by treatment, which may interfere with the completion of the study. 
20. Prior external beam radiation therapy to more than 25% of the bone marrow. 
21. Current spontaneous urinary incontinence. 
22. 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. 
23. 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. 
24. Hypersensitivity to any somatostatin analogues, the IMPs active substance or to any of the 
excipients. 
25. Patients who have participated in any therapeutic clinical study/received any investigational 
agent within the last 30 days. 
 
 
5.2.1 
Eligibility Criteria for Optional Treatment Extension Phase (cross-over) 
Any centrally confirmed RECIST progressive patient has the option to enroll for post-progression 
cross-over and receive maximum 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles; cumulative 
dose: 29.6 GBq / 800mCi) plus octreotide long-acting (30 mg every 8 weeks), provided that the 
following criteria are met: 

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­ Patients have provided a signed informed consent form to participate in the study treatment 
extension phase, obtained prior to the start of any related procedures. 
­ Expression of somatostatin receptors on all target lesions (based on post-progression new 
baseline assessment) documented by CT/MRI scans (Note: Cross-over Eligibility CT/MRI 
scan doesn’t need to be repeated if performed within the previous 12 weeks), assessed by 
any of the following somatostatin receptor imaging (SRI) modalities within 3 months prior 
to Lutathera treatment: [68Ga]-DOTA-TOC (e.g. Somakit-TOC®) PET/CT imaging (or 
MRI when applicable based on target lesions), [68Ga]-DOTA-TATE PET/CT (or MRI 
when applicable based on target lesions) imaging (e.g. NETSPOT®), Somatostatin 
Receptor scintigraphy (SRS) with [111In]-pentetreotide (Octreoscan® SPECT/CT), SRS 
with [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET/CT imaging (or MRI when 
applicable based on target lesions). 
­ All protocol inclusion/exclusion criteria are met (see Sections 5.1 and 5.2). 
­ The time window to start cross-over is 4 years after last patient randomized. 
­ Note: Prior each Lutathera administration a 6-week washout period from last octreotide 
long-acting administration has to be applied. 
If RECIST progression occurs after Week 72 post the primary end point analysis, the decision to 
enroll the patient in cross-over will be based on local assessment. 
Images (Cross-over Eligibility SRI and CT or MRI scan) will be also submitted to the central 
imaging center for a second review: there is no central ‘real time’ assessment of the Cross-Over 
Eligibility SRI uptake; however, the images should be submitted to the central imaging center 
possibly within 1 month. Images submission is not required for screening failure patients. 
 
5.2.2 
Eligibility Criteria for Optional Re-Treatment Phase 
In the Lutathera arm, patients with radiological progression based on RECIST criteria in central 
assessment, have the option to enroll for post-progression re-treatment, upon signature of a new 
informed consent, to receive 2 to 4 additional cycles of 7.4 GBq/200 mCi of Lutathera. 
For enrolment in the optional re-treatment phase, patients must meet all following requirements: 
­ Randomized to Lutathera arm, received 4 doses of Lutathera in initial treatment and 
experienced either disease stabilization (SD) or objective response (PR/CR) (centrally 
confirmed) for at least 6 months after the 4th Lutathera dose. If a patient’s response has 
changed from PR/CR to SD within 6 months after the 4th Lutathera dose, the patient is still 
eligible for re-treatment, provided there is no documented progression within 6 months. A 
window of -2 weeks is allowed for the confirmation of 6 months of SD/PR/CR response. 
­ Lutathera was overall well tolerated; no recorded SAEs related to Lutathera that were not 
resolved before the next Lutathera dose and led to treatment interruption. 
­ After the SD/PR/CR response, experienced radiological RECIST progression (centrally 
confirmed). If RECIST progression occurs after Week 72 post the primary end point 
analysis, the decision to enroll the patient in re-treatment will be based on local assessment. 
­ Patient did not receive any other systemic treatment for GEP-NET after progression 
(somatostatin analogues are allowed). 

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­ Investigator’s agreement that re-treatment is in the best interest for the patient 
­ Patients have provided a signed informed consent form to participate in the re-treatment 
phase, obtained prior to the start of any related procedures. 
­ Time window to start re-treatment: 4 years after last patient randomized (see Section 9.2). 
­ Expression of somatostatin receptors on all target lesions (based on post-progression new 
baseline assessment) documented by CT/MRI scans (Note: Re-treatment Eligibility 
CT/MRI scan doesn’t need to be repeated if performed within the previous 12 weeks), 
assessed by any of the following somatostatin receptor imaging (SRI) modalities within 3 
months prior to Lutathera re-treatment: [68Ga]-DOTA-TOC (e.g. Somakit-TOC®) 
PET/CT imaging (or MRI when applicable based on target lesions), [68Ga]-DOTA-TATE 
PET/CT (or MRI when applicable based on target lesions) imaging (e.g. NETSPOT®), 
Somatostatin Receptor scintigraphy (SRS) with [111In]-pentetreotide (Octreoscan® 
SPECT/CT), SRS with [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET/CT imaging (or 
MRI when applicable based on target lesions). 
Images (Re-treatment Eligibility SRI and CT or MRI scan) will be also submitted to the central 
imaging center for a second review: there is no central ‘real time’ assessment of the Re- 
treatment Eligibility SRI uptake, however the images should be submitted to the central 
imaging center possibly within 1 month. Images submission is not required for screening 
failure patients. 

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6 
Treatment 
In this study, approximately 222 patients with advanced G2-3 GEP-NET will be randomized (2:1 
randomization ratio) to receive treatment with Lutathera (7.4 GBq or 200 mCi x 4 administrations 
every 8± 1 weeks; cumulative dose: 29.6 GBq or 800 mCi) plus octreotide long-acting standard 
dose (30 mg every 8 weeks during Lutathera treatment and every 4 weeks after last Lutathera 
treatment) or octreotide long-acting high dose (60 mg every 4 weeks). 
The investigational drug product Lutathera® (177Lu-DOTA0-Tyr3-Octreotate) will be provided by 
the Sponsor. The Sponsor will also provide the 2.5% Lys-Arg sterile amino acid solution for 
infusion (if it can’t be compounded at the hospital Pharmacy), as well as octreotide long-acting 
(Sandostatin® LAR Depot) for the entire duration of the Treatment Phase (and optional Treatment 
Extension Phase) of the study. For the optional Re-treatment Phase, the Sponsor will provide 
Lutathera and 2.5% Lys-Arg sterile amino acid solution; octreotide-long acting administration is 
not mandatory and is at investigator discretion. Patients will switch to prescribed drugs in the 
follow up phase. 
Anti-emetics, SRI imaging agents, short-acting octreotide or any other supportive care medication 
will not be supplied by the Sponsor. 
 
6.1 Study treatments 
6.1.1 
Investigational and control drugs 
The investigational and control drugs supplied by Sponsor are listed in Table 6-1. 
Table 6-1. Investigational and control drug 
 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical Dosage 
Form 
Route of 
Administration 
Supply 
type 
Supplier 
Study 
arm 
Lutathera® 
Radiopharmaceutical 
solution for infusion (7.4 
GBq of Lutathera per 30 
ml vial) 
Intravenous use 
Open 
label; 
vials 
Sponsor 
Lutathera 
2.5% Lys-Arg 
sterile amino acid 
solution 
25g L-lysine-HCl and 
25g L-arginine-HCl in 
1000 mL 
Intravenous use 
Open 
label; 
flex 
bags 
Sponsor* 
Lutathera 
Octreotide long- 
acting 
(Sandostatin 
LAR® Depot) 
For injectable 
suspension: strengths 10 
mg per 6 mL, 20 mg per 6 
mL, or 30 mg per 6 mL 
vials 
Intragluteal 
injection 
Open 
label, 
vials 
Sponsor 
Lutathera; 
Control 
*Sponsor will provide the 2.5% Lys-Arg sterile amino acid solution for infusion (if it can’t be compounded 
at the hospital Pharmacy). 

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Table 6-3. 2.5% Lys-Arg sterile solution composition* 
 
Component 
Quantity/1000 ml 
 
L-lysine HCL 
25g 
L-arginine HCl 
25g 
Water for injection 
qs 1000 ml 
 
*The recommended pH range of the 2.5% Lys-Arg sterile solution is 
5.0-7.0 with an osmolarity of 420-480 mOsm/kg. 
 
In addition to the antiemetic premedication (see Section 6.6), in case of persistent nausea or 
vomiting during the administration of amino acids, 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®). 
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 (please see Section 6.2.3). 
 
6.1.1.1.3 Concomitant Treatment: 30 mg octreotide long-acting (Sandostatin® LAR Depot) 
Sandostatin® LAR Depot (octreotide long-acting) is a pharmaceutical that is available in a single- 
use kit containing a 6-mL vial of 10 mg, 20 mg, or 30 mg strength for intramuscular injection, a 
syringe containing 2.5 mL of diluent, two sterile 1½” 19 gauge needles, and two alcohol wipes. 
For prolonged storage, Sandostatin® LAR Depot should be stored at refrigerated temperatures 
between 2°C and 8°C (36°F-46°F) and protected from light until the time of use. An instruction 
booklet for the preparation of drug suspension for injection is also included with each kit. 
Octreotide long-acting 30 mg (Sandostatin® LAR Depot) is preferably administered the day after 
each administration of Lutathera and no earlier than 4 hours after completion of the Lutathera 
infusion. Due to the 6-weeks washout period before each Lutathera injection, no additional 
octreotide long-acting administrations are recommended between Lutathera treatments. Once 
Lutathera treatment completed, and also in case the Lutathera infusions have been suspended (e.g 
due to Dose Modifying Toxicity), patients will continue the 4-week interval administrations of 30 
mg octreotide long-acting until the completion of the Treatment Phase (see Treatment Phase 
definition in Section 3). 
 
 
6.1.1.2 
Control arm 
 
6.1.1.2.1 60 mg octreotide long-acting (Sandostatin® LAR Depot) 
Sandostatin® LAR Depot (octreotide long-acting) is a pharmaceutical that is available in single- 
use kits containing a 6-mL vial of 10 mg, 20 mg, or 30 mg strength for intramuscular injection, a 

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syringe containing 2.5 mL of diluent, two sterile 1½” 19 gauge needles, and two alcohol wipes. 
For prolonged storage, Sandostatin® LAR Depot should be stored at refrigerated temperatures 
between 2°C and 8°C (36°F-46°F) and protected from light until the time of use. An instruction 
booklet for the preparation of drug suspension for injection is also included with each kit. 
In the control arm, patients will receive administrations of octreotide long-acting 60 mg 
(Sandostatin® LAR Depot) at 4-week intervals (+/- 3 days) until the completion of the Treatment 
Phase (see Treatment Phase definition in Section 3), according to the schedule in Table 8-4 (i.e., 
two injections of Sandostatin® LAR 30 mg per treatment), unless the patient progresses or dies. 
Patients who were SSA-naïve before enrolment in the study, should receive first planned dose at 
30mg and the second (and subsequent) planned dose(s) at 60mg (full dose). 
 
6.2 Other treatment(s) 
6.2.1 
Rescue medication 
 
6.2.1.1 
Short-acting Octreotide 
Subcutaneous, short-acting octreotide injections may be indicated for control of symptoms (i.e. 
diarrhoea and flushing) in patients in both study arms, in accordance with the manufacturer’s 
prescribing information. Short-acting octreotide for symptom control is administered by the patient 
(at home) at investigator’s discretion. 
 
6.2.2 
Other anti-cancer treatments 
The patient may not receive any other systemic therapy for the treatment of GEP-NET 
(chemotherapeutic, biologic, or any investigational agent) other than Lutathera and/or short-acting 
octreotide and/or octreotide long-acting during the study Treatment Phase. Localized therapy such 
as surgery or external beam irradiation may be performed on additional site(s), provided that it 
does not affect treatment response assessment; no surgeries are allowed within 12 weeks prior to 
Lutathera administration. 
The last administration of long-acting SSA before the start of the study treatment is allowed during 
the screening period, before randomization, but should be carefully planned to allow a 6 weeks 
washout period prior to the administration of Lutathera. 
New anti-cancer treatments administered after progression or during the Follow up Phase must be 
registered in the eCRF. 
 
6.2.3 
Prohibited medication 
Somatostatin and its analogues competitively bind to somatostatin receptors. Therefore, 
administration of long-acting somatostatin analogues should be avoided within 6 weeks prior to 
the administration of Lutathera. If necessary, patients may be treated with short acting somatostatin 
analogues during the 6 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. Patients with a history of chronic use of 
glucocorticosteroids should be carefully evaluated for sufficient somatostatin receptor expression. 
It is not known if there is any interaction between glucocorticosteroids used intermittently for the 

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prevention 
of 
nausea 
and 
vomiting 
during 
Lutathera 
administration. 
Therefore, 
glucocorticosteroids should 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, OCT1, 
OCT2, OATP1B1, OATP1B3 and BCRP transporters in pre-clinical studies suggest that Lutathera 
has a low probability of causing clinically relevant metabolism- or transporter-mediated 
interactions. 
The following cautions regarding possible Octreotide Drug-Drug-Interactions (DDI) must be 
observed (according to the Octreotide label): 
- 
Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or 
agents to control fluid and electrolyte balance may be necessary when administered 
concomitantly. 
- 
Dose adjustments of insulin and antidiabetic medicinal products may be required when 
administered concomitantly. 
- 
Octreotide has been found to reduce the intestinal absorption of ciclosporin and to delay that 
of cimetidine. 
- 
Concomitant administration of octreotide and bromocriptine increases the bioavailability of 
bromocriptine. 
- 
Drugs mainly metabolized by CYP3A4 and which have a low therapeutic index should be used 
with caution (e.g. quinidine, terfenadine). 
- 
Octreotide may alter absorption of dietary fats in some patients. 
- 
Depressed vitamin B12 levels and abnormal Schilling’s tests have been observed in some 
patients receiving octreotide therapy. Monitoring of vitamin B12 levels is recommended 
during therapy with Octreotide LAR in patients. 
 
 
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. 
It is encouraged to complete the vaccination for COVID-19 (i.e. receive the two vaccine doses if 
necessary) prior to initiation of study treatment. If the vaccination should occur while a patient is 
on-treatment, vaccine may be administered per routine clinical practice. 

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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. 
 
 
6.3 Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
For all patients who have signed the ICF, a screening number will be assigned in chronological 
order starting with the lowest number available on site. Patients will be identified by a unique 
patient identification number (Patient ID No.) composed of the center number and the screening 
number. 
 
6.3.2 
Treatment assignment, randomization 
After the screening period, eligible patients will be randomly assigned (ratio 2:1) to one of the two 
study groups for treatment with Lutathera plus octreotide long-acting (30 mg) or high dose 
octreotide long-acting (60 mg). The randomization system will assign a unique randomization 
number to the patient, which will be used to link the patient to a treatment arm. Randomization 
will be stratified by tumor Grade (G2 vs G3) and tumor origin (pNET vs other origin) according 
to a stratified permuted block scheme. 
The details of the procedure to obtain the patient randomization number will be described in the 
Investigator’s Manual. 
 
6.4 Treatment blinding 
Due to the radioactive nature of Lutathera and its method of infusion, it is not possible to 
implement a blinded design for this study. 
 
6.5 Dose compliance, modification and discontinuation 
6.5.1 
Dose compliance 
For each single-dose of Lutathera a deviation of ±10% from the scheduled dose is allowed. 
 
6.5.2 
Dose modification 
Modifying Toxicities (DMT) will apply in both arms as discussed in Sections 6.5.2.1 and 6.5.2.2. 
Patients whose treatment is interrupted or permanently discontinued due to toxicities that fulfil the 
criteria for a DMT, must be followed up at regular intervals (at least once a week), until resolution 
or stabilization of the event(s), whichever comes first. 
Appropriate clinical experts such as cardiologists, endocrinologists, hepatologists, nephrologists 
etc. should be consulted as deemed necessary. 

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6.5.2.1 
Dose modifying toxicities (DMTs) for 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. 
If a patient requires a dose delay of > 16 consecutive weeks of Lutathera from the day of the 
previous dose, then the patient should be discontinued from the study treatment. In exceptional 
situations, if the patient is clearly benefiting 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 AAA Medical Monitor, 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. 
These dose changes must be recorded on the appropriate electronic case report form (eCRF). 
 
 
Table 6-4. 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). 
If AE resolves before next planned 
Lutathera dose (i.e. within 9 weeks 
after the previous dose), administer 
next full dose of Lutathera (7.4 GBq 
/ 200 mCi). 
If AE resolves within 9 – 16 weeks 
after the previous dose, resume 
Lutathera at 3.7 GBq (100 mCi). If 
reduced dose does not result in Grade 
2,  3  or  4  thrombocytopenia, 
administer Lutathera at 7.4 GBq (200 
mCi) for next dose. 
If AE does not resolve within 16 
weeks after the previous dose, 
permanently discontinue Lutathera. 
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). 
If AE resolves before next planned 
Lutathera dose (i.e. within 9 weeks 
after the previous dose), administer 
next full dose of Lutathera (7.4 GBq 
/ 200 mCi). 

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If AE resolves within 9 – 16 weeks 
after the previous dose, resume 
Lutathera at 3.7 GBq (100 mCi). If 
reduced dose does not result in Grade 
3 or 4 anemia, administer Lutathera at 
7.4 GBq (200 mCi) for next dose. 
If AE does not resolve within 16 
weeks  after  the  previous  dose, 
permanently discontinue Lutathera. 
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). 
If AE resolves before next planned 
Lutathera dose (i.e. within 9 weeks 
after the previous dose), administer 
next full dose of Lutathera (7.4 GBq 
/ 200 mCi). 
If AE resolves within 9 – 16 weeks 
after the previous dose, resume 
Lutathera at 3.7 GBq (100 mCi). If 
reduced dose does not result in Grade 
3 or 4 neutropenia, administer 
Lutathera at 7.4 GBq (200 mCi) for 
next dose. 
If AE does not resolve within 16 
weeks  after  the  previous  dose, 
permanently discontinue Lutathera. 
Recurrent Grade 3 or 4 
Permanently discontinue Lutathera. 
Renal Toxicity 
First occurrence of: 
• Creatinine clearance less than 40 
mL/min; 
calculated 
using 
Cockcroft Gault formula with 
actual body weight, or 
• 40% increase from baseline serum 
creatinine, or 
• 40% 
decrease 
from 
baseline 
creatinine clearance; calculated 
using Cockcroft Gault formula 
with actual body weight. 
Withhold 
dose 
until 
complete 
resolution. 
If AE resolves before next planned 
Lutathera dose (i.e. within 9 weeks 
after the previous dose), administer 
next full dose of Lutathera (7.4 GBq 
/ 200 mCi). 
If AE resolves within 9 – 16 weeks 
after the previous dose, resume 
Lutathera at 3.7 GBq (100 mCi). If 
reduced dose does not result in renal 
toxicity, administer Lutathera at 7.4 
GBq (200 mCi) as next dose. 

