A Prospective, Randomised, Controlled, Open-label, Multicentre Phase III Study to Evaluate Efficacy and Safety of Peptide Receptor Radionuclide Therapy (PRRT) With 177Lu-Edotreotide Compared to Targeted Molecular Therapy With Everolimus in Patients With Inoperable, Progressive, Somatostatin Receptor-positive (SSTR+), Neuroendocrine Tumours of Gastroenteric or Pancreatic Origin (GEP-NET)
Phase: PHASE3
Conditions: Neuroendocrine Tumors
Sponsor: ITM Solucin GmbH

 
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Title Page 
 
A prospective, randomised, Controlled, Open-label, Multicentre phase III 
study to evaluate efficacy and safety of Peptide Receptor Radionuclide 
Therapy (PRRT) with 177Lu-Edotreotide compared to targeted molecular 
therapy with Everolimus in patients with inoperable, progressive, 
somatostatin receptor-positive (SSTR+), neuroendocrine tumours of 
gastroenteric or pancreatic origin (GEP-NET). 
 
177Lu-edotreotide vs. Everolimus in GEP-NET – COMPETE 
 
Study purpose: 
Confirmation of efficacy and safety of 177Lu-edotreotide PRRT in  
GEP-NET  
Clinical study phase: 
III  
Date: 
29-Sep-2022 
EudraCT No.: 
2016-001897-13 
Version No.: 
8.5, Amendment 11 
IND No.: 
136823 
 
 
Authors: 
Dr. 
 
Prof. Dr. 
 
 
 
 
 
Document History: 
 
 
Date 
Version 
Amendment  
Region 
05-Oct-2016 
Initial Protocol Version 2.2 
NA 
Global  
25-Jul-2017 
Amendment 01  
Substantial 
Global  
20-Mar-2018 
Amendment 02 
Substantial  
Global 
29-Jun-2018 
Amendment 03 
Substantial 
Global 
08-Jun-2020 
Version 3.0, Amendment 04 Substantial 
Global 
02-Dec-2020 
Version 4.0, Amendment 05 Substantial 
European Union and 
United Kingdom 
23-Dec-2020 
Version 5.0, Amendment 06 Substantial 
Australia, South Africa, 
Switzerland, United States 
03-Feb-2021 
Version 6.0, Amendment 07 Substantial 
European Union and 
United Kingdom 
18-Aug-2021        Version 7.0, Amendment 08   Substantial 
United States 
20-Oct-2021 
Version 8.3, Amendment 09   Substantial 
Australia, South Africa, 
Switzerland, United 
States, United Kingdom 
01-Aug-2022 
Version 8.4, Amendment 10   Non-substantial 
Australia, South Africa, 
Switzerland, United 
States, United Kingdom 

 
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29-Sep-2022 
Version 8.5, Amendment 11   Non-substantial 
Australia, South Africa, 
Switzerland, United 
States, United Kingdom 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation. Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 

··1tm 
SOLUCIN 
Clinical Study Protocol 
ITM-LET-01 
Sponsor Approval Signature Page 
V. 8.5, Amendment 11 
29-Sep-2022 
I agree to conduct this trial in accordance with this Clinical Trial Protocol and also in accordance 
with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki 
• 
Good Clinical Practice/ International Conference on Harmonisation (CPMP/ICH/135/95) 
• 
All applicable laws and regulations 
Study Title: 
A prospective, randomised, controlled, open-label, multicentre phase Ill study to 
evaluate efficacy and safety of Peptide Receptor Radionuclide Therapy (PRRT) with 
177Lu-edotreotide (177Lu-DOTATOC) compared to targeted molecular therapy with 
everolimus in patients with inoperable, progressive, somatostatin receptor-positive 
(SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin (GEP-NET). 
Version: 
8.5 
Date: 
29-Sep-2022 
Amended: 
Amendment 11 
 
(Signature) 
 
 (Signature) 
2 9. SEP. 2022 
Date 
2 9. SEP. 2022 
Date 
COMPETE Protocol Version 8.5, Amendment 11, FINAL 29-Sep-2022 
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Principal Investigator Agreement Page 
 
Study Title: 
A prospective, randomised, controlled, open-label, multicentre phase III study to 
evaluate efficacy and safety of Peptide Receptor Radionuclide Therapy (PRRT) with 
177Lu-edotreotide (177Lu-DOTATOC) compared to targeted molecular therapy with 
everolimus in patients with inoperable, progressive, somatostatin receptor-positive 
(SSTR+), neuroendocrine tumours of gastroenteric or  pancreatic origin (GEP-NET). 
 