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If AE does not resolve within 16 
weeks after the previous dose, 
permanently discontinue Lutathera. 
Recurrent renal toxicity Grade 3 or 4 
Permanently discontinue Lutathera. 
Hepatotoxicity 
First occurrence of: 
Bilirubinemia greater than 3 times the 
upper limit of normal (Grade 3 or 4), 
or 
Withhold dose until complete or 
partial resolution (Grade 0, 1 or 2). 
If AE resolves before next planned 
Lutathera dose (i.e. within 9 weeks 
after the previous dose), administer 
next full dose of Lutathera (7.4 GBq 
/ 200 mCi). 
If AE resolves within 9 – 16 weeks 
after the previous dose, resume 
Lutathera at 3.7 GBq (100 mCi). If 
reduced Lutathera dose does not 
result in G3 or 4 bilirubinemia, 
administer Lutathera at 7.4 GBq (200 
mCi) as next dose. 
If AE does not resolve within 16 
weeks after the previous dose, 
permanently discontinue Lutathera. 
Defined as: 
Hypoalbuminemia less than 30 g/L 
with International Normalized Ratio 
(INR) >1.5. 
Withhold dose until complete or 
partial resolution (Grade 0 to 1). 
If AE resolves before next planned 
Lutathera dose (i.e. within 9 weeks 
after the previous dose), administer 
next full dose of Lutathera (7.4 GBq 
/ 200 mCi). 
If AE resolves within 9 – 16 weeks 
after the previous dose, resume 
Lutathera at 3.7 GBq (100 mCi). If 
reduced Lutathera dose does not 
result in G2, 3 or 4 
hypoalbuminemia, administer 
Lutathera at 7.4 GBq (200 mCi) as 
next dose. 
If AE does not resolve within 16 
weeks after the previous dose, 
permanently discontinue Lutathera. 
Recurrent hepatotoxicity 
Permanently discontinue Lutathera. 
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). 

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If AE resolves before next planned 
Lutathera dose (i.e. within 9 weeks 
after the previous dose), administer 
next full dose of Lutathera (7.4 GBq 
/ 200 mCi). 
If AE resolves within 9 – 16 weeks 
after the previous dose, resume 
Lutathera at 3.7 GBq (100 mCi). If 
reduced dose does not result in 
Grade 3 or 4 toxicity, administer 
Lutathera at 7.4 GBq (200 mCi) as 
next dose. 
If AE does not resolve within 16 
weeks after the previous dose, 
permanently discontinue Lutathera. 
Recurrent Grade 3 or 4 
Permanently discontinue Lutathera. 
Severe heart failure 
NYHA class III or IV 
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 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. 
 
After resolution of a DMT, a patient may receive subsequent planned treatment(s) at the full dose 
(if resolved within 9 weeks after the previous dose), or at 50% of the standard treatment dose (if 
resolved within 9 – 16 weeks after the previous dose), if this is felt to be safe for the patient, or the 
risk-benefit assessment is favourable. If the same DMT reoccurs after treatment with the reduced 
Lutathera dose, the patient will remain in the study and continue the scheduled clinical / tumor 
assessments until tumor progression, but no further Lutathera treatment will be given. Octreotide 
long-acting 30 mg will be continued at monthly intervals. 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. 
If a patient experiences a DMT during Lutathera therapy, subsequent treatments with Lutathera 
are permissible, provided the DMT resolves within 16 weeks following the non-tolerated 
administration. In any case, the patient will continue the administration of 30 mg octreotide long- 
acting. 

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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 (see pharmacy manual). 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. 
 
6.5.2.2 
Dose modifying toxicities (DMTs) for Octreotide LAR 
 
 
Control arm (Octreotide LAR 60 mg) 
In the treatment arm with octreotide long-acting, a dose adjustment will be applied in case of Grade 
3 or 4 toxicity, especially in presence of severe abdominal symptoms, and hypoglycaemia/ 
hyperglycemia possibly related to octreotide long-acting. The dose adjustment will also be applied 
if such adverse events are observed which are unlikely related to the study drug, but to other 
possible or concomitant causes, and the full administration of octreotide long-acting would 
represent a safety risk for the patient. 
If a patient experiences a DMT during octreotide long-acting treatment, the subsequent treatment 
dose will be reduced from 60 mg to the previous well-tolerated dose (or even temporarily 
suspended) and then at the next treatment, the dose will be increased to the initial 60 mg dose of 
octreotide long-acting, if this is felt to be safe for the patient, or the risk-benefit assessment is 
favorable. 
In any case (also in case of octreotide long-acting treatment dose suspension), the patient remains 
in the study and continues the scheduled clinical / tumor assessments until tumor progression, 
unless the patient’s withdrawal becomes inevitable (Section 9 – Study discontinuation). 
 
 
Lutathera arm (Octreotide LAR 30 mg) 
All DMT recommendations in the control arm (Octreotide LAR 60 mg) are also applicable to the 
Lutathera arm, where Octreotide LAR is administered at the standard approved dosage (30 mg). 
Overall, the exact dose reduction levels, duration of suspension and criteria for re-increase and 
continuation of dose in the control arm will be defined by the treating physician based on clinical 
judgment and product leaflet. 

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6.5.3 
Dose discontinuation 
The discontinuation of either study treatments in both arms (Lutathera or octreotide long-acting) 
is not a reason for patient’s withdrawal either from the clinical/tumor assessments until tumor 
progression, or for early study termination (reasons for the patient’s withdrawal are discussed in 
Section 9 – Study discontinuation). However, in case of a patient’s withdrawal from the 
clinical/tumor assessments or early study termination (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 8-3, Table 8-4). 
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. 
 
6.6 
Preparation and dispensation of Lutathera 
There is no need for the patients to fast before treatment. 
Treatment with Lutathera will consist of a cumulative amount of radioactivity of 29.6 GBq (800 
mCi) with the dosing divided among 4 administrations of Lutathera at 8±1-week intervals or up 
to 16 weeks to accommodate resolving acute toxicity (see Section 6.5.2.1). Each dose is infused 
over 30 minutes. 
In addition to treatment with Lutathera, patients will receive 30 mg octreotide long-acting until 
the completion of the Treatment Phase (see Treatment Phase definition in Section 3). 
Before each Lutathera treatment: 
1. Unless clinically impossible, octreotide long-acting must not be administered within 6 weeks 
of the next treatment of Lutathera. In other words, between 2 Lutathera injections performed 
at regular interval (8 weeks) only one 30mg octreotide long-acting injection can be 
administered (possibly one day after Lutathera administration or at least after 4 hours after 
the end of Lutathera infusion). While not treated with octreotide long-acting, the patient must 
be treated with an equivalent dosing of short acting octreotide s.c. "Clinically impossible" 
means that the actual clinical condition of the patient would contraindicate the suspension of 
treatment because of an otherwise untreatable carcinoid syndrome. After enrollment, 
octreotide long-acting injections should be planned in order to allow for suitable washout 
time before first Lutathera treatment. If the time interval between treatments with Lutathera 
(see Section 6.5.2.1) is prolonged for any reason, octreotide long-acting administration 
continues every 4 weeks, however it should not be administered within 6 weeks of the next 
Lutathera treatment. 
2. Short-acting octreotide is not allowed during the 24 h before the Lutathera treatment date, 
unless the actual patient clinical conditions would contraindicate the treatment suspension 
due to otherwise untreatable carcinoid syndrome symptoms. Short-acting octreotide can only 

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be continued if the tumor uptake on SRI imaging during continued somatostatin analogue 
medication is greater than liver uptake (see Exclusion criteria). 
3. Treatment with 30 mg octreotide long-acting can be resumed after the administration of 
Lutathera. Specifically, the recommended period before resuming octreotide long-acting (or 
short acting octreotide s.c.) is one day, however the minimum interval to receive octreotide 
long-acting (or short acting octreotide s.c.) after Lutathera is 4 hours, unless contraindicated 
as noted above. 
The total amount of administered radioactivity is determined by measuring the radioactivity in 
the Lutathera vial before and after administration (the procedure is provided in Appendix 8). 
The scheme for supportive treatment with 30 mg octreotide long-acting is presented in Figure 
6-1. 
 
Figure 6-1. Lutathera Arm: schedule for administration of Lutathera, 30 mg octreotide 
long-acting, and short acting octreotide sc1. 
 
Treatment 
Wk0 
Wk1 Wk2 Wk3 Wk4 
Wk5 
Wk6 
Wk7 
Wk8 
Lutathera2,3 
X······ · 
· 
· 
· 
· 
· 
· 
X······ 
Octreotide 
long-acting 
30 mg4 
·X····· · 
· 
· 
· 
· 
· 
· 
·X····· 
Octreotide 
s.c. short 
acting 
······· · 
· 
· 
X→ 
X→ 
X→ 
XXXXXX· ······· 
↑ Octreotide long-acting is 
resumed the day after 
Lutathera treatment 
Octreotide S.C. stopped 24hr 
before Lutathera treatment 
↑ 
 
1 
Symbols: (X) treatment with Lutathera, (X) treatment with octreotide long-acting, (X, X→) daily injections 
of octreotide s.c., (·) no treatment 
2 
Lutathera treatment interval can be increased to 16 weeks to resolve acute toxicity 
3 
If Lutathera treatment is delayed due to DMT, octreotide long-acting may be continued at 4-week intervals, 
but should not be administered within 6 weeks before next Lutathera treatment; patient should use 
octreotide s.c. during the washout period 
4 
After patients receive all 4 Lutathera administrations at 8±1 week intervals, or Lutathera treatment stopped 
because of toxicity, patients continue to receive 30 mg octreotide long-acting (1 im injection every 4 weeks) 
until end of Treatment Phase, unless progression occurs. 
 
 
On the day of Lutathera treatment, and before the infusion with 2.5% Lys-Arg solution is started, 
an intravenous bolus of anti-emetic is given (suggested options: Granisetron (3 mg), or 
Ondansetron (8 mg), or Tropisetron (5 mg)). Prednisone must be avoided as preventive anti- 
emetic treatment because of potential somatostatin receptor down-regulation. 

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Hyperkaleamia must be corrected prior to 2.5% Lys-Arg infusion if >6.0 mmol/L (CTCAE 
Grade 3). 
In case nausea or vomiting occurs despite this medication, patients can be treated with other anti- 
emetic drugs at the discretion of the physician. 
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 or 
slowing the infusion rate). During amino acid infusion patient is allowed to void. 
Infusion rates are listed in Table 6-5 and see Pharmacy Manual for the infusion system scheme. 
 
 
Table 6-5. Administration procedure of antiemetic, sterile amino acid solution and 
Lutathera 
 
Administered agents 
Start time 
(min) 
Infusion rate 
(mL/h) 
Duration 
Antiemetic: Granisetron 3 mg (or 
alternative) 
0 
as per 
prescribing 
information 
as per prescribing 
information 
2.5% Lys-Arg sterile amino acid 
solution (1L) 
30 
250 
4 hours 
Lutathera with sodium chloride 9 
mg/mL (0.9%) solution for injection 
60 
Up to 400 
30 ± 10 minutes 
 
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 4). At the time of release, patients are given written instructions (Appendix 
5) which outline the precautions the patient must take to minimize radiation exposure to people 
around them. 
Crises due to excessive release of hormones or bioactive substances may occur following 
treatment, therefore, observation of patients by overnight hospitalization should be considered. 
Recommended treatments of patients with hormonal crises are: i.v. high dose somatostatin 
analogues, i.v. fluids, corticosteroids, and correction of electrolyte disturbances in patients with 
diarrhea and vomiting. 
 
6.6.1 
Handling of study treatment and additional treatment 
Lutathera, amino acids and octreotide long-acting must be administered at the investigational 
site. Short-acting octreotide is self-administered by the patient. 

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The study medication must be stored, handled and administered only by qualified/authorized 
personnel and must be prepared in accordance with pharmaceutical quality requirements, and 
radiation safety regulations for Lutathera. 
Drug inventory and accountability records for the study medication and rescue medication, as 
well as drug returns by the patient, will be kept by the Investigator/Pharmacist, and must be 
documented throughout the study. Returned supplies should not be distributed again, not even to 
the same patient. The Investigator will not supply investigative study medication to any person, 
except the patients in this study. 
The octreotide long-acting and amino acids not used must be stored at site and made available 
till the monitoring visits, to allow the CRA to monitor the drug accountability. 
The used/unused medications, except for Lutathera, which will be locally discarded according to 
all disposal requirements for radioactive materials, will be returned to the proper local depot for 
destruction at the study completion or upon expiration, according to IPM/Sponsor decision and 
approval. 
On an ongoing basis the Investigator/Pharmacist agrees to conduct a study medication supply 
inventory and to record the results of this inventory on the study Medication Accountability 
Record. 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. 

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7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
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 informed consent must be 
documented in the subject source documents. 
Advanced Accelerator Applications will provide to investigators in a separate document a 
proposed 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 consent 
form suggested by the investigator must be agreed by Advanced Accelerator Applications before 
submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject informed consent and should be 
discussed with the subject 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 finding. New 
information might require an update to the informed consent and then must be discussed with 
the subject. 
Women of child bearing potential must be informed that taking Lutathera 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 subjects must 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. Subjects must be 
informed of the contraception requirements outlined in the Inclusion/Exclusion Criteria (Section 
5). 
A copy of the approved version of all consent forms must be provided to Advanced Accelerator 
Applications after IRB/IEC approval. 
It is recommended that the Investigator inform the patient’s general practitioner of his/her 
participation in the study, provided that the patient has a general practitioner and the patient 
agrees to disclose this information. 
The informed consent form (ICF) signed at the time of the inclusion foresees the patient’s 
participation in the Study until the end of the Follow-up Phase (adolescents will sign a dedicated 
informed consent). Patients should sign an addendum to the consent to participate in the Follow- 
up Phase assessment phase only in case they have withdrawn the initially signed consent. 

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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 medication number. 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. 
Patients randomized in the Lutathera arm will also receive written instructions which outline the 
precautions the patient must take to minimize radiation exposure to people around them. 
Patients who will decide to participate after progression to the optional Treatment Extension 
Phase (cross-over) or Re-treatment Phase will need to sign a new informed consent before 
starting the treatment. 

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8 
Visit schedule and assessments 
Randomization must be performed once all screening/baseline assessments are complete. 
The baseline CT/MRI scan should be taken possibly on the same day of randomization or 
immediately before (within 1 week) to ensure that it reflects the disease status closely before the 
therapy start. The results of baseline CT/MRI must be assessed by Investigator before 
randomization. 
The screening phase must be shortened as much as possible in order to treat the patients shortly 
after the informed consent signature. 
Randomization should occur as soon as possible after all screening assessments have been 
completed and eligibility confirmed. As Lutathera production and shipment will take 
approximately 12 days, if a patient is randomized in the Lutathera arm, Lutathera first dose must 
be ordered immediately after randomization. 
During the study, patients will be evaluated for safety and tolerability in accordance with the 
Visit Schedules for the Lutathera arm and the octreotide long-acting arm as indicated in Table 
8-3, and Table 8-4 (variations of ±1 week in the visits schedule are allowed). 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study treatment for any 
reason should be scheduled for a visit as soon as possible, at which time all of the assessments 
listed for the EOT/Early Termination visit will be performed (Table 8-3). At the EOT/Early 
Termination visit, all dispensed investigational product should be reconciled, and the adverse 
event and concomitant medications recorded on the eCRF. 
As the date of randomization and the date of first treatment might not be the same, it should be 
observed that a misalignment may occur between the tumor imaging exams (CT/MRI scans) 
which are scheduled from the date of randomization, and the other clinical and laboratory 
assessments which are scheduled from the first treatment date. 
The assessments listed in Table 8-1 will be performed centrally. Procedures for centralized 
evaluations will be detailed in the Laboratory Manuals provided to each participating site. 
Assessment schedule lists all of the assessments and when they are performed. All data obtained 
from these assessments must be supported in the subject’s source documentation. 
 
 
Table 8-1. Centrally Performed Assessments. 
 
Assessment 
Material to be Delivered 
Study 
Phase 
Section 
SRI tumor uptake in all documented target 
lesions will be assessed locally at screening 
to verify that tumor uptake in all target 
lesions is greater than the liver uptake. 
SRI modality: [68Ga]-DOTA- 
TOC (e.g. Somakit-TOC®) 
PET/CT (or MRI when 
applicable based on target 
Screening & 
before 
cross- 
8.1.4 

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If the patient will participate to the optional 
Treatment 
Extension 
Phase 
after 
progression, SRI tumor uptake in all 
documented target lesions will be re- 
assessed locally before cross-over. 
lesions) imaging or [68Ga]- 
DOTA-TATE PET/CT (or MRI 
when applicable based on 
target lesions) imaging (e.g. 
NETSPOT®) Somatostatin 
Receptor scintigraphy (SRS) with 
[111In]-pentetreotide 
(Octreoscan® SPECT/CT), SRS 
with [99mTc]-Tektrotyd, 
[64Cu]-DOTA-TATE PET/CT 
(or MRI when applicable 
based on target lesions) 
imaging. 
SRI obtained within 3 months of 
randomization will be accepted 
for inclusion; if older, the exam 
will need to be repeated at 
screening. 
If the patient participates to the 
optional Treatment Extension or 
re-treatment 
Phase 
(after 
progression), SRI imaging must be 
repeated before cross-over/re- 
treatment. The SRI images should 
be submitted to the central 
imaging center (uploading into the 
dedicated e-platform) possibly 
within 1 month. 
See Imaging Manual for further 
details. 
over/re- 
treatment 
Images will be also submitted to the central 
imaging center for a second review (there is 
no central ‘real time’ assessment of the SRI 
images, however the images should be 
submitted to the central imaging center 
possibly  within  1  month.  SRI  images 
submission is not required for screening 
failure patients. 
Objective tumor response according to 
CT/MRI scans. 
Treatment 
8.3 
RECIST Criteria. 
It is recommended that for each 
Phase 
Tumor response according to RECIST is re- 
evaluated centrally (real-time reading) 
during the study. 
patient identical acquisition and 
reconstruction protocols be used at 
all time-points. 
The images must be submitted 
(uploading into the dedicated e- 
platform) to the central imaging 
center as soon as possible for real- 
time assessment. 
See Imaging Manual for further 
details. 
Measurements of the RR, PR, QRS, and QT 
interval durations. 
12-lead ECGs will be performed 
using the device provided by 
Sponsor. 
Baseline & 
Treatment 
Phase 
8.5.5 

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12-lead ECGs in triplicate will be re- 
assessed centrally at baseline and during 
the study. 
Data will be transferred after 
acquisition 
to 
the 
central 
laboratory 
for 
the 
central 
cardiologist assessment. 
See ECG Manual for further 
details. 
PK of high dose octreotide long-acting (60 
Blood will be collected using the 
sampling 
tubes 
provided 
by 
Sponsor. The storage temperature 
for PK samples should be at or 
below minus 20°C (-20°C). 
Samples will be shipped regularly 
to the central laboratory for 
central PK assessment. 
See PK Manual for further details. 
Treatment 
8.6 
mg), to evaluate steady-state trough plasma 
Phase/contr 
concentration  assessment  (all  Countries 
ol arm only 
except China). 
Blood samples (2.5 mL each sample) will be 
collected at the pre-specified pre-dose time- 
points to yield approximately 1 mL plasma 
for analysis of octreotide concentration. 
 