Version: 
8.5  
Date: 
29-Sep-2022 
Amended: 
Amendment 11  
 
 
Principal Investigator Signature: 
I confirm that I have read and that I understand this Protocol, the Investigator’s Brochure, and any 
other Product Information provided by the sponsor. 
I agree to conduct this study in accordance with the requirements of this protocol, the ethical 
principles that have their origin in the Declaration of Helsinki, the International Conference on 
Harmonisation (ICH) guideline for Good Clinical Practice (GCP), and the applicable regulatory 
requirement(s). 
I will also appropriately direct and assist the personnel at the trial site who will be involved in the 
conduct of the study. 
 
 
 
 
(Name and Function) 
(Signature)  
 
Date 

 
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Serious Adverse Event Reporting 
 
 
Notification in case of Serious Adverse Events 
 
All serious adverse events (SAEs) should be reported via paper form using the following email 
address: 
Email: 
SAE-reporting@itm-radiopharma.com 
 
Only in situations when email cannot be used, SAEs should be reported via paper form using the 
following Fax number: 
Fax: +49 89 329 8986 6068  
 
 
 

 
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Synopsis 
 
 
Study title  
A prospective, randomised, Controlled, Open-label, Multicentre 
phase III study to evaluate efficacy and safety of Peptide Receptor 
Radionuclide Therapy (PRRT) with 177Lu-Edotreotide compared to 
targeted molecular therapy with Everolimus in patients with 
inoperable, progressive, somatostatin receptor-positive (SSTR+), 
neuroendocrine tumours of gastroenteric or pancreatic origin 
(GEP-NET).  
Short title 
177Lu-edotreotide vs. everolimus in GEP-NET – COMPETE 
Clinical study phase 
III 
Study objective(s) 
Primary objective 
To demonstrate the efficacy of PRRT with 177Lu-edotreotide to 
prolong progression-free survival (PFS) in patients with inoperable, 
progressive, SSTR+ GEP-NET, compared to everolimus 
Key secondary objectives 
1. To assess objective response rates (ORR), defined as the 
proportion of patients achieving partial response (PR) or 
complete response (CR) as best outcome, after treatment with 
177Lu-edotreotide compared to everolimus 
2. To assess overall survival (OS), defined as the time from the date 
of randomisation until death  
Exploratory secondary objectives 
3. To assess the duration of disease control (DDC), defined as the 
time of initial diagnosis of response (SD, PR or CR) until 
diagnosis of progression, after treatment with 177Lu-edotreotide 
compared to everolimus 
4. To determine disease control rates (DCR), defined as the 
proportion of patients achieving stable disease (SD), PR or CR 
as best outcome 
5. To determine response rate (RR), considering Cg-A and specific 
hormones (where increased at baseline) 
6. To assess the safety and tolerability of 177Lu-edotreotide in 
GEP-NET patients 
7. To determine the health-related quality of life (HRQL) in 
GEP-NET patients during and after therapy (EORTC QLQ-C30 
questionnaire) 
8. To evaluate symptomatic tumour response (EORTC GI.NET21 
questionnaire) 
9. To evaluate the impact of patient characteristics (time from 
primary diagnosis, time from diagnosis of progression, number of 
prior therapies (1st vs 2nd line), type of prior therapies, KPS at 
randomisation) on tumour response 
10. To evaluate the impact of tumour histology (histological entity, 
tumour grade, Ki-67 expression, SSTR expression, functional 

 
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state) as determined in primary or current bioptic tumour 
specimen on tumour response 
Tertiary objectives (in 177Lu-edotreotide patients) 
1. To assess differences in tumour and kidney radiation dose 
estimates, obtained with conventional 2D (planar), compared to 
hybrid (2D/3D), and 3D (SPECT) imaging 
2. To evaluate the value of pre-therapeutic SSTR imaging (SRI) to 
predict tumour response (globally/at lesion level) 
3. To evaluate the relationship between PRRT radiation dose (in 
Gy) and tumour response (globally/at lesion level) 
4. To assess metabolic stability and excretion pattern of 
177Lu-edotreotide 
5. To assess bone marrow radiation dose 
Project code 
ITM-LET-01 
Investigational Medicinal 
Product (IMP) 
177Lu-edotreotide, an octreotide-derived somatostatin analogue 
containing the chelator DOTA, radiolabelled with n.c.a. lutetium-177, 
a radio-lanthanide, emitting β- and γ-radiation. 
Name of active ingredients 
177Lu-edotreotide (synonyms, e.g.: 177Lu-Edo, 177Lu-DOTATOC) 
Doses 
A maximum of four cycles of 7.5 ± 0.7 GBq 177Lu-edotreotide, each 
containing a mass dose of 150 µg of DOTATOC. The cumulative 
177Lu-edotreotide dose will be up to 30 GBq, gauged individually not 
to exceed an absorbed dose of 23 Gy to the kidneys. 
Route of administration 
Slow intravenous infusion/injection (IV) 
Duration of treatment 
4 cycles, 90 (±14) days apart (total duration: 270 days/9 months) 
Reference product (RP) 
Everolimus, an mTOR inhibitor 
Name of active ingredients Everolimus 
Doses 
10 mg/d  
Route of administration 
Oral 
Duration of treatment 
Continuous daily treatment until diagnosis of progression or EOS 
Indication 
Treatment of patients with well-differentiated, somatostatin receptor-
positive, unresectable or metastatic neuroendocrine tumors (NETs) 
of gastroenteric or pancreatic origin 
 
Diagnosis and main criteria 
for inclusion 
All patients must meet all of the following criteria: 
1. 
Written informed consent 
2. 
Male or female ≥18 years of age 
3. 
Histologically confirmed diagnosis of well-differentiated neuro-
endocrine tumour of non-functional gastroenteric origin 
(GE-NET) or both functional or non-functional pancreatic origin 
(P-NET), tumour grade G1 or G2 (Ki-67 ≤20%), unresectable or 

 
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metastatic, in a patient who is either treatment-naïve (1st line) or 
who has progressed under prior therapy (2nd line) 
4. 
Availability of existing biopsy specimen from primary tumour or 
metastasis or, if unavailable, willingness to undergo current 
biopsy for secondary central analysis 
5. 
Measurable disease per RECIST 1.1, on CT/MRI scans, defined 
as at least 1 lesion with ≥1 cm in longest diameter, and ≥2 
radiological tumour lesions in total. A maximum of 5 target 
lesions visible on CT/MRI will be defined, thereof not more than 
2 lesions per organ 
6. 
Somatostatin receptor positive (SSTR+) disease, as evidenced 
by SSTR imaging (SRI) within 4 months prior to randomisation, 
as locally authorised, by: 
• 
68Ga-based SSTR positron emission tomography (PET) 
imaging (68Ga-edotreotide or 68Ga-DOTATATE), or 
• 
111In-pentetreotide SSTR SPECT/planar imaging, or 
• 
99mTc-octreotide SSTR SPECT/planar imaging 
• 
64Cu-based SSTR PET imaging (64Cu-DOTATATE), if 
approved, according to local regulations 
All target lesions and ≥90% of non-target lesions need to be 
positive for SSTR; this relates to lesions of at least 15 mm in 
diameter acquired on SRI images with SPECT, and of at least 
10 mm in diameter acquired on SRI images with PET systems. 
7. The patient must have progressive disease based on RECIST 
1.1 Criteria as evidenced by two morphological imaging 
examinations made with the same imaging method (either CT or 
MRI), within a maximum of 36 months prior to randomisation. 
The most recent scan must not be older than 90 days prior to 
randomisation date. The minimum interval between the two 
scans must be ≥90 days. 
8. 
Karnofsky performance status (KPS) scale ≥70 
9. 
Life expectancy allows the patient to participate in the study 
based on the investigator’s assessment 
10. Glomerular filtration rate (GFR, CKD-EPI) ≥60 mL/min/1.73 m2 
11. For patients included in France only, verification and 
confirmation of their affiliation with a social security 
12. Patients with functional P-NETs who require SSA for symptom 
control may continue SSA treatment throughout the study, on 
condition that: 
a) they have been on a stable dose for at least three months 
prior to study enrolment  
b) that progressive disease has been diagnosed while under 
such stable dose 

 
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Exclusion criteria 
A patient will be excluded from participation in the trial if one or more 
of the following criteria are met: 
1. Known hypersensitivity to edotreotide or everolimus 
2. Known hypersensitivity to DOTA, lutetium-177, or any excipient 
of edotreotide or everolimus or any other Rapamycin derivative 
3. Known hypersensitivity to lysine, arginine, or any excipient of the 
nephroprotective amino acid solution 
4. Prior exposure to any peptide receptor radionuclide therapy 
(PRRT), including 177Lu-edotreotide, 90Y-edotreotide or other 
SSTR-targeting agents (e.g. 
177Lu-octreotate or high-dose 
111In-pentetreotide) 
5. Prior therapy with mTOR inhibitors 
6. Prior EFR (external field radiation) to GEP-NET lesions within 
90 days before randomisation or radioembolisation therapy (e.g. 
90Y microspheres, 131I-lipiodol) with administration to the liver 
7. Prior therapy with chemotherapy, immunotherapy, interferon, 
chemo-embolisation, bland embolisation, cyclosporine-A within 
4 weeks before randomisation; any new cancer treatment 
between screening and randomisation 
8. Therapy with an investigational compound and/or medical 
device within 30 days or 5 half-life periods (whichever is longer) 
prior to randomisation 
9. Subjects who have received a live vaccine up to 4 weeks prior 
to first dose  
10. Current 
therapy 
with 
any 
prohibited 
medication 
(see 
Section 6.1.1) 
11. Ongoing toxicity grade 2 according to CTCAE version 4.03 from 
previous standard or investigational therapies  
12. Indication for surgical lesion removal with curative potential 
13. Planned (for the period of study participation): chemotherapy, 
immunotherapy, 
interferon, 
radiation 
therapy, 
chemo-
embolisation, bland embolisation, radio-embolisation, treatment 
with cyclosporine-A 
14. Neuroendocrine tumours, not meeting the inclusion criteria: 
• 
With known non-GEP-NET origin (e.g. pulmonary or 
gonadal primaries) 
• 
Functional GE-NET 
• 
Explicit diagnosis of unknown primary (CUP) 
• 
G3 
neuroendocrine 
tumours 
and 
neuroendocrine 
carcinomas 
• 
NET for which no histological specimen for secondary 
histological analysis can be obtained 
15. Total hepatic tumour burden >70%  
16. Brain metastases 
17. Other malignancy within previous 5 years (except basal cell 
carcinomas and in situ squamous cell carcinomas of the skin) 