 
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of 
providing continuing care may be implemented. Phone calls and virtual contacts (e.g. 
teleconsult) can 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 
patient’s 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 (e.g. chemistry and hematology) 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. 
-Scheduled or unscheduled patient study visits can be performed once feasible and considered 
safe for patients to attend the clinical appointments. 
If contact is made with a patient via telephone/video call, the Visit Date should be entered into 
the eCRF for the corresponding visit / next closest visit. If multiple contacts are made prior to 
the next scheduled visit, an unscheduled visit per contact can be entered to capture the Visit Date. 

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CRFs that can be completed as a result of the telephone/video-visit should be completed, e.g. 
Adverse Events, Concomitant Medications, and Dose Administration Record. If any protocol 
required assessments were not completed, CRFs should be ‘Inactivated’ or marked 'Not Done'. 
The Protocol Deviation process will be used to capture visits not performed at site due to 
COVID-19 (see Section 14). 
 
8.1 Demographics and Baseline Characteristics 
Each patient’s date of birth, gender, ethnicity, weight, height and relevant baseline characteristics 
will be recorded in the e-CRF. 
 
8.1.1 
Diagnosis and Extent of Cancer 
The patient’s disease history, including documented primary diagnosis of gastro-entero- 
pancreatic tumor, date of diagnosis (diagnosis date of metastasized or locally advanced disease 
should not be greater than 6 months prior to screening), as well as disease status at study entry, 
will be collected. This includes the date of first diagnosis and presence of metastases with 
specification of the metastatic site(s). TNM criteria will be used for the determination of the 
stage of disease at the time of first diagnosis. 
 
8.1.2 
Ki67 
All patients are required to have documented local assessment of the Ki67 proliferation index 
based on surgery/biopsy specimens of the primary tumor or liver metastases or soft tissue 
metastases and assessed by microscopy and immunohistochemical staining. 
Ki67 must be ≥10% and ≤ 55% for a patient to be eligible. 
 
8.1.3 
Prior Antineoplastic Medications / Radiotherapy / Surgery 
Information pertaining to any chemotherapy, hormonal therapy, immunotherapy, radiation, or 
surgery the patient has previously received will be documented. Previous treatment with 
somatostatin analogs will be also documented if applicable. 
 
8.1.4 
SRI Tumor Uptake in Documented Lesions 
All patients are required to have [68Ga]-DOTA-TOC (e.g. Somakit-TOC®) PET/CT (or MRI 
when applicable based on target lesions) imaging or [68Ga]-DOTA-TATE PET/CT (or MRI 
when applicable based on target lesions) imaging (e.g. NETSPOT®) or Somatostatin Receptor 
scintigraphy (SRS) with [111In]-pentetreotide (Octreoscan® SPECT/CT) or SRS with [99mTc]- 
Tektrotyd or [64Cu]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) 
imaging performed within 3 months prior to the projected randomization date in the study 
(available exams older than 3 months need to be repeated to evaluate the patient’s eligibility). 
SRI imaging must be repeated before cross-over (after progression in the control arm), if the 
patient participates to the optional Treatment Extension Phase, and before the optional re- 
treatment (after progression in the Lutathera arm). 

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SRI tumor uptake in documented target lesions will be assessed locally to evaluate patient’s 
eligibility before randomization, cross-over and re-treatment. Tumor uptake in all target lesions 
must be greater than the liver uptake. 
Images will be also submitted to the central imaging center for a second review: there is no 
central ‘real time’ assessment of the SRI images, however the images should be submitted to the 
central imaging center possibly within 1 month. SRI images submission is not required for 
screening failure patients. 
Lytic bone lesions, with an identifiable soft tissue component, evaluated by CT or MRI, can be 
considered as measurable lesions if the soft tissue component otherwise meets the definition of 
measurability according to RECIST 1.1 (in any case, blastic bone lesions are not measurable). 
Therefore, if the bone lesion has the characteristic as above, and SRI is positive, the patient may 
be enrolled. 
If the primary tumor has been resected, tumor evaluations including SRI will be performed on 
metastases. 
Operating details and quality certificates are specified in the Imaging Manual and Imaging 
Charter. 
 
8.2 Prior/Concomitant Medications 
All medications taken at the start of screening until the end of the Treatment Phase/optional 
Treatment Extension Phase/optional Re-treatment Phase, or early termination, are to be recorded. 
This includes prescription and over-the-counter medications taken during this time frame. 
During the Follow up Phase, concomitant medications must be collected only if administered for 
related SAEs/AESI and/or for secondary hematological malignancies. In addition, further anti- 
tumor treatments administered after progression must be reported until the end of the Follow up 
Phase. 
If any additional medication or procedure has been given for treatment of suspected or confirmed 
COVID-19 during the study, the site is requested to please enter them as a concomitant 
medication or procedure (e.g. intubation) and state/ select ‘reason’ to match the relevant Adverse 
Event reported when applicable. 
 
Tests performed to diagnose symptoms of COVID-19 should be reported as Adverse Events only 
per Section 10.1.1 and not duplicated in Concomitant Medications/ Surgical and Medical 
Procedures or equivalent CRFs. 
 
8.3 Efficacy Assessment 
8.3.1 
Progression Free Survival 
The primary efficacy end-point is PFS as measured by objective tumor response, which is 
determined by RECIST criteria, Version 1.1 (Eisenhauer, et al., 2009). Tumor response will be 
assessed locally and centrally. 

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Triphasic CT imaging is the preferred modality over MRI for determining objective tumor 
response. Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of IV contrast media. 
The baseline CT/MRI scan should be taken possibly on the same day of randomization or 
immediately before (within 1 week) to ensure that it reflects the disease status closely before the 
therapy start. The results of baseline CT/MRI must be assessed by the Investigator before 
randomization. 
The tumor diameters of indicator lesions used for response assessment should be measured in 
the closest position to that used for the baseline CT or MRI assessment. 
Restaging is scheduled at regular intervals in the two treatment arms (week 16±1, week 24±1 
and then every 12 ±1 weeks) starting from the date of randomization (see Table 8-3, and Table 
8-4). Every effort should be done to avoid differences between these timings for patients in the 
two arms. In case of delays, the reason of the delay has to be documented and the CT/MRI 
assessment has to be done as soon as possible. 
If a CT/MRI scan is done on the same day of a Lutathera administration (e.g. in case of therapy 
postponement due to DMT or scheduling issues), the scan should be taken before the drug 
administration. When a CT/MRI assessment is >6 weeks earlier or later than the original 
schedule, the next reassessments have to be discussed and adjusted with the Medical Monitor of 
the study in a way to progressively come back to the original schedule. 
It is recommended that for each patient identical acquisition and reconstruction protocols be used 
at all time-points. Central, blinded, real-time IRC (Independent Review Committee) assessment 
will be conducted for determining progressive disease. Changes from randomization date will be 
assessed at week 16±1, week 24±1 and then every 12 ±1 weeks until the PFS primary analysis 
End-Point has been reached, then until Week 72 after randomization, unless the patient 
progresses or dies. 
Sponsor will notify all the Centers and their Ethic Committees as soon as the 99 PFS events have 
occurred. 
Additional PFS/PFS2 data will be collected up to 3 years from the end of the Treatment Phase 
of the last patient (during the follow-up phase RECIST 1.1 assessment will be performed only 
locally every 6 months (± 1 month)). 
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment. These additional scans should be provided to the IRC for central assessment. If an 
off-schedule imaging assessment is performed because progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule. 
After progression and during the follow-up every effort must be made by the Investigator to 
collect additional information on further anti-tumor therapies and scan assessments outcome 
(RECIST 1.1 local evaluation) to evaluate the Time to Second Progression (PFS2) in the two 
study arms. 

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For progressive patients participating in cross-over or re-treatment, CT/MRI scans performed 
after the cross-over or re-treatment eligibility will follow the visits schedule counted from the 
1st Lutathera dose. 
For patients that are re-treated with Lutathera, a separate PFS analysis will be conducted during 
the re-treatment phase using the same definition as in Section 12.5.2 except that the baseline will 
be based on the tumor assessment which demonstrated progression thus allowing re-treatment 
with Lutathera. This PFS analysis during re-treatment will be descriptive only. 
Operating details and quality certificates are specified in the Imaging Manual and Imaging 
Charter. See Section 8.8 for further details. 
 
8.3.2 
Objective Response Rate (ORR), Duration of Response (DOR), Time to Second 
Progression (PFS2) 
Objective Response Rate (ORR) will be calculated as the rate of patients with a best overall 
response of partial response (PR) or complete response (CR). Response duration will be 
calculated from the time of initial response until documented tumor progression. 
The Duration of Response (DOR) is defined as the time from initially meeting the criteria for 
response (CR or PR) until the time of progression by RECIST or death due to underlying disease. 
DOR will be reported descriptively for each group without comparison between groups. 
As additional secondary exploratory end-point (local RECIST assessment), the Time to Second 
Progression (PFS2) will be assessed in the two study arms. PFS2 is defined as the time from 
randomization to the time of disease progression or death due to any cause (on any treatment) 
following the first episode of disease progression. 
For patients that are re-treated with Lutathera, a separate analysis for ORR, DoR, and PFS2 will 
be conducted during the re-treatment phase using the same definition as in Section 12.5.2 for 
ORR and DoR, except that the new baseline will be based on the tumor assessment which 
demonstrated progression thus allowing re-treatment with Lutathera. The PFS2 definition is the 
same as that in Section 12.6.1. This ORR, DoR, and PFS2 analysis during re-treatment will be 
descriptive only. 
It is recognized that the limitation of including cross-over and the lower scans frequency during 
follow-up will reduce the possibility to reach firm conclusions on PFS2. 
After the first progression is confirmed centrally and the second progression is confirmed locally 
(i.e. after PFS2 event), the sites which do not routinely perform 6-monthly follow up CT/MRI 
scans for progressive GEP-NET patents can omit this examination at the subsequent patient’s 
visits (no protocol deviation). 
 
8.3.3 
Overall Survival 
Overall Survival (OS) will be calculated from the randomization date until the day of death due 
to any cause; OS will not be censored if a patient receives other anti-tumor treatments after study 
medication. 

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Overall Survival will also be separately estimated for patients that receive re-treatment with 
Lutathera. The definition for OS is the same to that in Section 12.5.2, and this analysis with re- 
treatment patients will be descriptive only. 
Survival data will be analyzed at the time of the analysis of the primary end-point (PFS), and 
will continue to be assessed up to 4 years from the randomization of the last patient or 6 months 
after the last cross-over/re-treatment dose in the study, whichever occurs last. 
 
8.4 Quality of Life 
The impact of treatment on health related QoL will be assessed using the EORTC QLQ- 
G.I.NET21, EORTC QLQ-C30 and EQ-5D-L5 questionnaires, which will be filled in by the 
patient prior to know CT scan/MRI result. Changes from baseline will be assessed every 12±1 
week from the first treatment date until the end of treatment. 
Forms in Country-specific languages will be provided by the Sponsor. 
 
8.5 Safety and Tolerability 
8.5.1 
Adverse Events 
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 Phase/optional Treatment 
Extension Phase. 
During the Follow up Phase only related SAEs and related AESI other than secondary 
hematological malignancies will be recorded. AESI of secondary hematological malignancies 
will be recorded during the whole study irrespective of causality. Definitions and reporting 
procedures are outlined in Section 10. An Independent Steering Committee Board will evaluate 
patient’s safety throughout the study (Section 10.2). During the Follow-up Phase, concomitant 
medications must be collected in the eCRF if administered for related SAEs/AESI and/or for 
secondary hematological malignancies. 
 
During the COVID-19 pandemic that limits or prevents on-site study visits, 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. 
 
8.5.2 
Laboratory Assessments 
The laboratory assessments require that blood samples for hematology and blood chemistry, and 
a urine sample for urinalysis are taken (Table 8-3, and Table 8-4). Laboratory assessments will 
be performed at the investigational site. 
At Screening: all patients will have screening laboratory assessments including hematology and 
blood chemistry within 3 weeks (preferably 2 weeks in the Lutathera arm) before the projected 
first treatment date. 
During the Treatment Phase (including cross-over and re-treatment): 

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• 
In the Lutathera arm: within 2 weeks before and 4±1 weeks after each Lutathera treatment. 
In addition, for the second, third, and fourth Lutathera treatment, an additional laboratory 
assessment will be performed on the same day, or within one day prior Lutathera 
administration. Blood tests performed 4 weeks after any treatment cannot serve as baseline 
values for the next treatment. After the end of Lutathera treatment, laboratory assessments 
will be performed every 12+1 weeks (see Table 8-2 and Visit Schedule in Table 8-3). 
• 
In the 60 mg octreotide long-acting arm: throughout the study laboratory assessments will be 
performed 4 weeks (+3 days) after the first treatment till Week 28, and every 12+1 weeks 
from Week 36 onwards (see Visit Schedule in Table 8-4). 
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 safety laboratory results must be evaluated by the Investigator before administration of study 
medication. 
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. 
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. 
 
Table 8-2. Laboratory Assessments1. 
 
Haematology 
Blood Chemistry 
Pregnancy test 
• 
WBC with differential2 
• 
Platelets2 
• 
Hb2 
• 
MCV 
• 
Haematocrit 
• 
BUN or urea 
• 
Serum creatinine3 
• 
Creatinine Clearance3 
• 
Uric acid 
• 
Albumin 
• 
Total bilirubin3 
• 
AP 
• 
AST/ASAT 
• 
ALT/ALAT 
• 
Gamma-GT 
• 
Sodium 
• 
Potassium 
• 
Magnesium 
• 
LDH 
• 
CgA4 
• 
GlycoHb (haemoglobin 
A1C) 
• 
Pregnancy test, if 
applicable (urine 
pregnancy test is 
accepted5) 

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• 
TSH (and free Thyroxine 
(fT4) if TSH is abnormal) 
• 
Calcium 
• 
Fasting blood Glucose 
1 Laboratory assessments performed on the same day or within one day prior to administration of the second, third, and fourth 
doses of Lutathera must include at minimum: 
• 
serum urea or blood urea nitrogen and creatinine (including creatinine clearance calculation) 
• 
serum potassium, serum total bilirubin, aspartate aminotransferase and alanine aminotransferase 
• 
hemoglobin, platelet count, total leukocyte count, and absolute neutrophil count. 
2 Before each Lutathera dose, patients must meet the criteria for Hb, WBC, and platelets, as defined in the inclusion criteria, at 
baseline and before each subsequent treatment. If the patient cannot be retreated due to haematological abnormalities, the 
evaluation must be repeated at least once weekly until re-treatment. 
3 Before each Lutathera dose, patients must meet the criteria for creatinine clearance and total bilirubin as defined in the 
eligibility criteria at baseline and before every re-treatment. As entry criterion, patients must not have creatinine clearance <40 
mL/min calculated by the Cockroft Gault method. During the course of the study, if in the Lutathera arm a 40% increase over 
the baseline serum creatinine value occurs during the course of treatment, or a decrease of over 40% in creatinine clearance as 
calculated from serum creatinine concentrations according to Cockcroft-Gault formula, DMT rules must apply (Table 6-4) and 
patients must also have a measured creatinine clearance (or GFR) performed. Measured creatinine clearance should be through 
a 24-h urine collection. Total urinary protein should also be measured in this collection. If the measured urinary creatinine 
clearance shows decrease of ≤40% compared to baseline, treatment can continue. 
The Cockcroft-Gault formula allows this estimation based on the occurrence of creatininemia, and correlating patient muscular 
mass (and so the consequent creatinine production) to weight, gender and age: 
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(umol/L)] 
(multiply by 0.85 for women) 
4 In South Korea only, CgA assessment being discontinued in Q3 2022 due to lab kits shortage 
5 For UK, serum pregnancy test is mandatory at baseline 
 
During the Follow-up Phase, in both study arms laboratory assessments (hematology and blood 
chemistry) will be performed every 6 months (± 1 month). 
 
8.5.3 
Pregnancy Test 
Women who receive Lutathera in the study, including those who crossed over to Lutathera and 
those re-treated with Lutathera, should not procreate during Lutathera treatment and until six 
months after the end of their last treatment with Lutathera, or until the end of treatment period 
of the study, whichever is longer. Women in the control arm should not procreate until the end 
of treatment period. 
A pregnancy test (either on urine or blood) must be performed at baseline and within 14 days 
(preferably 7 days) prior to each Lutathera treatment for every female patient of childbearing 
potential (Section 5 and Appendix 1). 
Ionizing radiations of lutetium (177Lu) oxodotreotide may potentially have temporary toxic 
effects on female and male gonads (decrease of inhibin-B and concomitant increase of FSH, 
suggesting radiation damage to Sertoli cells). Fertility is usually restored 12 to 18 months after 
treatment. The participant will be recommended to seek genetic consultation before starting 
treatment if the patient wishes to have children after treatment, which includes the option of 
cryopreservation of sperm or eggs before treatment starts. 
For UK only: 

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A pregnancy test (blood) must be performed at baseline in both arms and within 7 days prior to 
the first Lutathera treatment. A urine or blood pregnancy test must be performed within 7 days 
prior to each Lutathera treatment for every female patient of childbearing potential (Section 5 
and Appendix 1). A urine or blood pregnancy test must be performed in both arms at the end of 
the relevant systemic exposure to octreotide. 
 
For Germany only: 
A pregnancy test must be performed at baseline in both arms (either on urine or blood). In the 
Lutathera arm, a urine or blood pregnancy test must be performed monthly during the treatment 
phase (within 7 days prior to each Lutathera treatment) (Section 5 and Appendix 1) and for the 
following six months after the end of treatment with Lutathera for every female patient of 
childbearing potential. 
 
 
8.5.4 
Cardiac Ejection Fraction 
Patients with uncontrolled congestive heart failure (NYHA II, III, IV) are not eligible according 
to exclusion criteria. 
Patients with history of congestive heart failure who do not violate this exclusion criterion will 
undergo an evaluation of their cardiac ejection fraction prior to randomization via 
echocardiography. The results from an earlier assessment (not exceeding 30 days prior to 
randomization) may substitute the evaluation at the discretion of the Investigator, if no clinical 
worsening is noted. The patient’s measured cardiac ejection fraction in these patients must be 
≥40% before randomization. 
 