 
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18. Serious non-malignant disease (e.g. psychiatric, infectious, 
autoimmune or metabolic), that may interfere with the objectives 
of the study or with the safety or compliance of the subject, as 
judged by the investigator 
19. Clinically 
relevant 
renal, 
hepatic, 
cardiovascular, 
or 
haematological organ dysfunction, potentially interfering with the 
safety of the study treatments, as follows: 
• 
Renal 
o Renal obstruction 
• 
Hepatic 
o Total bilirubin >1.5 x ULN 
o AST or ALT >2.5 x ULN  
o Alkaline phosphatase >5 x ULN 
o Albumin <3 g/dL, unless prothrombin time is within 
normal range 
• 
Cardiovascular 
o New York Heart Association classification III & IV 
o Uncontrolled hypertension 
• 
Haematopoietic 
o Platelets 80 × 109/L 
o  Absolute neutrophil count (ANC) <1 x 109 cells/L  
20. Pregnant or breast-feeding women. Female patients of 
childbearing potential or male patients with female partners of 
childbearing potential, unless willing to practice full and true 
sexual abstinence or who are surgically/permanently sterile 
(bilateral tubal occlusion, hysterectomy, or vasectomy), or 
female patients whose male partners have medically successful 
vasectomy (provided the partner is the sole sexual partner of the 
female patient of childbearing potential), or who are not willing to 
practice highly effective contraception in combination with a 
barrier method of contraception (e.g. condom). Contraception 
methods that are considered highly effective are: oral or non-oral 
(injected or implanted) non-oestrogen progesterone-based 
hormonal method; oral, intravaginal, or transdermal combined 
oestrogen and progesterone-based hormonal methods; and/or 
intrauterine device (IUD), and/or intrauterine hormone-releasing 
system (IUS). Sexual abstinence or the contraception methods 
described above must be followed throughout the entire study 
period and for 56 days after treatment in the everolimus group 
and 66 days in the PRRT group (10 half-lives of 177Lu) after the 
last treatment cycle. 
21. Subjects not able to declare meaningful informed consent on 
their own (e.g. with legal guardian for mental disorders) or any 
other vulnerable population to that sense (e.g. persons 
institutionalised, incarcerated etc.). 
Study design 
This will be a confirmatory, prospective, randomised, controlled, 
parallel group, open-label, multi-centre phase III study to evaluate 

 
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the efficacy and safety of 177Lu-edotreotide in comparison to 
molecular targeted therapy with everolimus in patients with 
inoperable, progressive, somatostatin receptor-positive (SSTR+), 
neuroendocrine tumours of gastroenteric or pancreatic origin 
(GEP-NET). 
In total, 300 GEP-NET patients will be randomised in 2:1 fashion to 
receive either 
• 
PRRT with 177Lu-edotreotide consisting of a maximum of four 
cycles (7.5 ± 0.7 GBq 177Lu-edotreotide, each), administered as 
IV infusion at 3-monthly intervals for 9 months, or until 
diagnosis of progression (200 patients), or 
• 
10 mg everolimus (Afinitor®) daily, administered orally as a 
tablet until diagnosis of progression (100 patients) 
Study duration per patient will be 30 months. Collection of survival 
data and information on further antineoplastic treatments as well as 
the development of secondary malignancies will be continued for 
5 years (60 months) after EOS. 
The primary endpoint is progression-free survival (PFS). Diagnosis 
of progression and liver tumour burden will be established based on 
radiological information from morphological imaging (MRI and/or CT) 
according to RECIST 1.1. Stratification will be made for primary 
tumour origin (GE-NET vs. P-NET) and prior medical therapy (1st line 
vs. 2nd line). Tumour grade (G1, G2), and baseline Karnofsky score 
will be used for further statistical subgroup analyses.  
Secondary endpoints include parameters of morphological and 
biomarker tumour response such as objective response rate (ORR), 
overall survival (OS), disease control rates (DCR), as well as 
duration of disease control (DDC), safety, health-related quality of life 
(HRQL). Furthermore, exploratory analyses will be performed on 
patient and tumour characteristics, as well as the degree of 177Lu-
edotreotide uptake for traits predicting PRRT efficacy. 
The study is designed to confirm the trial hypothesis of a 
progression-free survival benefit, relative to comparator with a power 
of at least 0.8 and significance level (p) of <0.05 (two-sided). The 
sample size will also be sufficient, to confirm a progression-free 
survival benefit with a power (P) of 0.90 and significance level (p) of 
<0.01 (two-sided), if the difference in mPFS is more than 11 months. 
Patients with histologically confirmed diagnosis of GEP-NET will be 
recruited globally by approximately 60 oncological centres 
specialised in endocrinology or gastroenterology, and with local 
access to or own experience in PRRT. Confirmatory histology from 
existing or current specimens will be centrally performed to uniformly 
characterise the study population. 
All successfully screened patients will be randomised in a 2:1 fashion 
to undergo PRRT with 177Lu-edotreotide or everolimus treatment, 
respectively, and will be followed-up for outcome for a maximum of 
30 months. 