8.5.5 
ECG 
Standard 12-lead ECGs will be performed using the device provided by the Sponsor (central 
assessment). ECGs will be recorded at baseline, after each Lutathera treatment procedure 
(following the completion of the amino acids infusion), at the end of study treatment and at the 
end of study follow up phase to measure the different ECG intervals (RR, PR, QRS, and a more 
extended QT evaluation according to ICH E14). ECGs will be taken also in the 60 mg octreotide 
long-acting arm at same time points (before the octreotide long-acting injection). See ECG 
Manual for further details and visits schedule in Table 8-3, and Table 8-4). 
An ECG in triplicate (at least 5 minutes apart) will be taken supine, after 10 minutes rest, and 
not immediately after a meal. The parameters will be measured as a mean value of minimally 3 
beats. The preferred sequence of cardiovascular data collection during study visits 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. Local cardiologist ECG assessments may also be 
performed at any time during the study at the discretion of the investigator. 
All ECGs, including unscheduled triplicate safety ECGs with clinically relevant findings, 
collected during the study should be transmitted to the central core ECG laboratory for review. 

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The Investigator/local cardiologist 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 based 
on their own review of the ECG tracing. Relevant abnormalities at baseline 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. Any identifier details must 
be redacted e.g. subject initials, date of birth. Each ECG tracing should be labeled with the study 
number, subject initials (where regulations permit), subject number, date, and kept in the source 
documents at the study site. 
The results of the centrally assessed ECGs are automatically transferred into the clinical 
database. 
 
8.5.6 
Physical Examination and Vital Signs 
Physical examinations will be performed by the Investigator, or qualified designee. All body 
systems will be examined and any relevant findings will be documented in the source documents 
and eCRF. Physical examinations should include heart rate, blood pressure and weight 
measurement (height will only be measured at baseline). Blood pressure and pulse rate will be 
performed after the patient rests for 5 minutes. For each patient, all blood pressure recordings 
shall be made using the same type of instrument (i.e., manual BP recording vs. automatic digital 
vital signs monitor) on the same arm. 
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. 
 
8.5.7 
Karnofsky Performance Score 
KPS forms must be completed by a medical professional at each treatment and follow-up visit, 
and before any current clinical information is given to the patient (Appendix 3). 
 
 
8.5.8 
Ultrasonic examination of the gallbladder (Germany only) 
Only for Germany: 
Ultrasonic examination of the gallbladder before and at six-monthly intervals during Octreotide 
LAR treatment in order to detect and prevent possible cholecystitis and biliary duct dilatation 
risks for the patients is recommended according to the Octreotide label. 
 
 
8.5.9 
SPECT/CT and whole body planar imaging (Germany only) 
Only for Germany: 

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SPECT/CT imaging and whole body planar imaging should be performed after each Lutathera 
injection (local assessment only), as per local standards. The dosimetry results will be collected 
in eCRF. 
In other Countries, physicians may also decide to perform SPECT/CT scans for treatment 
verification purposes following the drug administration(s), based on institutional guidelines and 
their discretion. 
 
8.5.10 
Assessments Schedule 
The Assessment Schedule in the two study arms is shown in Table 8-3, and Table 8-4. 
 
In the Lutathera arm, safety laboratory assessments will be performed within 2 weeks before and 
4±1 weeks after each Lutathera treatment. In addition, for the second, third and fourth Lutathera 
treatment, an additional safety laboratory assessment will be performed on the same day or 
within one day before each treatment (see Table 8-2). 
The Lutathera treatment / assessment schedule shown in Table 8-3 is idealized in the sense that 
all Lutathera treatments occur at defined 8-week interval (±1 week). In the event that the intervals 
are greater than the defined 8-week interval (±1 week), the investigator will need to ensure that 
the correct safety assessments before and after each treatment have been conducted (safety 
assessments must be performed within 2 weeks before and 4 weeks after each Lutathera 
treatment, see Table 8-3). 
Exams to be done in relation to the Lutathera treatments (within two weeks before the infusion, 
one the day of the infusion, 4±1 weeks after infusion) can be combined with those required at 
other visits during the study, if less than 2 weeks apart. 
During the Follow-up Phase, in both study arms study visits will be performed every 6 months 
(± 1 month) up to 3 years. 

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Table 8-3. Assessment Schedule Lutathera Arm. 
 
Visit Name 
Scre 
enin 
g 
Treatment 
Further Visits 
after 72 weeks1 
EOT or 
early 
terminati 
on 
Optional re- 
treatment 
(2-4 Lutathera 
cycles) 
3 
years 
follow- 
up 
EOS 
or 
early 
FUP 
termi 
natio 
n 
Weeks 
-2 - 0 
0 4 
6 
8 
12 14 16 20 22 24 28 32 36 40 44 48 52 56 60 64 68 72 Every 
4 weeks 
Every 
12 
weeks 
Within 4 
weeks 
from last 
treatment 
Every 
6 
month 
s 
Last 
FUP 
visit 
Treatment 


 
 
 

 
 
  

 
 
2-4x 
Informed 
consent 
X 
Complete all 
assessments and 
procedures in Table 8- 
3 from week -2 
(except demography, 
INC/EXC criteria, 
cancer diagnosis and 
grading, medical 
history, randomization, 
QoL) until disease 
progression, after 
which EoT visit is 
done and patient 
proceeds into follow 
up. Patients must sign 
the new consent and 
have SRI imaging 
documenting tumor 
uptake before re- 
treatment. SSA 
administration at 
investigator judgment. 
Demography 
X 
Inclusion/exclusi 
on criteria 
X 
Cancer 
diagnosis and 
grading 
X 
Prior therapy for 
carcinoid tumor 
X 
Medical history 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky 
Performance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac Ejection 
Fraction2 
X 
Randomization 
and Lutathera 
order (after all 
elig bility criteria 
are verified)3 
X 
Blood chemistry 
X 
X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Assessment Schedule Lutathera Arm – cont. 
 
Visit Name 
Screeni
ng 
Treatment 
Further 
Visits 
after 72 
weeks1 
EOT or early 
termination 
Optional re- 
treatment 
(2-4 Lutathera 
cycles) 
3 years 
follow- 
up 
EOS or 
early 
FUP 
termin 
ation 
Weeks 
-2 - 0 
0 
4 
6 
8 
12 14 16 20 22 24 28 32 36 40 44 48 52 56 60 64 68 72 Every 
4 weeks 
Every 
12 
weeks 
Within 4 
weeks 
from last 
treatment 
Every 
6 
months
Last 
FUP 
visit 
Treatment 
 

 

 

 



 
 
2-4x 
 
Pregnancy Test 
X 
X4 
X X4 
X X4 
X X4 X4 X4 X4 X4 X4 X4 
X4 
Complete all 
assessments and 
procedures in Table 
8-3 from week -2 
(except demography, 
INC/EXC criteria 
cancer diagnosis and 
grading, medical 
history, 
randomization, QoL) 
until disease 
progression, after 
which EoT visit is 
done and patient 
proceeds into follow 
up. Patients must sign 
the new consent and 
have SRI imaging 
documenting tumor 
uptake before re- 
treatment. SSA 
administration at 
investigator 
judgment10. 
Serum CgA5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SRI (eg SomaKit or 
Netspot or 
OctreoScan)6 
X 
SPECT/CT and 
WBPI7 
X7 
X7 
X7 
X7 
CT/MRI (central re- 
assessment during 
treatment phase) 
X 
X 
X 
X 
X 
X 
X 
X 
X9 
X 
X11 
ECG (central re- 
assessment; Sponsor 
device) [at the end of 
amino acids infusion 
during treatment] 
X 
X 
X 
X 
X 
X 
X 
Adverse Events8 
X 
X X X X X X X X X X X X X X X X X X X X X X X 
X 
X 
X 
X 
Prior/Concomitant 
Medications/New 
Anticancer therapy 
X 
X X X X X X X X X X X X X X X X X X X X X X X 
X 
X 
X12 
X12 
Lutathera/Amino 
Acid/Anti-emetics 
X 
X 
X 
X 
Octreotide long- 
acting 30 mg 
Injections to be administered at least after 4 hours after each Lutathera treatment or the day after (preferred option), 
Last injection should be administered at least 6 weeks before each Lutathera infusion 
Octreotide SC 
Octreotide s.c. injection can be given as needed but must be stopped 24h before each Lutathera infusion 
QoL(QLQ-G.I.NET21, 
QLQ-C30, EQ-5D-5L) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival information 
X 
X X X X X X X X X X X X X X X X X X X X X X X 
X 
X 
X 
X 

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-TREATMENT PHASE: 
  TREATMENT: Lutathera; 4 administrations at 8±1-week intervals 
  TREATMENT: 30 mg octreotide long-acting injections to be administered the day after each Lutathera infusion 
Due to the 6 weeks washout prior to each Lutathera injection, octreotide long-acting 30 mg is administered every 8 weeks during Lutathera 
treatment (including during the optional treatment extension phase) and every 4 weeks after last Lutathera treatment. 
IF REQUIRED, RESCUE TREATMENTS: Octreotide s.c. injections (to be stopped 24 h before each Lutathera infusion) 
 
1- Before the PFS primary analysis (i.e. 99 evaluable and centrally confirmed disease progressions or death events), patients continue the Treatment Phase 
until progression. After the PFS primary analysis, the Treatment Phase duration becomes fixed (72 weeks). 
2- Via echocardiography, only in patients with history of congestive heart failure (patients with uncontrolled congestive heart failure (NYHA II, III, IV) 
aren't eligible according to exclusion criteria) 
3- Randomization must be performed once all screening assessments are complete. The screening phase must be shortened as much as possible in order 
to treat the patients possibly within 2 weeks from the consent date. As Lutathera production and shipment will take approximately 12 days to be 
arranged, if a patient is randomized in the Lutathera arm, Lutathera first dose must be ordered immediately after randomization. 
The baseline CT/MRI scan should be taken possibly on the same day of randomization or immediately before (within 1 week) to ensure that it reflects 
the disease status closely before the therapy start. 
4- Additional pregnancy tests for Germany only. The pregnancy test at EoT is for Germany and UK. 
5- CgA assessment being discontinued in Q3 2022 due to lab kits shortage in South Korea only 
6- There is no central ‘real time’ assessment of the SRI images; the images should be submitted to the central imaging center possibly within 1 month. 
7- SPECT/CT and WBPI post Lutathera injection requested in Germany only. 
8- Only related SAEs & AESI will be collected during the Follow-up Phase, with the exception of AESI of secondary hematological malignancies which will 
be collected during the Follow-up Phase irrespective of causality (see Section 10.1.5 for AESI definition). 
9- Only if a scan was not taken in the previous 12 weeks; if no post-baseline scan is available, a scan is needed at EOT. 
10- For patients who entered the Lutathera re-treatment phase, since there are no procedures requiring in-person patient’s attendance, the following visits 
can be performed by phone: Visits W32, 40, 44, 52, 56, 64 and 68 following Lutathera re-treatment (for Germany only: visits W56, 64 and 68). 
Post progression Re-Treatment Eligibility CT/MRI scan doesn’t need to be repeated if performed within the previous 12 weeks. Both Re-treatment 
Eligibility SRI and CT/MRI scans need to be submitted to the central imaging center for a second review: there is no central ‘real time’ assessment of the 
Re-treatment Eligibility SRI uptake; however, the images should be submitted to the central imaging center possibly within 1 month. 
11- Only if a scan was not taken in the previous 6 months. 
12- During Follow-up Phase and at the EOS visit, concomitant medications must be collected only if administered for related SAEs/AESI and/or for 
secondary hematological malignancies. In addition, all new anticancer therapies administered must be collected till EOS. 

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Table 8-4. Assessment Schedule Octreotide Long-Acting 60 mg Arm. 
 
Visit Name 
Scree 
ning 
Treatment 
Further Visits 
after 72 weeks1 
EOT or 
early 
termination 
Optional 
cross-over 
(4 Lutathera 
cycles)2 
3 years 
follow- 
up 
EOS or 
early 
FUP 
terminati 
on 
Weeks 
-2 - 0 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
Every 
4 
weeks 
Every 
12 
weeks 
Within 4 
weeks from 
last 
treatment 
Every 
6 
months 
Last FUP 
visit 
Treatment 
                    
 
4x   
Obtain 
informed 
consent 
X 
Complete all 
assessments in 
Table 8-3 from 
week -2 (except 
demography, 
cancer 
diagnosis and 
grading, medica
history, 
randomization) 
to Week 24 (last
Lutathera dose)
after which EoT 
visit is done and
patient 
proceeds into 
follow up. 
Patients must 
sign the new 
consent before 
cross-over and 
have SRI 
imaging 
documenting 
tumor uptake. 
All protocol 
inclusion/exclusi 
on criteria must 
be re-verified. 
Demography 
X 
Inclusion/exclu 
sion criteria 
X 
Cancer 
diagnosis and 
grading 
X 
Prior therapy 
for carcinoid 
tumor 
X 
Medical history 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky 
Performance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac 
Ejection 
Fraction3 
X 
Randomization 
(after all 
eligibility 
criteria are 
verified)4 
X 
Blood 
chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Assessment Schedule Octreotide Long-Acting 60 mg Arm – cont. 
 
 
 
 
 
 
 
 
 
Visit Name 
Scree 
ning 
Treatment 
Further Visits 
after 72 weeks1 
EOT or 
early 
terminatio 
n 
Optional 
Treatment 
Extension 
(4 Lutathera 
cycles)2 
3 years 
follow- 
up 
EOS or 
early 
FUP 
termin 
ation 
Weeks 
-2 - 0 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
Every 
4 
weeks 
Every 
12 
weeks 
Within 4 
weeks from 
last 
treatment 
Every 
6 
months 
Last 
FUP 
visit 
Treatment 
             
       
 
4x   
Pregnancy Test 
X 
X5 
Complete all 
assessments in 
Table 8-3 from 
week -2 (except 
demography, 
cancer diagnosis 
and grading, 
medical history, 
randomization) to 
Week 24 (last 
Lutathera dose), 
after which EoT 
visit is done and 
patient proceeds 
into follow up. 
Patients must 
sign the new 
consent before 
cross-over and 
have SRI imaging 
documenting 
tumor uptake. 
All protocol 
inclusion/exclusio 
n criteria must be 
re-verified. 
Serum CgA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SRI (SomaKit or 
Netspot or 
OctreoScan)7 
X 
CT/MRI (central 
re-assessment 
during treatment 
phase) 
X 
X 
X 
X 
X 
X 
X 
X 
X10 
X 
X11 
ECG (central re- 
assessment; 
Sponsor device) 
X 
X 
X 
X 
X 
X 
X 
PK (central 
assessment)8 
X 
X 
X 
X 
Adverse Events9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant 
Medications/New 
Anticancer 
therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
X12 
Octreotide long- 
acting 60 mg 
Injections to be administered every 4 weeks. Patients who were SSA-naïve before enrolment in the study, should receive first planned dose at 30mg 
and the second (and subsequent) planned dose(s) at 60mg (full dose). 
Octreotide SC 
Octreotide s.c. injection can be given as needed 
QoL(QLQ- 
G.I.NET21, QLQ- 
C30, EQ-5D-5L) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival 
information 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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-TREATMENT PHASE: 
  TREATMENT: 60 mg octreotide long-acting injections every 4 weeks (±3 days) 
  TREATMENT: Lutathera; 4 administrations at 8±1-week intervals 
-OPTIONAL EXTENSION TREATMENT PHASE: 
  TREATMENT: 30 mg octreotide long-acting injections to be administered the day after each Lutathera infusion 
Due to the 6 weeks washout prior to each Lutathera injection, octreotide long-acting 30 mg is administered every 8 weeks during Lutathera 
treatment. IF REQUIRED, RESCUE TREATMENTS: Octreotide s.c. injections (to be stopped 24 h before each Lutathera infusion). 
 
1- Before the PFS primary analysis (i.e. 99 evaluable and centrally confirmed disease progressions or death events), patients continue the Treatment Phase 
until progression. After the PFS primary analysis, the Treatment Phase duration becomes fixed (72 weeks). 
2- Any progressive patient (based on central imaging assessment) has the option to enroll for post-progression cross-over to Lutathera, upon signature of 
a new consent, if the eligibility criteria are met. If RECIST progression occurs after Week 72 post the primary end point analysis, the decision to enroll 
the patient in cross-over will be based on local assessment. 
The EoT visit and evaluation of cross-over eligibility can occur on the same day. If these two visits are done on separate days, EoT can be done remotely 
by phone, and all applicable assessments can be done at the cross-over eligibility visit. If a patient continues to cross-over, 28-day window for EoT visit 
does not need to apply. 
3- Via echocardiography, only in patients with history of congestive heart failure (patients with uncontrolled congestive heart failure (NYHA II, III, IV) 
aren't eligible according to exclusion criteria). 
4- Randomization must be performed once all screening assessments are complete. The screening phase must be shortened as much as possible in order 
to treat the patients possibly within 2 weeks from the consent date. 
The baseline CT/MRI scan should be taken possibly on the same day of randomization or immediately before (within 1 week) to ensure that it reflects 
the disease status closely before the therapy start. 
5- Additional pregnancy test for UK only. 
6- CgA assessment being discontinued in Q3 2022 due to lab kits shortage in South Korea only 
7- There is no central ‘real time’ assessment of the SRI images; the images should be submitted to the central imaging center possibly within 1 month. 
8- PK assessment is done in all Countries, except China. 
9- Only related SAEs & AESI will be collected during the Follow-up Phase, with the exception of AESI of secondary hematological malignancies which will 
be collected during the Follow-up Phase irrespective of causality (see Section 10.1.5 for AESI definition). 
10- Only if a scan was not taken in the previous 12 weeks; if no post-baseline scan is available, a scan is needed at EOT. 
Post progression Cross-Over Eligibility CT/MRI scan doesn’t need to be repeated if performed within the previous 12 weeks. Both Cross-over Eligibility 
SRI and CT/MRI scans need to be submitted to the central imaging center for a second review: there is no central ‘real time’ assessment of the Cross- 
over Eligibility SRI uptake; however, the images should be submitted to the central imaging center possibly within 1 month. 
11- Only if a scan was not taken in the previous 6 months 
12- During Follow-up and at the EOS visit, concomitant medications must be collected only if administered for related SAEs/AESI and/or for secondary 
hematological malignancies. In addition, all new anticancer therapies administered must be collected till EOS. 