 
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177Lu-edotreotide therapy usually requires short-term hospitalisation 
at a radionuclide therapy ward for each administration (details 
subject to local radiation safety regulations). 
Biodistribution of 177Lu-edotreotide, and consequently the absorbed 
dose (AD) to kidneys varies considerably between subjects. To 
minimise the risk of radiation-induced renal damage, the cumulative 
177Lu-edotreotide dose (D1 - D4) will be individually monitored, so 
that the resulting AD to kidneys does not exceed 23 Gy, generally 
considered to be safe. However, if the predicted absorbed dose to 
the kidneys is likely to exceed 23 Gy upon administration of the next 
PRRT cycle, dosing can be continued up to a maximum of 29 Gy, 
provided that a pre-PRRT tubular extraction rate (TER, 99mTc-MAG3 
renal scintigraphy) is >50% of the value at baseline. 
In addition, before receiving the next 177Lu-edotreotide treatment 
after cycle 1, all patients in the PRRT arm will be assessed for 
specific safety criteria during the pre-treatment evaluations on 
Day 90 post first cycle, including hematological as well as renal 
safety parameters. If the safety criteria are not met, the patients will 
not receive the next dose. 
After administration of D1, patients will be subjected to sequential 
dosimetric whole body imaging immediately after end of infusion 
(approximately 0.5 h p.i, prior to voiding, preceded by a blank and a 
transmission scan), 6, 24 and 72 – 96 h p.i. using conventional planar 
scintigraphy, complemented by abdominal SPECT imaging at 24 h. 
Based on the first cycle, the cumulative AD to kidneys from the 
planned full dose of four doses of 7.5 ± 0.7 GBq 177Lu-edotreotide 
will be estimated. In selected patients, the accuracy of AD predictions 
made based on the first cycle will be verified by repeated dosimetry 
in cycles D2 – D4 (Sub-study A).  
177Lu-edotreotide dosimetry will be centrally analysed for the 
absorbed kidney and target tumour doses in a standardised fashion. 
Dosimetry will be performed according to the current regulatory 
standard (conventional planar (2D) dosimetry), and according to the 
emerging clinical standard (2D/3D hybrid dosimetry) for a more 
accurate determination of the kidney dose. 
Quantitative SPECT reconstruction is a recent option to directly 
derive quantitative information on 177Lu activity distribution in vivo, 
allowing to assess absorbed doses to kidneys (safety) and tumour 
(efficacy) with higher accuracy, compared to planar scintigraphy. In 
selected study sites, 177Lu-edotreotide SPECT/CT (3D) will be 
performed at each time point in addition to planar scintigraphy (2D). 
Data will be quantitatively reconstructed, and dosimetrically analysed 
in comparison to planar (2D) and hybrid (2D/3D) dosimetry (Sub-
study B).  
To assess in vivo stability of 177Lu-edotreotide, urine will be collected 
from all voids beginning immediately post-dose to 1 hour, and in 
intervals of 1-6, 6-24 and 24-48 hours post-injection in a subgroup of 
20 patients at selected sites only and will be analysed using radio-

 
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HPLC and gamma-counting (Sub-study C). In addition, bone marrow 
dosimetry will be assessed by measuring radioactivity in blood 
samples 
taken 
at 
pre-defined 
intervals 
between 
end 
of 
177Lu-edotreotide injection to 7 days post-injection. Sub-study C will 
be performed during any one of the four 177Lu-edotreotide treatment 
cycles (the choice of which of the four cycles to collect urine and 
blood samples for Sub-study C will be at the investigator’s 
discretion). In order to facilitate the patient recruitment in the 
regulatory required Sub-study C, 
 
 at the sites participating in Sub-study C and 
only at those sites: Following approval of this Study Protocol 
Amendment and activation of 
 by the 
Sponsor, the patients who consent to participate in Sub-study C and 
who comply with all protocol inclusion and exclusion criteria will 
directly be allocated to the PRRT arm until a global cumulative 
number of 20 evaluable patients is reached for the Sub-study C. 
 the tests conducted 
for Sub-study C, the treatment regimen and patient care 
management will remain identical to that implemented in the main 
study. 
 