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8.6 Pharmacokinetics 
This section is applicable to all countries, except for China. No PK samples will be collected in 
China. 
The steady-state plasma concentrations of high dose octreotide long-acting will be assessed in 
the control arm of the study. 
All samples will be taken by either direct venipuncture or indwelling cannula inserted in a 
forearm vein. Blood samples (2.5 mL each sample) will be collected to yield approximately 1 
mL plasma for analysis of octreotide concentration. Immediately after blood is drawn into 
K3EDTA tubes, they should be inverted gently several times to ensure the mixing of tube 
contents. Prolonged exposure to rubber stopper should be avoided. The tube should be placed 
upright in tube rack surrounded by ice until centrifugation. Within 20 minutes, the sample should 
be centrifuged between 3ºC and 5ºC for 10 minutes at approximately 1000 x g. Immediately after 
centrifugation, 1.0 mL plasma should be transferred to a polypropylene screw-cap tube immersed 
in dry ice. The storage temperature for PK samples should be at or below minus 20°C (-20°C). 
The samples will be sent to an external laboratory for central assessment (see further details in 
the PK Manual). 
 
Table 8-5. Octreotide long-acting PK blood collection plan 
 
CONTROL ARM 
Sample 
Volume (mL) 
Week 
PK Collection # 
Scheduled time (h) 
Blood 
2.5 
4 
1 
0 (pre-dose)* 
Blood 
2.5 
12 
2 
0 (pre-dose)* 
Blood 
2.5 
16 
3 
0 (pre-dose)* 
Blood 
2.5 
24 
4 
0 (pre-dose)* 
*Blood sample for PK must be collected before octreotide long-acting injection. 
 
 
8.6.1 Analytical method 
Octreotide plasma concentration will be measured using a validated radio-immunoassay (RIA). 
All PK samples will be shipped to the central laboratory where they will be stored and forwarded 
to the pharmacokinetic facility for bioanalysis. 
 
8.7 Biomarkers 
Serum Chromogranin A (CgA) will be locally assessed at 12-weeks intervals during the 
treatment. The CgA assessment is discontinued in South Korea in Q3 2022 due to lab kits 
shortage. 

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8.8 Imaging 
Central, blinded, real-time IRC (Independent Review Committee) CT/MRI assessment is 
implemented in this trial. Images will be also assessed by the site local radiologist. 
The primary efficacy end-point of the study is PFS as measured by objective tumor response, 
which is determined by RECIST criteria, Version 1.1 (Eisenhauer, et al., 2009). Sponsor will 
notify all the Centers and their Ethic Committees as soon as the 99 PFS primary End-Points have 
occurred. 
Changes from randomization date will be assessed centrally until the completion of the 
Treatment Phase, unless the patient progresses or dies. Additional PFS data will be collected up 
to 3 years (follow-up phase) from the end of Treatment Phase of the last patient. If a patient 
participates after progression to the optional Treatment Extension Phase or optional Re-treatment 
Phase, scans will be assessed locally according RECIST 1.1, according to the frequency indicated 
in Table 8-3, and Table 8-4. 
During the Treatment Phase, restaging is scheduled at week 16±1, week 24±1 and then every 12 
±1 weeks (from the date of randomization). The first CT/MRI re-staging at week 16 will ensure 
that control arm patients who are SSA-naïve will receive at least 12 weeks of octreotide long- 
acting full dose (60mg) after the completion of the dose escalation phase (see Section 6.5.2), 
while patients in the Lutathera arm will receive at least 2 Lutathera doses before the first tumor 
response assessment. As described in Section 12.8.1, the study sample size has been estimated 
considering a median PFS of approximately 15 months in the control arm and 30 months in the 
Lutathera arm, therefore the proposed CT/MRI schedule, and in particular, the first re-staging at 
week 16, is consistent with the protocol assumptions. 
Clinical suspicion of disease progression before week 16 and at any time during the study 
requires a physical examination and imaging assessments to be performed promptly rather than 
waiting for the next scheduled imaging assessment. These additional scans should be provided 
to the IRC for central assessment. If an off-schedule imaging assessment is performed because 
progression is suspected, subsequent imaging assessments should be performed in accordance 
with the original imaging schedule. 
In case of delays, the reason of the delay must be documented, and the CT/MRI assessment must 
be done as soon as possible. When a CT/MRI assessment is > 6 weeks earlier or later than the 
original schedule, the next reassessments must be discussed and adjusted with the Medical 
Monitor of the study in a way to progressively return to the original schedule. 
Every effort should be made to avoid differences between these timings for patients in the two 
arms, unless this would result in a deviation of the protocol (re-staging at week 16±1, week 24±1 
and then every 12 ±1 weeks from randomization). The CT/MRI scans should be avoided in the 
6-weeks period following Lutathera administration due to the PRRT-induced pseudo- 
progression phenomenon described in literature (Brabander, et al., Pitfalls in the response 
evaluation after peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate., 
2017b). If a CT/MRI scan is planned on the same day of a Lutathera treatment, the scan must be 
taken before the drug administration. As reported by Brabander et al. (2017b), an increase in the 
diameter of lesions of 10% or more on imaging was seen in 9% of patients with SD at 6 weeks 

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post PRRT and was reversible at 6 months follow-up in 50% of patients. This transient increase 
was probably caused by inflammation causing localized oedematous tissue at the site of the 
metastases and not based on progression. This radiogenic oedema has been described previously 
for PRRT and external beam radiation of brain tumors (Kneifel, et al., 2006; Barani & Larson, 
2015). In studies with cytokines, cancer vaccines and monoclonal antibodies an early increase in 
tumor burden has been demonstrated in patients with CR, PR or SD as treatment outcome. This 
phenomenon was described as pseudo-progression and resulted in a new response method, the 
immune-related response criteria (irRC) (Wolchok, et al., 2009). This increase in the tumor size 
after immunotherapy is probably related to infusion of lymphocytes and macrophages in the 
tumor and new lesions are not always considered as PD. 
In case of discrepancies between Investigator and central assessor on the evaluation of the 
progression of disease, the following is recommended: 
1. Investigator assessment: non-PD; central assessment: PD. The Treatment Phase of the 
study is terminated and the patient should proceed to the Follow-up Phase. The 
investigator may request the continuation of treatment (Lutathera until the cumulative 
dose limit has been reached and/or octreotide long-acting provided by the Sponsor 
according to randomization; 12-week local tumor assessments; safety assessments as in 
the treatment/assessment phase of the study) until progression has been documented by 
the Investigator, thereafter, the patient will proceed to the follow-up assessment phase. 
Alternatively, the patient can be enrolled in the optional Treatment Extension Phase, if 
the eligibility criteria are met (see Section 5.2.1). 
2. Investigator assessment: PD; central assessment: non-PD. The Treatment Phase of the 
study should be continued as planned. However, the Investigator may decide to withdraw 
the patient from the Treatment Phase because of unethical continuation of the study in 
his/her opinion, and start the Follow-up Phase of the study. Such cases should be limited 
as much as possible and discussed with the Sponsor Medical Monitor before withdrawing 
the patient and all attempts should be made to continue central scans assessment until 
central confirmation of progression according to RECIST. 
The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers. 
The methods for assessment and recording are specified in the imaging manual and imaging 
charter. 
See Section 8.3.1 for further details. 

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9 
Study discontinuation and completion 
9.1 Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being. 
Study treatment must be discontinued under the following circumstances: 
• 
Disease progression 
• 
Unacceptable adverse event, including meeting stopping criteria as described in Section 6.5.2 
• 
Subject/guardian decision 
• 
Pregnancy 
• 
Use of prohibited treatment as per recommendations in Section 6.2.3 
• 
Any situation in which study participation might result in a safety risk to the subject. 
 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort to 
understand the primary reason for the subject’s premature discontinuation of study treatment and 
record this information. 
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. 
 
Subjects 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. Where possible, they should return for the assessments 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 subject/predesignated contact as specified 
in the lost to follow-up section (Section 9.1.3). This contact should preferably be done according 
to the study visit schedule. 

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If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This telephone 
contact should preferably be done according to the study visit schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact (per assessment schedule in 
Table 8-3 and Table 8-4): 
• 
new / concomitant treatments including any radiotherapy, surgical procedure or new 
anticancer therapy 
• 
adverse events/Serious Adverse Events 
• 
survival status 
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 by telephone 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. 
 
9.1.1.1 
Replacement policy 
Not applicable. Subjects will not be replaced on study. 
A subject can be re-screened with a new study number when intercurrent conditions emerging 
after consent signature and impeding the planned randomization are resolved. Such cases must 
be discussed and approved by the Sponsor. The site will be informed about the procedures to be 
followed for re-screening. 
 
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 based on consent and when a 
participant: 
• Explicitly requests to stop use of their data 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 

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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. All efforts should be 
made to have any study drug returned to the Investigator. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. All efforts should be made to complete the assessments prior to 
study withdrawal. A final evaluation at the time of the subject’s study withdrawal should be 
made as detailed in the assessment table. 
Advanced Accelerator Applications will continue to retain and use all research results (data) that 
have already been collected for the study evaluation. 
 
9.1.3 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study. 
 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Advanced Accelerator Applications at any time for any reason. 
This may include reasons related to the benefit/ risk assessment of participating in the study, 
practical reasons (including slow enrollment), or for regulatory or medical reasons. In taking the 
decision to terminate, Advanced Accelerator Applications will always consider the subject 
welfare and safety. Should early termination be necessary, subjects must be seen as soon as 
possible (provide instruction for contacting the subject, when the subject should stop taking drug, 
when the subject should come for a final visit) and treated as a prematurely withdrawn subject. 
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 subject’s interests. The investigator or 
sponsor depending on the local regulation will be responsible for informing IRBs/IECs of the 
early termination of the trial. 
 
9.2 Study completion and post-study treatment 
Subjects will be followed during the study per the schedule of assessments (refer to Table 8-3 
and Table 8-4). 
Before the PFS primary analysis (99 evaluable and centrally confirmed disease progressions or 
death events), patients continue the Treatment Phase until progression; after the PFS primary 
analysis, the Treatment Phase duration becomes fixed (72 weeks). 
 
Following the end of treatment or early treatment discontinuation, alive patients will enter in the 
Follow up Phase unless unfeasible (e.g. consent withdrawal, patient lost to follow-up). All treated 
subjects should have a safety follow up visit conducted 30 days after last administration of study 
treatment (EoT visit). The information collected is kept as source documentation. Documentation 
of attempts to contact the subject should be recorded in the source documentation. 

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At any time during the study (before or after the primary End-Point analysis) any progressive 
patient (based on central imaging assessment) immediately ceases the Treatment Phase and 
proceeds to the Follow-up Phase assessment. 
Patients randomized in the control arm have the option to enroll for post-progression cross-over 
upon signature of a new consent (optional Treatment Extension Phase) and receive maximum 4 
cycles of Lutathera (7.4 GBq / 200 mCi x 4 cycles; cumulative dose: 29.6 MBq / 800mCi) plus 
octreotide long-acting every 8 weeks. For these patients, the EoT visit and evaluation of cross- 
over eligibility can occur on the same day. If these two visits are done on separate days, EoT can 
be done remotely by phone, and all applicable assessments can be done at the cross-over 
eligibility visit. If a patient continues to cross-over, 28-day window for EoT visit does not need 
to apply. 
Patients randomized in the Lutathera arm have the option to enroll for post-progression Re- 
treatment Phase upon signature of a new consent and receive 2-4 additional cycles of Lutathera 
(7.4 GBq / 200 mCi) every 8 weeks. Re-treatment Phase will last until a locally confirmed disease 
progression or until EoS, whichever occurs first. 
The control arm patients who will consent to post-progression cross-over with Lutathera, and the 
Lutathera arm patients who will consent to post-progression re-treatment with Lutathera, will 
continue study assessments as planned in Table 8-4; these patients will enter in the Follow up 
Phase after the end of Lutathera treatment. 
The End of Study (EOS) is when 4 years have elapsed from the randomization of the last patient, 
or 6 months after the last cross-over or re-treatment dose, whichever occurs last. The time 
window to start cross-over/re-treatment is further discussed in Sections 5.2.1, 5.2.2 and 9.2.1. 
At the End of Treatment (EOT) or End of Study (EOS) or early discontinuation visit, any repeat 
assessments associated with this visit should have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
and reason of that decision. 
At the EoT, a CT/MRI scan for RECIST assessment is required only if not taken in the previous 
12 weeks. If no post-baseline scan is available, a scan is needed at EoT. At the EoS, a CT/MRI 
scan for RECIST assessment is required only if a scan was not taken in the previous 6 months. 
Each subject will complete their EOS visit at the end of the study (after 3 years of follow up from 
the end of the Treatment Phase, at early withdrawal from the study, death, withdrawal of consent, 
lost to follow-up or when the end of study is communicated by Sponsor). The last 6-monthly 
follow-up visit will be considered EOS visit, when all assessments need to be performed as 
indicated in the Assessment Schedule for EOS. 
Post relapse therapy will be permitted during the study in the Follow-up Period per Investigator 
discretion, but not provided or administered as study treatment. 
The final OS analysis will be performed when the last subject completes their EOS visit. All 
available data from all subjects up to this cut-off date will be analyzed. All adverse events during 
the study period must be reported as described in Section 10. 

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In the event the study is terminated due to futility, study subjects currently on study treatment in 
the Treatment Phase and who are still deriving clinical benefit will be eligible to continue their 
Lutathera treatment through a locally established Advanced Accelerator Applications program. 
Lutathera treatment through a locally established Advanced Accelerator Applications program 
will not be part of this clinical trial and will follow the applicable local regulations. 
 
9.2.1 
Post-trial access to Lutathera 
The time window to start re-treatment in this study is within 4 years after the last patient has 
been randomized (Section 3.4). Patients who are eligible to Lutathera re-treatment beyond this 
window and would derive clinical benefit from it based on the investigator’s evaluation may 
receive post-trial access (PTA) to Lutathera. PTA to Lutathera may be granted via Post Study 
Drug Supply (PSDS) programs, based on local regulation in a non-trial setting. The PSDS must 
comply with local laws and regulations in the participating trial countries. 

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10 
Safety monitoring and reporting 
10.1 Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
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 subject or 
clinical investigation subject 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. 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
AAA 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 event monitoring must be 
continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose of 
study treatment. 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 subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject 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): 
1. The Severity grade OR the Common Toxicity Criteria (CTC) AE grade. 
a. If “severity grade” is selected, include the following: 
i. mild: usually transient in nature and generally not interfering with normal 
activities 

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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 from 1 to 5. 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on 
a single patient 
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 SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met. 
5. Action taken regarding with study treatment 
6. All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 
• 
Dose not changed 
• 
Dose Reduced 
• 
Drug interrupted/withdrawn 
7. Its outcome i.e., its recovery status or whether it was fatal 
 
If the event worsens the event 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. 
Conditions that were already present at the time of informed consent should be recorded in the 
medical history of the patient. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment 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. 

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Information about adverse drug reactions for the investigational drug can be found in the 
Investigator’s Brochure (IB). 
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 subjects with 
the underlying disease. 
Progression of GEP-NET (including fatal outcomes), if documented by use of appropriate 
method, should not be reported as a serious adverse event, except if the investigator considers 
that progression of malignancy is related to study treatment. 
If patients in the study have been infected and/or tested for SARS-CoV-2 (COVID-19), sites 
should capture the patient-relevant details in the patient charts/source data, i.e. start and end dates 
of suspected infection when information is available, any date of test(s) performed, test 
name/method together with the result (positive/ negative), treatment interruptions or 
discontinuations for each of the impacted patients enrolled in the trial. 
If an infection is suspected based on symptoms suggestive of COVID-19, sites are requested to 
enter an AE with AE term as ‘Suspected COVID-19’ or as ‘Confirmed COVID-19’ if confirmed 
by testing (e.g. antigen/radiologic) 
 
• For Suspected cases, if a test is performed and confirms COVID-19, sites are requested to 
update the Suspected COVID-19 AE record with AE term as ‘Confirmed COVID-19’, however, 
not altering the start date. 
 
• For Suspected cases, if a test is performed and does not confirm COVID-19, sites are requested 
to follow the normal Adverse Event reporting process and record the AE term as the diagnosis, 
or if no diagnosis, the symptoms. If COVID-19 is still suspected (e.g. false negative suspected), 
the AE term can remain as ‘Suspected COVID-19’ per the Investigator’s judgement. 
 
In normal circumstances, “testing” for COVID-19 would not be reported as an Adverse Event, 
however, in order to adequately capture the impact of COVID-19 on trial patients, these will be 
required to understand the patients’ health status and sequence of events for tests performed to 
diagnose symptoms of COVID-19. 
- If a test was/tests were performed; sites are requested to enter additional AE(s) with appropriate 
AE term for the type of test with the result, such as ‘SARS-CoV-2 test negative’, ‘SARS-CoV- 
2 test positive’, etc. 
- Start Date and End Date should be entered as the date of the test 

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- All other fields on Adverse Event CRFs should remain blank. Any resulting queries will be 
closed by Data Management 
- Tests performed after a patient has died should not be reported as Adverse Events 
 
The infection is considered serious and to be reported as Serious Adverse Event (SAE) only 
when it fulfills the protocol definition of a Serious Adverse Events (see Section 10.1.2 and 
Section 10.1.6). 
 
10.1.2 
Serious adverse events 
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 
• 
life-threatening 
• 
Life-threatening in the context of a SAE refers to a reaction in which the subject 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 (please 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 information consent 
­ social reasons and respite care in the absence of any deterioration in the subject’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 
• 
medically significant, e.g. defined as an event that jeopardizes the subject 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 subject 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 

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not result in hospitalization or development of dependency or abuse (please refer to the ICH- 
E2D Guidelines). 
All 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. 
COVID-19 infections are considered serious and have to be reported as Serious Adverse Event 
(SAE) only when it fulfills the protocol definition of a Serious Adverse Events. All SAE data 
should be entered as per the study level CRF completion guidelines e.g. report outcome as ‘fatal’ 
if the patient died due to COVID-19. 
In case a patient died due to COVID-19, it must be clear from the eCRF if the death was due to 
underlying COVID-19 or a different reason. Therefore, ‘Primary Cause/ Reason for Death’ 
should indicate ‘Suspected COVID-19’ or ‘Confirmed COVID-19’. If a test is performed after 
the patient died and the assessment indicates death was due to COVID-19 infection, the ‘Primary 
Cause/ Reason for Death’ should be retrospectively changed from ‘Suspected COVID-19’ to 
‘Confirmed COVID-19’. 
 
 
10.1.3 
Adverse Drug Reaction (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. 
In the case of octreotide, “expectedness” will be assessed based on octreotide Reference Safety 
Information (RSI) reported in the prescribing information. 
 