 
The patients at Sub-study C participating sites who consent to 
participate in the main study but not in the Sub-study C, or the 
patients who are consented and screened out of or after the end 
 
 can be randomised in the 
main study provided they comply with all protocol inclusion and 
exclusion criteria. The sites not participating in the Sub-study C 
continue to only enroll patients using the randomization procedure of 
the main study. 
Everolimus: Patients randomised to everolimus therapy will undergo 
out-patient visits only. Patients will receive a standard dose of 10 mg 
daily, which may be reduced, where required for acceptable 
tolerability, according to manufacturer´s product information. 
For both study arms: Study visits will be monthly in the first 
12 months, thereafter 3-monthly until end of study at month 30 or 
until progression (whatever occurs first). For symptom control, all 
patients are allowed to receive somatostatin analogues (SSA), as 
clinically indicated (best supportive care) in required doses, not to 
exceed licensed doses. In the 177Lu-edotreotide arm, clinically 
established wash-out periods prior to 177Lu-edotreotide dosing have 
to be considered (1 day for immediate release, and 28 days for 
sustained release SSA). 
Safety, tolerability and symptom control parameters, as well as 
tumour markers are captured at regular intervals. 
To assess efficacy, serial morphological imaging, comprising native 
liver and contrast-enhanced liver and 3-regional (pelvis, abdomen, 
thorax) MRI or CT (see Clinical Imaging Manual for details), is 
scheduled every three months, consistently using baseline methods. 
In case of clinically suspected tumour progression, investigators may 

 
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schedule appropriate diagnostic imaging at any time. Diagnosis of 
progression will be made by the local investigator.  
All image analyses will be confirmed centrally. For establishment of 
PFS (primary endpoint) blinded reading in duplicate, with appropriate 
adjudication in case of discordance will be used. 
Patients who progressed under everolimus may be offered 
177Lu-edotreotide therapy based on the personal judgement of the 
Investigator, if he/she considers it appropriate and likely to be 
beneficial for the individual patient.  
Study participation 
duration 
• 
Screening period: 90 days (day -90 to day -1) 
• 
Study period: 
- 
Treatment period IMP: Four single doses administered on 
days 0, 90, 180 and 270, unless diagnosis of progression or 
EOS.  
- 
Treatment period RP: Daily oral administration from day 0 
until diagnosis of progression or EOS. 
- 
Study period: day 0 – month 30 (or until diagnosis of 
progression, whichever is earlier). 
• 
Post-study Follow-up (5 years [60 months] post-EOS): 
- 
177Lu-edotreotide therapy for patients (having progressed 
under everolimus therapy): Administration and follow-up as 
for study patients, until secondary progression. 
- 
All patients: Collection of overall survival (OS) and 
progression data, as well as information on further cancer 
treatments and the development of secondary malignancies. 
Methodology 
Tumour characterisation and staging 
1. Somatostatin receptor imaging (SRI) 
To clinically establish somatostatin receptor expression at 
baseline, patients undergo somatostatin receptor imaging (SRI) 
according to local guidelines, preferably with 68Ga-based PET 
(68Ga-edotreotide or 68Ga-DOTATATE). Where not available, 
111In-pentetreotide (OctreoScan®), 99mTc-octreotide SPECT/CT 
imaging or, less preferable, planar imaging can be used. 
2. Histology 
Central histological re-assessment will be made at baseline 
using tissue specimens from primary diagnosis or, where 
unavailable, a current biopsy to characterise histological entity, 
tumour grade, SSTR, Ki-67 expression status, and others. 
3. Morphological imaging (MRI or CT) 
To document tumour lesions in the body, and tumour burden in 
the liver, at baseline, one native liver and contrast-enhanced liver 
and 3 regional (pelvis, abdomen, thorax) MRI or CT (see Clinical 
Imaging Manual for details) must be available (performed within 
28 days prior to randomisation) or has to be repeated as baseline 
MRI/CT. Where established, combined imaging (e.g. abdominal 
MRI / thoracic CT) can be used. The baseline imaging method 