10.1.5 
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 

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communication by the Investigator to the Sponsor is appropriate. Such events require further 
investigation in order to characterize and understand them. 
AESI are defined based on the NETTER-1 study established AESI list as well as on the basis of 
an ongoing review of the safety data collected during Lutathera clinical programs and post 
marketing. 
These potential risks deserve special attention even if they do not fulfill any of the seriousness 
criteria. AESI occurring in patients enrolled in both arms should be reported to the Sponsor for 
safety analysis following the reporting procedure and timelines for SAEs. During the treatment 
phase, all AESI need to be reported to the Sponsor irrespective of causality. During the follow- 
up phase, AESI need to be reported only if considered related to the study treatment except for 
all secondary hematological malignancies which need to be reported as AESI irrespective of 
causality. 
The following AESI categories representing main risks of Lutathera and amino acid treatment 
are listed in Table 10-1. 
 
Table 10-1. Adverse events of special interest 
 
AESI categories 
Hematotoxicity 
Secondary hematological malignancies 
Nephrotoxicityg 
Cardiovascular and electrolyte disorders 
 
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 anaemia, 
leuko-/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. 
Secondary haematological malignancies: any secondary hematological malignancies, 
irrespective of causality, including MDS and acute myeloid leukemia, should be reported in 
every case, as AESI/SAE. 
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 sterile 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- 

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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). 
Cardiovascular and electrolyte disorders: All clinically significant changes in blood pressure, 
heart rate, and electrocardiogram parameters must be reported as AESI if they occur within 
reasonable propinquity of Lutathera and/or amino acid administration in the judgment of the 
Investigator. Likewise, clinically manifest and/or consequences of hypo-/hypertension, 
arrhythmias, cardiac conduction disturbances, and other cardiac pathologies evidenced by 
objective findings / changes on electrocardiogram or echocardiography should also be 
considered for AESI reporting. In addition, any clinically significant event of hyperkalemia or 
hypokalemia must be reported as AESI. 
 
 
10.1.6 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the patient has stopped study treatment must 
be reported to AAA pharmacovigilance immediately, without undue delay and under no 
circumstances later than 24 hours following knowledge of its occurrence. 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 
immediately, without undue delay and under no circumstances later than 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 AE/SAEs is collected and recorded on the SAE Report 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 AE/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 under no circumstances later than 24 hours following knowledge 
to AAA pharmacovigilance. 
Follow-up information is submitted in the same way as the original AE/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, AAA pharmacovigilance 
associate may urgently require further information from the investigator for health authority 

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reporting. AAA 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 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 30 day period should only be reported to AAA Safety if the 
investigator suspects a causal relationship to study treatment, except for secondary hematological 
malignancies which need to be reported irrespective of causality. 
 
10.1.7 
Pregnancy reporting 
To ensure subject safety, each pregnancy occurring after signing the informed consent form must 
be reported to Advanced Accelerator Applications within 24 hours of learning of its occurrence. 
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. 
Pregnancy should be recorded and reported by the investigator to the AAA Pharmacovigilance. 
Pregnancy follow-up should be recorded on the same form and should include an assessment of 
the possible relationship to the study treatment and any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported. 
 
10.1.8 
Reporting of study treatment errors including misuse/abuse 
Not applicable. 
 
10.1.9 
Annual Safety Report 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
Once per year, the sponsor or PI will supply a report on the safety of trial patients with all 
available relevant information concerning patient safety during the reference period to the 
Competent Authorities of all Countries where the trial is being conducted. This report will also 
be supplied to the responsible ethics committee. 
The annual safety report will be compiled according to the corresponding ICH guideline E2F 
“Development Safety Update Report – DSUR”. 
The data lock point for the patient data to be included and analyzed should be the last day of the 
one-year reporting period calculated from The Development International Birth Date (DIBD). 
The sponsor will submit the report within 60 calendar days after the reference date (data-lock 
point). 

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10.2 Additional Safety Monitoring 
Lutathera safety profile is well documented during Erasmus and NETTER-1 clinical trials as 
well as during post marketing surveillance, therefore additional data monitoring will not be used 
for this study. Safety data will be reviewed on regular basis by both clinical and 
pharmacovigilance departments. 
 
10.2.1 
Steering Committee 
The steering committee will be established comprising investigators participating in the trial and 
Advanced Accelerator Applications representatives from the Clinical Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the membership and role of the Steering Committee will be defined in a Steering 
Committee charter. 

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11 
Data Collection and Database management 
11.1 Data collection 
The 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 Principal investigator is responsible for assuring that the data (recorded on eCRFs) 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 subject 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 
Advanced Accelerator Applications personnel (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 is 
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 
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. 
Data about all study treatment (s) dispensed to the subject and all dosage changes will be tracked 
on the study drug accountability logs. An electronic system for the Drug Supply Management 
might be implemented for this trial. The local monitor will provide training material to order the 
study drugs during the initiation visit. Once all the necessary actions have been completed and 
the database has been declared to be complete and accurate, it will be locked. Any changes to 
the database after that time can only be made after written agreement by Advanced Accelerator 
Applications development management. 
After database lock, the investigator will receive a CD-ROM or paper copies of the subject data 
for archiving at the investigational site. 
 
11.3 Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, an Advanced 
Accelerator Applications representative will review the protocol and data capture requirements 
(eCRFs) with the investigators and their staff. During the study, Advanced Accelerator 

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Applications 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 subject 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 Advanced Accelerator Applications. Additionally, a central 
analytics organization may analyze data & identify risks & trends for site operational parameters, 
and provide reports to Advanced Accelerator Applications clinical teams to assist with trial 
oversight. 
The investigator must maintain source documents for each subject 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 eCRFs must be traceable to these source documents in the 
Subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Advanced Accelerator Applications 
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 eCRFs are 
performed according to the study-specific monitoring plan. No information in source documents 
about the identity of the subjects will be disclosed. 

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12 
Data analysis and statistical methods 
The primary efficacy and safety analyses will be performed after observing approximately 99 
PFS events per central assessment. The primary CSR will be produced after the primary PFS 
analysis. The key secondary endpoints will be tested hierarchically at the time of the primary 
PFS analysis. Any additional data for participants continuing to receive study treatment past this 
time and for participants continuing for efficacy follow-up (PFS, OS) and quality of life follow- 
up, as allowed by the protocol, will be further summarized at the time of the final analysis. A 
final report to support the final analysis will be planned after End of Study (EOS). 
Advanced Accelerator Applications and/or a designated contract research organization (CRO) 
will perform all analysis. 
Any data analysis carried out independently by the investigator should be submitted to Advanced 
Accelerator Applications before publication or presentation. 
 
12.1 Analysis sets 
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, subjects will be analyzed according 
to the treatment and strata they have been assigned to during the randomization procedure. 
The Safety Set includes all subjects who received at least one dose of study treatment. Patients 
will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized treatment if the subject took at least one dose of that treatment or the first 
treatment received if the randomized/assigned treatment was never received. 
The pharmacokinetic analysis set (PAS) consists of all randomized patients who received at least 
one dose of study drug and had at least one post dosing evaluable PK assessment. 
The cross-over set is comprised of all patients randomized to the Sandostatin LAR Depot 
(octreotide long-acting) arm who received at least one dose of Lutathera after cross-over 
following confirmed disease progression per central, blinded, real-time images reading in the 
randomized period. 
The re-treatment set is comprised of all patients randomized to the Lutathera arm who received 
at least one dose of Lutathera during re-treatment period after confirmed disease progression per 
central, blinded, real-time images reading in the randomized period. 
 
12.2 Subject demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS and Safety set. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented. 
Relevant medical history and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by treatment group. 

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12.3 Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure in months to Lutathera plus Standard Dose octreotide long-acting (30 
mg), and, High Dose octreotide long-acting (60 mg) as well as the dose intensity (computed as 
the ratio of actual cumulative dose received and actual duration of exposure) and the relative 
dose intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized by means of descriptive statistics using the safety set. 
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, by treatment group. 
The number of subjects with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group and all dosing data will 
be listed. 
 
12.4 Analysis of the primary endpoint(s) 
The primary aim of the study is to demonstrate a prolongation of Progression Free Survival (PFS) 
time (centrally assessed according to RECIST 1.1). 
 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint of the study is progression-free survival (PFS), defined as the time from 
the date of randomization to the date of the first documented progression or death due to any 
cause. PFS will be assessed via central review according to RECIST 1.1. Censoring conventions 
are provided in Section 12.4.3. 
 
12.4.2 
Statistical model, hypothesis, and method of analysis 
Assuming proportional hazards model for PFS, the null hypothesis will be tested at one-sided 
2.5% level of significance: 
H01 (null hypotheses): Θ1≥ 0 vs. Ha1 (alternative hypotheses): Θ1 < 0 
Where Θ1 is the log hazard ratio of PFS in the Lutathera plus Standard Dose octreotide long- 
acting (30 mg) (investigational) arm vs. High Dose octreotide long-acting (60 mg) (control) arm. 
The primary efficacy analysis to test this hypothesis and compare the two treatment groups will 
consist of a stratified log-rank test at an overall one-sided 2.5% level of significance in favor of 
the Lutathera plus Standard Dose octreotide long-acting (30 mg) arm. The stratification will be 
based on following randomization stratification factors (grade: G2 vs. G3; and tumor origin: 
pNET vs other origin). 
Analyses will be based on the FAS population according to the randomized treatment group and 
strata assigned at randomization. The PFS distribution will be estimated using the Kaplan-Meier 
method, and Kaplan-Meier curves, median and associated 95% confidence intervals will be 

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presented for each treatment group. The hazard ratio for PFS will be calculated, along with its 
95% confidence interval, from a stratified Cox model using the same stratification factors as for 
the log-rank test. 
In case of few events in some stratum, the primary analysis will instead be unstratified (the 
precise handling of strata will be described in the SAP). Both stratified and unstratified analyses 
will be presented. 
 
12.4.3 
Handling of missing values/censoring/discontinuations 
In cases of incomplete data to determine the exact time of tumor progression or death, the 
principle for imputation is to be conservative. The following rules can be used to determine the 
event/censoring date as well as the status of event or censoring at the time of the analysis of the 
primary end-point PFS depending on data pattern: 
In the primary analysis, PFS will be censored at the date of the last adequate tumor assessment 
if no PFS event is observed prior to the analysis cut-off date. The censoring rules will be detailed 
in the SAP. 
For sensitivity analyses, see next Section 12.4.4. 
 
12.4.4 
Sensitivity and Supportive analyses 
Sensitivity analyses 
A sensitivity analysis will assess PFS events if a patient has disease progression or death 
regardless of whether the patient had missing scheduled visits, treatment discontinuation for 
toxicity, or new anticancer treatment started without progression. 
As sensitivity analyses performed in the FAS, the hazard ratio and 95% confidence interval for 
PFS per blinded independent central review will be obtained from an unstratified and covariate 
unadjusted Cox model, except when the primary analysis is unstratified, see Section 12.4.2. 
 
Further sensitivity analyses will be specified in the SAP. 
 
Supportive analyses 
As a supportive analysis, PFS as per local assessment will be analyzed using a stratified Cox 
model, with the same analysis conventions as the primary efficacy analysis, and the treatment 
effect will be summarized by the hazard ratio with its 95% confidence interval. Kaplan-Meier 
curves, medians and 95% confidence intervals of the medians will be presented for each 
treatment group. 
As supportive analyses performed in the FAS, the hazard ratio and 95% confidence interval for 
PFS per blinded independent central review will be obtained from: 
• 
A stratified and covariate adjusted Cox model including as covariates the following: ALP, 
Time since Diagnosis, Time since Metastasis. The final list of covariates to be included in 
the model will be provided in the SAP. 

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• 
Further supportive analyses will be specified in the SAP 
These analyses will include Kaplan-Meier medians with their 95% confidence intervals, and 
hazard ratios and their 95% confidence intervals from stratified Cox models. 
If the primary analysis is statistically significant, subgroup analyses to assess the homogeneity 
of the treatment effect across demographic and baseline disease characteristics will be 
performed. The subgroups will include the stratification factors (Grade and Site), Age, Gender, 
Race, Karnofsky score, Tumor burden at baseline, BMI. The subgroups will be further detailed 
in the SAP. 
The number of subjects censored and reasons for censoring will be summarized by treatment 
group using descriptive statistics, presented separately for local review and blinded independent 
central review. 
 
12.5 Analysis of secondary endpoints 
The key secondary objectives in this study are to compare the two treatment groups with respect 
to: 
­ ORR: rate of patients with best overall response of partial response (PR) or complete 
response (CR) (centrally assessed according to RECIST 1.1). 
­ Time to deterioration defined as the first deterioration of 10 points (TTD) defined for the 
EORTC QLQ-C30 and EORTC QLQ-G.I.NET21 global health scale, diarrhea, fatigue, 
and pain. 
Other secondary objectives of the study are to compare the two treatment groups with respect to: 
­ DOR: Duration of Response defined as time from complete or partial response to 
progression or death due to underlying cancer only. 
­ Rate of adverse events and laboratory toxicities (scored according to CTCAE grade). 
­ OS: time from the randomization date until the day of death due to any cause. 
12.5.1 
Key secondary objectives 
If the primary endpoint is significant, the key secondary endpoints of overall response rate (ORR) 
and QoL will be tested in a hierarchical fashion to protect the type I error rate. The order of the 
hypothesis testing shall be ORR followed by QoL Global Health Scale (TTD, see below), 
followed by QoL Diarrhea (TTD), (TTD)-fatigue, and, (TTD)-pain (TTD). The key secondary 
objectives will be tested at the time of the primary analysis. At the final analysis, only a 
descriptive analysis will be performed. 
Overall response rate (ORR) is defined as the proportion of subjects with best overall response 
(BOR) of complete response (CR) or partial response (PR), as per central review and according 
to RECIST 1.1. 
ORR will be calculated based on the FAS and according to the ITT principle. ORR and its 95% 
confidence interval will be presented by treatment group. The Cochran-Mantel-Haenszel chi- 
square test, stratified by the randomization stratification factors, will be used to compare ORR 

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between the two treatment groups, at the 1-sided 2.5% level of significance. As a supportive 
analysis, ORR as per local review will be presented by treatment group, along with 95% 
confidence intervals. 
Time to deterioration (TTD) is defined as time from randomization to the first deterioration of 
10 points in domain score compared to the baseline score for the EORTC QLQ-C30 global health 
scale, diarrhea, fatigue, and pain assessments. The TTD distribution will be estimated using the 
Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% confidence intervals of 
the medians will be presented for each treatment group. Treatment effect will be tested by the 
stratified log-rank test. The hazard ratio for TTD will be calculated, along with its 95% 
confidence interval, using a stratified Cox model using stratified the randomization stratification 
factors. Patients with no baseline and/or no follow-up are censored at randomization. Diarrhea, 
fatigue and pain are considered clinically relevant (Strosberg, et al., 2018), identified as top 
symptoms in a patient survey (Singh, et al., 2018) and TTD associated with these symptoms 
domains was significant in a post-hoc analysis of NETTER-1. 
Further details regarding the planned sensitivity and supplementary analyses for the key 
secondary endpoints will be provided in the SAP. 
 
12.5.2 
Other efficacy endpoints 
Disease Control Rate (DCR) is defined as rate of patients with best overall response of partial 
response (PR), complete response (CR), or stable disease (SD) (centrally assessed according to 
RECIST 1.1). More precisely, it counts the presence of at least one confirmed CR or confirmed 
PR or SD. The DCR will be calculated based on FAS according to the ITT principle. DCR and 
its 95% confidence interval will be presented by treatment group. The Cochrane-Mantel- 
Haenszel chi-square test, stratified by the randomization stratification factors, will be used to 
compare DCR between the two treatment groups, at the one-sided 2.5% level of significance. 
The p-value to be generated using the Cochrane-Mantel-Haenszel chi-square test is considered 
nominal, and not to be considered confirmatory as it is not part of the testing strategy. The SAP 
will advise on how to proceed in case of few events in any stratum. 
Duration of response (DOR) only applies to subjects whose best overall response is complete 
response (CR) or partial response (PR) according to RECIST 1.1 based on tumor response data 
per local review. The start date is the date of first documented response of CR or PR (i.e., the 
start date of response, not the date when response was confirmed), and the end date is defined as 
the date of the first documented progression per local review or death due to underlying cancer. 
Subjects continuing without progression or death due to underlying cancer will be censored at 
the date of their last adequate tumor assessment. DOR will be listed and summarized by treatment 
group for all subjects in the FAS with confirmed BOR of CR or PR. 
OS is defined as the time from date of randomization to date of death due to any cause. If a 
subject is not known to have died, then OS will be censored at the latest date the subject was 
known to be alive (on or before the cut-off date). 
OS will be analyzed in the FAS population according to the randomized treatment group and 
strata assigned at randomization. At the time of the PFS primary analysis, the OS distribution 
will be estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 

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95% confidence intervals of the medians will be presented for each treatment group. The hazard 
ratio for OS will be calculated, along with its 95% confidence interval, using a stratified Cox 
model. 
At the final analysis time, a supportive analysis will adjust for cross-over from Control to 
Lutathera. This will be achieved by using a rank-preserving structural failure time method 
(RPSFT) to correct for confounding introduced by the change of treatment. The use of the 
RPSFT method allows survival time estimates gained by anyone receiving Lutathera (i.e. either 
as randomized to Lutathera or after cross-over from Control to Lutathera). The RPSFT model is 
based on an accelerated failure time model) and uses a structural assumption of time- 
proportionality instead of a proportional hazards assumption as used in the Cox model. The 
widely used Cox model measures drug effect on the hazard ratio scale, whereas the accelerated 
failure time model measures drug effect on the survival time ratio scale. 
Additionally, a supportive analysis of OS based on the Inverse Probability Censoring Weight 
method will be performed at the final analysis time. Further details regarding theses analyses 
will be given in the SAP. 
 
12.5.3 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. 
The frequency of adverse events and laboratory toxicities (scored according to CTCAE 5.0 grade 
or current version) will be presented. 
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 Phase. 
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). In addition, a separate summary for death including on treatment and post 
treatment deaths will 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 30 days 
after the date of the last actual administration of any study treatment. 
The overall observation period will be divided into three mutually exclusive segments: 
• 
pre-treatment period: from day of subject’s informed consent to the day before first dose of 
study medication 
• 
on-treatment period: from day of first dose of study medication to 30 days after last dose of 
study medication 
• 
post-treatment period: starting at day 30+1 after last dose of study medication. 
• 
There will be a dedicated presentation of safety for patients who cross-over. 

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Adverse events 
All information obtained on adverse events will be displayed by treatment group and subject. 
The number (and percentage) of subjects with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of double-blind treatment 
but increased in severity based on preferred term) will be summarized in the following ways: 
1. by treatment, primary system organ class and preferred term. 
2. by treatment, primary system organ class, preferred term and maximum severity. 
3. by treatment, Standardized MedDRA Query (SMQ) and preferred term 
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 subjects with AESI/related to identified and potential risks (see 
Section 10.1) will be summarized by treatment. 
A subject 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 treatment group, subject, and visit/time and if ranges are 
available, abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time. 
 
12-lead ECG 
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each subject 
during the study. ECG data will be read and interpreted (centrally/locally). 
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time. 
 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment group, subject, 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. 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 or current version. The 
calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 

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For laboratory tests where grades are not defined by CTCAE, results will be categorized as 
low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry tests: 
1. Listing of all laboratory data with values flagged to show the corresponding CTCAE grades 
if applicable and the classifications relative to the laboratory normal ranges 
2. For laboratory tests where grades are defined by CTCAE, 
3. Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only once for the worst grade observed post-baseline. 
4. Shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
5. For laboratory tests where grades are not defined by CTCAE, 
6. Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment value. 
CgA assessment is discontinued in Q3 2022 in South Korea due to lab kits shortage (assessments 
performed before discontinuation will be included in the analyses). 
 
12.6 Analysis of exploratory endpoints 
12.6.1 
PFS2 
PFS2 is defined as time from date of randomization to the first documented local progression on 
next-line therapy or death from any cause, whichever occurs first. The first documented 
progression on next-line treatment is based on investigator assessment of PD (i.e. as captured on 
the anti-neoplastic therapy after treatment discontinuation eCRF page); it is not necessary to 
continue to collect tumor assessments data for subsequent anti-neoplastic therapies for the 
purpose of PFS2. 
• 
Next-line therapy is defined as the first new (systemic) anti-neoplastic therapy initiated after 
discontinuation of study treatment regardless of EoT reason. Drugs given as part of the same 
regimen should be considered as first line (i.e. part of the next-line therapy). 
• 
New anti-neoplastic therapies after EoT will be collected in the anti-neoplastic therapy after 
treatment discontinuation eCRF page including start/end date, reason for discontinuation, 
date and type of progression («clinical» vs «radiologic»). 
• 
PFS2 will be censored if no PFS2 event (progression or death) is observed during next-line 
therapy before the analysis cut-off date; the censoring date will be the last contact date. 
• 
However, in case a second new anti-neoplastic therapy is introduced without prior PFS2 
event, then PFS2 will be censored at the end date of the first new anti-neoplastic therapy (i.e. 
next line therapy). 
• 
Any death prior to initiation of next-line therapy will be considered as an event for PFS2. 
Any death occurring following end of next line therapy will be considered as an event if no 
second new anti-neoplastic therapy has been introduced. 

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• 
PFS and PFS2 may be identical if a subject did not experience an event (i.e. progression) 
prior to initiation of next-line therapy, and adequate tumor assessments continue until 
RECIST 1.1-documented disease progression after initiation of next-line therapy. 
PFS2 will be analyzed in the FAS population according to the randomized treatment group and 
strata assigned at randomization. The PFS2 distribution will be estimated using the Kaplan-Meier 
method, and the Kaplan-Meier curves, medians and 95% confidence intervals of the medians 
will be presented for each treatment group. The hazard ratio for PFS2 will be calculated, along 
with its 95% confidence interval, using a stratified Cox model. 
Time to Second Progression (PFS2) in the two treatment arms will be evaluated as a secondary 
endpoint. This endpoint is defined as the time in months from the first progression to the second 
progression or death. The date of both the first and second progression will be derived 
programmatically through the RECIST criteria. 
It is recognized that due to cross-over, the lower scan frequency (every six months) after PEP, 
and, the relatively short follow-up, the possibility to draw firm conclusions is limited. 
 
12.6.2 
Patient reported outcomes not associated with key secondary endpoint 
TTD for items/scales derived from EORTC QLQ-G.I.NET21 and EORTC QLQ-30 not included 
among the key secondary endpoints will be analyzed as exploratory endpoints. The TTD 
distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, 
medians and 95% confidence intervals of the medians will be presented for each treatment group. 
The hazard ratio for TTD will be calculated, along with its 95% confidence interval, using a 
stratified Cox model. 
Quality of Life will also be assessed in terms of change from baseline in EORTC QLQ- 
G.I.NET21, EORTC QLQ-C30 and EQ-5D-5L through Mixed Model Repeated Measures 
(MMRM), which deals with missing values in a model based way, and implicitly imputes 
missing data under a missing at random assumption. The model will include the explanatory 
variables Treatment, Baseline, Week, and, the interaction between Treatment and Week. A test 
of treatment effect is performed at each week, and, overall. 
 
12.6.3 
Pharmacokinetics 
Patients in the control arm (all countries except for China) will yield PK data from blood 
sampling performed at pre-dose with respect to the octreotide long-acting i.m. injection for the 
2nd, 4th, 5th and 7th treatment cycle (that is respectively at week 4, 12, 16 and 24) for the 
determination of plasma trough levels. Data will be processed using a population based model, 
for exploratory purposes. More details on the presentation of results will be given in the SAP. 
Additionally, descriptive statistics and graphical display of octreotide plasma concentrations 
during the course of treatment will presented by dose group. Exploratory analysis will be 
performed to assess the dose-exposure relationship. More details on the presentation of results 
will be given in the SAP. 

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12.6.4 
Re-treatment with Lutathera 
Safety will be presented in a similar manner to that in Section 12.5.3 for those participants who 
receive re-treatment with Lutathera during the re-treatment period. The re-treatment period lasts 
from the date of first administration of re-treatment with Lutathera to progression or death during 
the re-treatment period. 
All information obtained on adverse events will be displayed by subject. 
All vital signs data will be listed subject, and visit/time and if ranges are available, abnormalities 
(and relevant orthostatic changes) will be flagged. Summary statistics will be provided by 
visit/time. 
All ECG data (as per local assessment) will be listed by subject and visit/time, abnormalities will 
be flagged. Summary statistics will be provided by visit/time. 
All laboratory data will be listed by subject, and visit/time and if normal ranges are available 
abnormalities will be flagged. Summary statistics will be provided by visit/time. Shift tables 
using the low/normal/high/ (low and high) classification will be used to compare the latest 
assessment before re-treatment to the worst re-treatment value. 
All efficacy analyses for ORR, DoR, PFS, PFS2, and OS will be descriptive. Definitions for 
ORR, DoR, and PFS (as per local assessment) are the same definitions in Section 12.5.2 except 
that the baseline will be based on the tumor assessment which demonstrated progression thus 
allowing re-treatment with Lutathera. Definitions for OS and PFS2 are the same to that in 
Section 12.5.2 and Section 12.6.1, respectively. 
 
12.7 Interim analyses 
An interim analysis with respect to OS will be performed at the time of the PFS final analysis. 
At this time point, only estimation of treatment effect will be performed (hazard ratio and its 
95% confidence interval). 
 
12.8 Sample size calculation 
12.8.1 
Primary endpoint(s) 
The sample size calculation is based on the primary variable PFS. Assuming a median PFS in 
the control arm (High Dose octreotide long-acting (60 mg)) of approximately 15 months, it is 
hypothesized that treatment with Lutathera added to standard dose octreotide long-acting will 
result in a 50% reduction in the hazard rate (corresponding to an increase in median PFS from 
15 months to 30 months). 
To ensure 90% power to test the null hypothesis: PFS hazard ratio = 1, versus the specific 
alternative hypothesis: PFS hazard ratio = 0.50, it is calculated that a total of 99 PFS events need 
to be observed. This calculation assumes analysis by a one-sided log-rank test at the overall 2.5% 
level of significance, patients randomized to the two treatment groups in a 2:1 ratio. Assuming 
that enrolment will continue for approximately 22.2 months at a rate of 10 patients per month 
and a 15% dropout rate by the time of the final PFS analysis, a total of 222 patients (148 for 
Lutathera arm and 74 for the control arm) will need to be randomized to observe the targeted 99 

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PFS events at about 12.8 months after the randomization date of the last patient, i.e., 35 months 
after the randomization date of the first patient. If the final analysis is performed when the 
targeted 99 PFS events are observed, the observed hazard ratio will have to be < 0.658 which 
corresponds to a difference in median PFS of 7.8 months to declare statistical significance. 
These calculations were made using the software package East 6.4. 
Randomization will be stratified by Grade (G2 vs G3) and tumor origin (pNET vs other origin). 

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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, 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, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. 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 Advanced Accelerator 
Applications monitors, auditors, Advanced Accelerator Applications Quality Assurance 
representatives, designated agents of Advanced Accelerator Applications, IRBs/IECs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform Advanced Accelerator Applications 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. 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 Advanced Accelerator 
Applications clinical trial results website and all required Health Authority websites (e.g. 
Clinicaltrials.gov, EudraCT etc.). 
 
Advanced Accelerator Applications (AAA) 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 AAA-sponsored, research-related publications are: 
• 
AAA supports the publication of study results for its innovative medicines in a timely 
manner, whatever their outcome. AAA policy is not to withhold, veto or suppress data. 
However, due consideration must be given to the rights of AAA to protect confidential and/or 
patentable information, and to the protection of personal information, in particular patient 
privacy. 
• 
Review by AAA 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 AAA 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 AAA 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 AAA. 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 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g. risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 
 
Advanced Accelerator Applications maintains a robust Quality Management System (QMS) that 
includes all activities involved in quality assurance and quality control, to ensure compliance 

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with written Standard Operating Procedures as well as applicable global/local GCP regulations 
and ICH Guidelines. 
Audits of investigator sites, vendors, and Advanced Accelerator Applications 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 Advanced Accelerator 
Applications processes. 
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 Sponsor. No records may be transferred to 
another location or party without written notification to Sponsor. 

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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 subjects 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 
Advanced Accelerator Applications 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 Advanced 
Accelerator Applications 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, in addition to 
capturing protocol deviations, there is also a need to record details on the relationship of COVID- 
19 to protocol deviations occurring during the COVID-19 time period in a manner that will allow 
analysis and reporting. In order to capture this information, sites will be queried to provide the 
relationship based on the below categories. When answering these queries, sites will be required 
to select the most appropriate relationship from the options below only: 
 
Predefined relationship options 
When to use 
COVID-19 health status related 
i.e. patients’ infection did lead to this PD 
COVID-19 situation: Site issue* 
e.g. site closed, personnel not available 
COVID-19 situation: Lockdown / Quarantine of 
patient 
e.g. site is active but patient not allowed to 
come 
COVID-19 situation: Patient concern 
e.g. site is active, patient could come but 
refused to come / do assessment 
COVID-19 situation: Drug supply issue 
e.g. drug was delivered to home 
COVID-19 situation: Other 
e.g. situation not already covered by the 
information above 
PD without COVID relationship 
e.g. situation was not in any way associated 
with COVID-19 
*As only one option is possible, if “Site issue” is one of the relationships to COVID-19 for a PD, this 
should be reported as the primary relationship to COVID-19 for the PD. 
 
Deviations related to COVID-19 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. 

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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 Advanced Accelerator Applications, health authorities where required, and 
the IRB/IEC prior to implementation. 
Only amendments that are required for subject 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 subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Advanced 
Accelerator Applications 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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pathology, 25(2), 186-192. doi:10.1007/s12022-014-9313-z 
Rinke, A., Müller, H.-H., Schade-Brittinger, C., Klose, K.-J., Barth, P., Wied, M., . . . Group, P. 
R. (2009, 10). Placebo-controlled, double-blind, prospective, randomized study on the 
effect of octreotide LAR in the control of tumor growth in patients with metastatic 
neuroendocrine midgut tumors: a report from the PROMID Study Group. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology, 27(28), 
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Rolleman, E. J., Valkema, R., Jong, M., Kooij, P. P., & Krenning, E. P. (2003, 1). Safe and 
effective inhibition of renal uptake of radiolabelled octreotide by a combination of lysine 
and arginine. European journal of nuclear medicine and molecular imaging, 30(1), 9-15. 
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Sackstein, P. E., O'Neil, D. S., Neugut, A. I., Chabot, J., & Fojo, T. (2018, 8). Epidemiologic 
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(PRRT) with 177Lu-DOTATATE and 90Y-DOTATOC. Cancer biotherapy & 
radiopharmaceuticals, 24(6), 659-665. doi:10.1089/cbr.2009.0641 
Singh, S., Carnaghi, C., Buzzoni, R., Pommier, R. F., Raderer, M., Tomasek, J., . . . RAD001 in 
Advanced Neuroendocrine Tumors, F. T.-4. (2018). Everolimus in Neuroendocrine 
Tumors of the Gastrointestinal Tract and Unknown Primary. Neuroendocrinology, 
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Strosberg, J., El-Haddad, G., Wolin, E., Hendifar, A., Yao, J., Chasen, B., . . . Investigators, N. 
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16 
Appendices 

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Appendix 1 – Precautions for Pregnancy 
Women who receive Lutathera, including those in cross-over arm and those who are re-treated with 
Lutathera, should not procreate until seven months after the date of their last treatment with 177Lu-DOTA0- 
Tyr3-Octreotate, or until the end of treatment period of the study (due to the CT scans foreseen during the 
study (every 12±1 weeks)), whichever is longer. Women in the control arm should not procreate until the 
end of treatment period. 
It is noteworthy that β-HCG may be secreted by a small percentage of NETs, such that, in addition to 
being a pregnancy marker it also is a tumor marker. Consequently, NET female patients with positive β- 
HCG at baseline can be eligible to enter the study and receive treatment if pregnancy can be excluded by 
lack of expected doubling of β-HCG. Normally in pregnant subjects β-HCG doubles every 2 days during 
the first 4 weeks of pregnancy and every 3 ½ days by weeks 6 to 7. 
Women of childbearing potential include any female who has experienced menarche and who has not 
undergone successful surgical sterilisation (hysterectomy, bilateral tubal ligation or bilateral 
ovariectomy) or is not postmenopausal (defined as amenorrhoea >12 consecutive months, and for women 
on hormone replacement therapy, only with a documented plasma follicle-stimulating hormone level >35 
mIU/mL). Even women who are using oral, implanted or injected contraceptive hormones, an IUD, or 
barrier methods (diaphragm, condoms, spermicidal) to prevent pregnancy, are practicing true abstinence 
(see definition below) or where the partner is sterile (e.g. vasectomy, see below) should be considered to 
be of childbearing potential. Postmenopausal women who have fertilised eggs implanted are also 
considered to be of childbearing potential. 
Highly effective methods of contraception must be used throughout the study and for 6 months after study 
drug discontinuation. Highly effective contraception methods include: 
• 
True abstinence must be in line with the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of exposure to IMP, and withdrawal are not acceptable methods of 
contraception. 
• 
Male or female sterilization (vasectomized partner is a highly effective birth control method 
provided that partner is the sole sexual partner of the trial participant and that the vasectomized 
partner has received medical assessment of the surgical success). 
• 
Combination of any two of the following (a+b or a+c or b+c): 
a. Use of oral, injected, or implanted hormonal methods of contraception. In case of use of oral 
contraception, women should be stable on the same pill for a minimum of 3 months before taking 
study treatment. 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/vaginal suppository. Post-menopausal women are allowed to 
participate in this study. Women 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) confirmed by a high follicle stimulating 
hormone (FSH) level, or have had surgical bilateral oophorectomy (with or without hysterectomy) 
or tubal ligation at least six weeks prior to screening. 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 males in the Lutathera arm must: 

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• 
remain abstinent (refrain from heterosexual intercourse) or be willing to use condoms and highly 
effective methods of contraception with female partners of childbearing potential or pregnant female 
partners (see above) during the treatment period and for at least 4 months after the last dose of 
Lutathera (including cross-over and re-treatment, if applicable). Men should not father a child in this 
period. A condom is required to be used also by vasectomized men in order to prevent delivery of the 
drug via seminal fluid. 
• 
refrain from donating sperm during this same period. 

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Appendix 2 – Lutathera Administration and Sterile Amino Acid Co-Infusion Scheme 
 
The gravity method is a recommended infusion method of Lutathera. Please refer to the pharmacy manual 
for detailed guidance on Lutathera administration and sterile amino acid co-infusion scheme. 

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Appendix 3 – Karnofsky Performance Scale 
 
 
Able to carry on normal activity and to work; no 
special care needed. 
100 Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
Unable to work; able to live at home and care for 
most personal needs; varying amount of assistance 
needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his personal 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 

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Appendix 4 – Radioprotection Precautions for Treated with Lutathera 177Lu-DOTA0-Tyr3- 
Octreotate 
• 
Technical Data 
The principle characteristics of lutetium-177 (177Lu) are specified in Table 1 (from Les principales 
caractéristiques du 177 lutetium (177Lu) and Guide Pratique Radionucléides & Radioprotection, D. 
Delacroix, J.P. Guerre, P. Leblanc, EDP Sciences, 2004). 
 
Table 1: Emissions of 177Lu 
 
177Lu is generally produced using enriched 176Lu placed in a reactor, following a reaction of the type 
[176Lu n,γ 177Lu]. This reaction results the production of a small amount of 177Lu meta-stable (177mLu) 
which varies according to sources between 10-5 and 4×10-4 per MBq of 177Lu produced. The 
characteristics of this radionuclide are given in Table 2. 
Table 2: Emissions of 177mLu 
 
 
• 
Recommendations 
 
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 177Lu- 
DOTA0-Tyr3-Octreotate. 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. 

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Appendix 5 – Recommendations for Patients Treated with Lutathera 
 
In accordance with the medical staff, you have agreed to receive a treatment using a radioactive medicine. 
We think that the potential activity of this medicine in treating your tumor is due to the radioactivity of 
this medicine; it is also for this reason that it is necessary to follow certain precautions in order to limit 
the exposure of the people around you and to avoid contaminating them with radioactivity. 
Because of knowledge and experience in the field, it is estimated that the health risks to your family 
members and the general public are low because of the physical and radiopharmaceutical properties and 
the metabolism of the radiopharmaceutical. You must adhere to the following rules to maximize the safety 
of other persons. They are the result of many years of experience in the use of radioactivity in medicine, 
and they include recommendations by international organizations. 
 
 
1- General rule 
You should limit close contact with people who live with you by keeping a distance of at least one meter 
for 7-days after you receive Lutathera. 
 
2- Use of toilets 
Toilets must be used in a seated position, even for men. It is absolutely necessary to use toilet paper each 
time. It is equally important to wash your hands to avoid contaminating the door handles. It is strongly 
recommended to have bowel movements every day and to use a laxative if you need help. Furthermore, 
empty your bladder (urinate) every hour or so on the day you received treatment and for day after. Follow 
your doctor’s advice on how much fluid to drink. Furthermore, after you receive treatment, empty your 
bladder (urinate) every hour on the day of treatment and for two more days after treatment. After expelling 
fluids, drink a glass of water. You can substitute juice or a sports drink as a means to replace expelled 
fluids. Follow any additional advice that your doctor provides on how much to drink. 
 
3- Contact with children (less than 10 years old) 
After your receive Lutathera, it is strongly recommended that you limit close contact (less than 1 meter) 
with children to less than 15 minutes per day for 7 days. 
 