 
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has to be used consistently throughout the whole study period. 
Where a 3-monthly imaging follow-up schedule departs from 
clinical routine, MRI is preferred for radiation protection reasons. 
All image analyses will be made according to RECIST 1.1. 
classification criteria. 
4. Tumour markers 
Chromogranin A (CgA) will be determined at baseline, and then 
monthly until month 12, thereafter in 3-monthly intervals until 
diagnosis of progression or EOS. In addition, specific hormones 
related to clinical symptoms (e.g. gastrin, insulin, etc.) will be 
determined in patients, if showing elevated levels at baseline 
work-up. 
177Lu-edotreotide dosimetry 
• 
177Lu-edotreotide planar scintigraphy 
177Lu-edotreotide whole body 2D planar images will be obtained 
at four points of time after first dosing (D1, day 0) of 
177Lu-edotreotide: immediately after end of infusion (approx. 
0.5 h, prior to voiding), 6 h, 24 h and 72-96 h post-infusion.  
a) Tumour targeting will be assessed qualitatively (signal 
accumulation in liver region). 
b) Whole body 2D planar scintigraphy in anterior and posterior 
projection, in conjunction with cobalt-57 or technetium-99m 
sheet source or if available whole body CT-based 
attenuation correction data and an external calibration 
source, will be used to determine 177Lu-edotreotide 2D 
standard dosimetry (reference method), with emphasis to 
kidney (safety) and target tumours (efficacy). 
• 
177Lu-edotreotide SPECT/CT 
Abdominal SPECT/CT scans, covering kidneys and liver (usually 
1 to 2 bed positions) will be acquired in supine position 
24 h after each 177Lu-edotreotide infusion (D1 to D4) in all sites.  
Where established (Sub-study B), abdominal SPECT/CT (or 
SPECT) scans may be acquired in addition to planar images at 
all other imaging time points (0.5, 6, 72-96 h p.i.). CT-derived 
information will be used for attenuation and scatter correction.  
a) Tumour targeting will be assessed by demonstration of 
177Lu-edotreotide binding inside or in the vicinity of the 
target lesion, seen on structural imaging using SPECT/CT 
acquired 24h post-infusion. 
b) 
To take superimposition and self-absorption of abdominal 
organs into consideration, quantitatively reconstructed 
abdominal SPECT images (Bq/mL) from a single time point 
(24h p. i.) will be used to calibrate time-activity curves 
derived from 2D planar scans (reference method/regulatory 
standard) for dosimetry of kidneys and target tumours 
(2D/3D hybrid dosimetry/emerging clinical standard). 
c) 
Sub-study B (3D dosimetry): available full dosimetric 
SPECT/CT series (4 time points), will be quantitatively 

 
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reconstructed, and analysed for kidney and tumour 
dosimetry (3D dosimetry). 
Dosimetry evaluations will be centrally analysed using a) the 
phantom-based MIRD methodology, and b) the Voxel-S 
methodology, which considers individual anatomy of the patient, 
allowing a more precise description of doses to tumours. 
• 
Pharmacokinetic urine analysis (Sub-study C) 
To assess in vivo stability of 177Lu-edotreotide, urine will be 
collected from all voids beginning immediately at 0 min post-dose 
into 4 pooled samples in intervals from 0 min post-dose to 1 hour, 
and 1-6, 6-24 and 24-48 hours post-injection in a subgroup of 20 
patients at selected sites only. Urine will be analysed with 
gamma-counting and radio-HPLC in order to investigate the 
radiochemical purity of the eliminated compound. 
• 
Bone marrow dosimetry (Sub-study C) 
As the radioactivity in blood was shown to be similar to that in 
bone marrow, bone marrow dosimetry will be assessed by 
measuring radioactivity in blood samples at pre-defined intervals 
from 10 minutes to 7 days post-injection of 177Lu-edotreotide in a 
subgroup of 20 patients at selected sites only. 
Safety and tolerability 
1. Kidney function 
A possible impact of study therapy on kidney function will be 
monitored assessing 
o 
Tubular 
extraction 
rate 
(TER, 
99mTc-MAG3 
renal 
scintigraphy) 
o 
GFR calculated from serum creatinine 
o 
Kidney volume (abdominal MRI/CT baseline, 3-monthly 
follow-up)  
2. General 
a) Standard laboratory 
b) Adverse event recording 
c) 
Concomitant medication recording 
Health-related quality of life (HRQL) and symptom control 
1. EORTC QLQ-C30 and 
2. EORTC GI.NET21 questionnaire 
Type of control 
Reference therapy: Everolimus 10 mg orally daily until progression 
Planned study dates (year) Start of study/ 
recruitment 
2017  
End of 
recruitment 
2021 
 
 
End of study 
2024 
Planned number of study 
centres/countries 
Approximately 60 centres/10-15 countries (Europe, North America, 
South Africa, Australia) 

 
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Number of patients 
Total: 300 subjects with morphologically progressive GEP-NET 
To facilitate patient recruitment in the Sub-study C, 
 
at all sites participating in the Sub-study C until 20 evaluable patients 
are obtained globally. 
 