4- Contact with spouse and people in the family circle 
You should sleep in a separate bedroom from other people for 7 days after you receive Lutathera. You 
should sleep in separate bedrooms from children and/or pregnant women for 15 days after you receive 
Lutathera. 
 
5- Seniors 
Older people are less sensitive to radioactivity (between 3 and 10 times less than a middle-aged 
person). Therefore, the previous recommendations can be followed with a little more flexibility in the 
presence of the elderly. 
 
6- Contact with pregnant women 
Contact with pregnant women should follow the same restrictions recommended for children less than 10 
years old. 

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7- Breastfeeding 
Breastfeeding should be stopped because it is not compatible with a treatment using a radioactive product. 
If treatment with Lutathera during breast feeding is necessary, the child must be weaned. 
 
8- Pregnancy 
Pregnancy must be excluded before the start of treatment. Any woman who has missed a period must be 
assumed to be pregnant until proven otherwise and alternative therapies which do not involve ionizing 
radiation must be then considered. 
There is a potential risk that ionizing radiation by Lutathera could cause toxic effects on female and male 
gonads. Due to the nature of the compound, women who receive Lutathera, including those in cross-over 
arm and those who are re-treated with Lutathera, should not procreate until seven months after the last 
Lutathera dose, or until the end of treatment period of the study (due to the CT scans foreseen during the 
study), whichever is longer. Sexually active males in the Lutathera arm must use condoms and highly 
effective methods of contraception with female partners of childbearing potential or pregnant female 
partners during the treatment period and for at least 4 months after the last dose of Lutathera (including 
cross-over and re-treatment, if applicable). Females of reproductive potential who are partners of male 
patients should be advised to use highly effective contraception during treatment and for 4 months after 
the last dose of Lutathera. 
 
 
9- People who need extra assistance 
People who are confined to the bed or have reduced mobility will preferably receive assistance by a care 
provider. It is recommended that when providing assistance in the bathroom, the care provider wear 
disposable gloves for 7 days after administration. In the case of the use of special medical equipment such 
as catheters, colostomy bags bedpan, water nozzle, or anything that could be contaminated by your body 
fluids they must be emptied immediately in the toilet and then cleaned. If anyone helps you clean up 
vomit, blood, urine, or stool they should wear plastic gloves; the gloves should then be put in the specified 
trash plastic bag. 
 
10- Dishes and bathroom accessories 
For the first two days after your treatment wipes and/or toilet paper must be flushed down the toilet. 
Always wash your hands well after using the toilet. 
It is strongly recommended to shower every day for at least the first 7 days after your treatment. 
Try to flush any tissues or any other items that contain anything from your body, such as blood, urine and 
faeces down the toilet (at least for two days after the therapy). Items that cannot be flushed, such as 
menstrual pads and bandages, must be placed in specified plastic trash bags. 
Wash your underwear, pyjamas, sheets and any clothes that contain sweat, blood or urine separately from 
the laundry of others in your household. Wash your items two or three times; use a standard washing 
machine; you do not need to use bleach and do not need extra rinses. 
 
11- Trash recommendations 
Keep the specified plastic trash bags separate from other trash; keep the bags away from children and 
animals. 
A member of the Study Staff will tell you how and when to get rid of the specified plastic trash bag; you 
may be asked to bring the bag back to your treatment facility, or, after 70 days, the bag may be removed 
as other trash bags. 

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12- Professional activities 
Lutathera could affect your ability to drive and to use machines, as dizziness has been reported as a 
common side effect. 
If there is a risk of frequent contact and being in close vicinity to the public and/or with children, the 
activity must be temporarily suspended. 
 
13- Use of public transportation 
For short trips (less than 30 minutes), the precautions are minimum. If you ride with someone else, 
confirm she is not pregnant, and maintain a distance of >1 meter (use the back seat on opposite side of 
the driver). If you are able to do so, it is best to drive yourself. 
 
14- Public activities 
Avoid assisting in shows or public meetings which could expose third-parties for more than 30 minutes 
in the first week after your treatment. 
Ask Your Doctor or a member of the Study Staff when: 
­ 
It will be safe to eat out, go shopping and attend events such as religious services, parties and 
movies; 
­ 
You will be able to return to work and to care for or teach others; 
­ 
It would be safe to donate blood; 
­ 
Special or longer distance travel is possible (Note: For up to 3 months or more following 
radioactive treatment you may set off radiation detectors at: national borders, airports, bus and 
train stations, tunnels, bridges, trash collection sites and even your place of employment); a 
member of your Study Staff will issue you a letter or card describing the therapy and the phone 
number of a person knowledgeable about your treatment (usually at the treating facility) in case 
local law enforcement agents need to check on this information; you should keep the letter or 
card containing the information with you whenever you are travelling for at least 3 months. 
15- Hospitalization 
In the case that an unplanned hospitalization occurs, it is important to notify your doctor. 
There is a possibility that due to an excessive release of hormones following the administration of 177Lu- 
DOTA0-Tyr3-Octreotate your doctor may request that you stay in hospital overnight for observation and 
treatment if necessary, normally consists of intravenous fluids, corticosteroids and the correction of any 
chemical imbalance in the blood. 
 
16- Domesticated animals 
The lifespan of domesticated animals is much less than that of humans. Therefore, the effect of the 
radioactivity is less. It is not necessary to take any particular precautions. But do not sleep with pets (ask 
your doctor for how long) since your secretions may be carried away by the pet. 
 
17- Emergency Care 
You will get an information card or letter at the time of your treatment that will show the date, type and 
amount of radioactivity that you were treated with; carry this card with you at all times for at least 3 
months following your treatment. 
If you are in a traffic accident or any other medical emergency and require medical assistance during the 
first week after your treatment, you should show this card to the medical providers to let them know about 
the date and dose of your radioactive treatment. 
 
18- Important information for patients on risks of radiation 

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Radiation exposure to others should always be As Low As Reasonably Achievable, a goal often 
abbreviated as ALARA. If you follow the above advice, the radiation from you to others is likely to be 
less than what they receive from radiation in nature over a year’s time. 
Please phone us if: 
• 
you have any questions, and particularly if 
• 
any of the above instructions cannot be followed and/or if 
• 
you see anything that may have accidentally or unavoidably increased exposure of others to 
radiation. 
 
19- Recommended Precautions after Lutathera treatments 
mCi (MBq) administered 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
200 
(7400) 
200 
(7400) 
200 
(7400) 
200 
(7400) 
Precaution Days 
Night-time restrictions 
Sleep in a separate bedroom from adults for days shown 
7 
7 
7 
7 
Sleep in a separate bedroom from pregnant partners, infants, or 
children for days shown 
15 
15 
15 
15 
Day-time restrictions 
You may return to work after days shown 
7 
7 
7 
7 
Limit close contact (less than 1 meter) with children and 
pregnant women to less than 15 minutes per day for days 
shown. 
7 
7 
7 
7 
Avoid extended time in public places for days shown 
7 
7 
7 
7 

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Appendix 6 – Instructions for Shipment, Storage and Handling of 177Lu-DOTA0-Tyr3- 
Octreotate (Lutathera) Solution for Infusion 
 
 
NAME OF THE MEDICINAL PRODUCT 
Lutathera 7400 MBq, radiopharmaceutical solution for infusion 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
Lutathera is supplied as a sterile ready for use radiopharmaceutical solution for infusion. 
A vial contains 7400 MBq of 177Lu-DOTA0-Tyr3-Octreotate with a specific activity greater than 
53 GBq/µmol and with a volumetric activity of 370 MBq/mL at reference date and time. 
PHARMACEUTICAL FORM 
Solution for infusion. 
Clear, colorless to slightly yellow solution, free from visible particles. 
 
PHARMACEUTICAL COMPONENTS 
List of excipients 
Acetic Acid 
Sodium Acetate 
Gentisic Acid 
Ascorbic Acid 
Pentetic acid (DTPA) 
Sodium chloride 
Sodium hydroxide 
Water for Injections 
 
Shelf life 
72 hours after end of production. 
 
 
Special precautions for storage 
Store below 25°C. 
Store in the original package to protect from ionizing radiation (lead shielding). 
Storage of radiopharmaceuticals should be in accordance with national regulation on radioactive 
materials. 
 
Nature and contents of container 
Clear colourless Type I glass vial (30 ml vial), closed with a bromobutyl rubber stopper and aluminium 
seal. 

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Each vial contains a volume varying from 20 to 25 mL of solution corresponding to an activity of 7,400 
MBq at date and time of infusion. 
The vial is enclosed within a lead container for protective shielding. The secondary package complies 
with the requirements of a Type A package as described by the International Atomic Energy Agency 
(IAEA), International Air Transport Association (IATA) and International Carriage of Dangerous Goods 
by Road (ADR) dangerous goods regulations. 
See below some pictures of example of packaging. 
 
 
 
 
 
 
Primary and secondary packaging is labeled in compliance with annex 13 of Current GMP regulations. 
An example of label is shown below. 

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Special precautions for disposal and other handling 
Radiopharmaceuticals should be received, used and administered only by authorized persons in 
designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations 
and/or appropriate licenses of the competent official organization. 
Radiopharmaceuticals should be prepared in a manner which satisfies both radiation safety and 
pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. 
If at any time in the preparation of this medicinal product the integrity of this container and vial is 
compromised it should not be used. 
Administration procedures should be carried out in a way to minimize risk of contamination of the 
medicinal product and irradiation of the operators. Adequate shielding is mandatory. 
It is necessary to wear waterproof gloves and suitable aseptic techniques when handling the medicinal 
product. 
The administration of radiopharmaceuticals creates risks for other persons from external radiation or 
contamination from spill of urine, vomiting etc. Radiation protection precautions in accordance with 
national regulations must therefore be taken. 
The surface dose rates and the accumulated dose depend on many factors. Measurements on the location 
and during work are critical and should be practiced for more precise and instructive determination of 
overall radiation dose to the staff. Healthcare personnel are advised to limit the time of close contact with 
patients injected with Lutathera. The use of television monitor systems to monitor the patients is 
recommended. Given the half life of 177Lu it is specially recommended to avoid internal contamination. 
It is necessary to use protective high quality (latex/nitrile) gloves to avoid direct contact with the 
radiopharmaceutical (vial/syringe). For minimizing radiation exposure, always use the principles of time, 
distance and shielding (reducing the manipulation of the vial and using the material already supplied par 
the manufacturer). 

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This preparation is likely to result in a relatively high radiation dose to most patients. The administration 
of 7,400 MBq may result in significant environmental hazard. 
This may be of concern to the immediate family of those individuals undergoing treatment or the general 
public depending on the level of activity administered, hence radioprotection rules should be followed. 
Suitable precautions in accordance with national regulations should be taken concerning the activity 
eliminated by the patients in order to avoid any contaminations. 
Any unused medicinal product or waste material should be disposed according to local requirements. 
 
 
INSTRUCTIONS FOR THE USE OF Lutathera (7400 MBq) 
Lutathera is for single use only. 
The solution should be visually inspected for damage and contamination before use, and only clear 
solutions free of visible particles should be used. The visual inspection of the solution should be 
performed under a shielded screen for radioprotection purposes. The vial must not be opened. 
If at any time in the preparation of this medicinal product the integrity of this vial is compromised, it 
should not be used. 
The amount of radioactivity in the vial must be measured prior to infusion using a suitable radioactivity 
calibration system in order to confirm that the actual amount of radioactivity to be administered is equal 
to the planned amount at the infusion time. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. The activimeter or dose calibrator must be periodically calibrated by means of a standard 
source of Lu-177. If this procedure is not in place at the clinical site, Advanced Accelerator Applications 
will provide a calibration protocol and will ship a source of Lu-177 to perform the calibration if needed. 
Lutathera does not need to be manipulated before administration because it is delivered as a ready to use 
monodose vial. 
Lutathera must not be used after the expiry date which is stated on the label of the outer package. 
Product receipt, tracking and administration data will be recorded using a informatics system provided 
by Advanced Accelerator Applications. In the event that the product is not administered for any reason, 
AAA will be notified, and a disposal verification record will be provided. 
 
 
Quality Control of Lutathera 
Minimum Quality Control is needed at the site, before the administration of Lutathera. The site will 
confirm that the product received has the correct release certificate. The results will be recorded. 
Additionally, the site’s measurement of total radioactivity and product administration data (start and stop 
time, and residual radioactivity not administered) will also be recorded. 

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Lutathera storage requirements 
Lutathera must be stored at a temperature below 25°C (77° F), in its original package for radioprotection 
purposes, according to national regulations concerning radioactive products. 
Shelf life: 72 hours after end of production. 
 
 
Further information 
The clinical site must request the required Lutathera dose for each patient at least 10 days before the 
scheduled treatment. A product order must be placed with AAA through the informatics system provided 
to each physician. The administration date of the product for each patient should not be confirmed until 
the clinical site has received both an order confirmation and a production dose confirmation from AAA. 
The scheduled date of treatment must be accepted by AAA so that the Manufacturer’s Production 
Planning matches patient treatment schedules. 

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Dysphagia 
Symptomatic, able 
to eat regular diet 
Symptomatic and 
altered 
eating/swallowing 
Severely altered 
eating/swallowing 
; tube feeding or 
TPN or 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by difficulty in swallowing. 
Esophagitis 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; 
altered 
eating/swallowing 
; oral 
supplements 
indicated 
Severely altered 
eating/swallowing 
; tube feeding, 
TPN or 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent operative 
intervention 
indicated 
Death 
Definition: A disorder characterized by inflammation of the esophageal wall. 
Gastric fistula 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; altered 
GI function 
Severely altered GI 
function; bowel rest; 
tube feeding, TPN or 
hospitalization 
indicated; elective 
operative intervention 
indicated 
Life-threatening 
consequences; 
urgent operative 
intervention 
indicated 
Death 
Definition: A disorder characterized by an abnormal communication between the stomach and another organ or anatomic site. 
Gastric ulcer 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; altered 
GI function; medical 
intervention indicated; 
limiting instrumental 
ADL 
Severely altered GI 
function; TPN 
indicated; elective 
operative or 
endoscopic 
intervention indicated; 
limiting self care ADL; 
disabling 
Life-threatening 
consequences; 
urgent operative 
intervention 
indicated 
Death 
Definition: A disorder characterized by a circumscr bed, inflammatory and necrotic erosive lesion on the mucosal surface of the 
stomach. 
Gastritis 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; altered 
GI function; medical 
intervention indicated 
Severely altered 
eating or gastric 
function; TPN or 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent operative 
intervention 
indicated 
Death 
Definition: A disorder characterized by inflammation of the stomach. 
Mucositis oral 
Asymptomatic or 
mild symptoms; 
intervention not 
indicated 
Moderate pain; not 
interfering with oral 
intake; modified diet 
indicated 
Severe pain; 
interfering with oral 
intake 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by inflammation of the oral mucosal. 
Nausea 
Loss of appetite 
without alteration 
in eating habits 
Oral intake decreased 
without significant 
weight loss, 
dehydration or 
malnutrition 
Inadequate oral caloric 
or fluid intake; tube 
feeding, TPN, or 
hospitalization 
indicated 
- 
- 
Definition: A disorder characterized by a queasy sensation and/or the urge to vomit. 
Small intestinal 
obstruction 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; altered 
GI function; limiting 
instrumental ADL 
Hospitalization 
indicated; elective 
operative intervention 
indicated; limiting self 
care ADL; disabling 
Life-threatening 
consequences; 
urgent operative 
intervention 
indicated 
Death 
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents. 

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Anorexia 
Loss of appetite 
without alteration 
in eating habits 
Oral intake altered 
without significant 
weight loss or 
malnutrition; oral 
nutritional 
supplements 
indicated 
Associated with 
significant weight 
loss or malnutrition 
(e.g., inadequate oral 
caloric and/or fluid 
intake); tube feeding 
or TPN indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by a loss of appetite. 
Tumor lysis syndrome 
- 
- 
Present 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by metabolic abnormalities that result from a spontaneous or therapy-related cytolysis of tumor 
cells. 
Metabolism and 
nutrition disorders 
- Other, specify 
Asymptomatic or mild 
symptoms; clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
Moderate; minimal, 
local or noninvasive 
intervention indicated; 
limiting age- 
appropriate 
instrumental ADL 
Severe or medically 
significant but not 
immediately life- 
threatening; 
hospitalization or 
prolongation of 
existing hospitalization 
indicated; disabling; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
 
 

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Appendix 8 – Determination of LUTATHERA Administered Radioactivity 
The total amount of radioactivity administered to the patient is determined by measuring the 
radioactivity present in the LUTATHERA (177Lu-DOTA0-Tyr3-Octreotate, Infusion Solution) 
Vial before and after administration. The procedure is as follows: 
 
A. Measurement of LUTATHERA Vial radioactivity before LUTATHERA administration: 
1) remove the LUTATHERA Vial from the original package; 
2) place the LUTATHERA Vial in the dose calibrator (activimeter) chamber; 
3) select the Lu-177 setting on the dose calibrator; 
4) press the “measure” button (or equivalent function button); 
5) record the measured radioactivity, and the time of measurement in the appropriate 
electronic Case Report Form (eCRF); 
6) remove the LUTATHERA Vial from the dose calibrator chamber; 
7) return the LUTATHERA Vial to its original package or prepare the Vial for patient 
administration. 
B. Measurement of LUTATHERA vial radioactivity after LUTATHERA administration: 
1) remove needles and tubing attached to the LUTATHERA Vial (NB: The investigator 
must confirm that there is no significant residual radioactivity remaining in delivery 
needles and tubing after administration (< 0.1% of original Total Radioactivity in 
LUTATHERA Vial); 
2) if the dose calibrator is in a different location, place the LUTATHERA Vial in the original 
package so that the material can be moved safely – otherwise go to step 4; 
3) remove the LUTATHERA Vial from the original package; 
4) place the LUTATHERA Vial in the dose calibrator chamber; 
5) select the Lu-177 setting on the dose calibrator; 
6) press the “measure” button (or equivalent function button); 
7) record the measured radioactivity, and the time of measurement in the appropriate eCRF; 
8) remove the LUTATHERA Vial from the dose calibrator chamber and dispose according 
to national and local regulations for disposal of radioactive waste; 
 
C. Calculation of Total Administered and Residual Radioactivity: 
1) Total Administered Radioactivity 
= (amount of radioactivity in LUTATHERA Vial before administration minus 
amount of radioactivity in LUTATHERA Vial after administration) times vial 
geometry correction factor 
 
2) Residual Radioactivity = amount of radioactivity remaining in LUTATHERA Vial after 
administration times vial geometry correction factor 
 
3) record Total Administered Radioactivity and Residual Radioactivity in the appropriate 
sections of the patient’s eCRF.