 
 
Total number based on statistical rationale: 
Sample size based on estimation, considering published outcome 
data for RP (everolimus), and evidence of 177Lu-edotreotide efficacy 
in GEP-NET from the Bad Berka academic study.  
Primary variable 
Progression-free survival 
a) Progression-free survival (PFS)  
Secondary variables 
Key secondary variables 
a) Objective response rate (ORR), % patients achieving PR or CR 
as best outcome 
b) Overall survival (OS) 
Exploratory efficacy variables 
c) Percentage patients progression-free at 2 years (% 2y-PFS) 
d) Disease control rate (DCR), % patients achieving PR, CR and 
SD 
e) Duration of disease control (DDC) 
f) Duration of response (DoR) 
g) Association between RECIST 1.1 tumour response and CgA 
and/or specific hormone levels. If relevant, percentage patients 
experiencing biomarker tumour response (CgA, specific 
hormones), classified as SD, PR, CR, PD 
Safety and tolerability 
a) Measured TER, percentage depart from baseline value  
b) Calculated GFR, percentage depart from baseline value 
c) Renal volume (Vkidney), percentage depart from baseline value 
d) Frequency of occurrence and severity of abnormal findings in 
safety investigations (vital signs, 12-lead ECG, clinical 
laboratory, adverse events) 
Health-related quality of life (HRQL) 
a) Maximum 
HRQL 
improvement 
(EORTC 
QLQ-C30 
and 
GI.NET21 questionnaires) total scores, relative to baseline 
b) Duration of maximum HRQL improvement 
c) Time to HRQL deterioration, defined as the time from 
randomisation to first HRQL deterioration 
Dosimetry 
a) Full dosimetry assessments of target organs and tumour lesions 

 
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b) Cumulative absorbed dose (in Gy) from 177Lu-edotreotide to 
target tumour lesions, estimated from 
177Lu-edotreotide 
dosimetry after first dose 
c) Sub-study A patients: cumulative absorbed dose to kidneys and 
to tumour lesions extrapolated from absorbed dose estimated at 
D1 compared with the cumulative absorbed dose measured at 
the different administration times (i.e. D1 to D4) 
d) Sub-study B patients: absorbed dose (in Gy) determined by 3D 
dosimetry compared to absorbed dose values obtained by planar 
(2D) and hybrid (2D/3D) dosimetry 
e) Sub-study C patients: bone marrow absorbed dose (in Gy) 
extrapolated from blood radioactivity 
Pharmacokinetics (Sub-study C) 
a) Urine radioactivity in percentage of injected activity (%IA) at 
pre-defined intervals within 48 hours post-injection to assess 
excretion pattern 
b) Blood radioactivity in %IA at pre-defined time points within 
7 days post-injection to assess clearance pattern 
c) Radiochemical purity assessed through HPLC of urine samples 
collected within 48 hours post-injection 

 
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Plan for statistical analysis Stratified randomisation will be used to control for primary tumour 
origin (GE-NET vs. P-NET) and for prior medical therapy (1st line vs. 
2nd line, as well as types of previous therapies). 
Sample size considerations:  
Considering that everolimus will be used as comparator in the 
planned study, a sample size estimation was conducted, based on a 
median PFS of 11.0 months reported for everolimus (Yao et al. 2011, 
2016) and a median PFS of 32 months in NET patients (34.5 months 
in GEP-NET patients), as determined for 177Lu-edotreotide in 
subjects, treated with ≥2 PRRT cycles in the retrospective study (van 
Echteld 2015; Baum et al. 2016). 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
The study was 
planned to last for 48 months of which subject accrual occurs in the 
first 24 months. The accrual across time is uniform. Of note, the trial 
sample size was not revised (i.e. decreased) after the protocol 
amendment that extended the patient follow-up from 24 months to 
30 months. 
Based on this HR a total sample size of 300 will compensate for a 
dropout rate (censored data) of 15% for primary endpoint analysis. 
Switching from the one group to the other is not allowed in this study 
and therefore not considered in the sample size calculation. 
With regard to overall response rates, group sample sizes of 200 in 
the 177Lu-edotreotide group and 100 in the everolimus group achieve 
 power to detect an odds ratio between the group ORRs of 
 
(that corresponds to rates of 
 and 
). The proportion in the 
177Lu-edotreotide group is assumed to be 
 under the null 
hypothesis and 
 under the alternative hypothesis. The proportion 
in the everolimus group is assumed to be 5% according to results of 
the RADIANT-3 study (Yao et al., 2011). The test statistic used is the 
two-sided Fisher's Exact Test. The significance level of the test is 
5%. A dropout rate of 15% is included in this calculation using PASS 
software. 

 
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With regard to overall survival, a two-sided logrank test with an 
overall sample size of N=300 subjects (
 events; 
, 
N1=100 subjects [
] in the everolimus group and N2=200 
subjects [
 events] in the 177Lu-edotreotide group) achieves 
 
power at a 
 significance level to detect a hazard ratio (HR) of 
 when the everolimus group median overall survival time is 44 
months as in the RADIANT-3 study (Yao et al., 2016; i.e., a difference 
of an additional 23 months in the 177Lu-edotreotide group). 
The sample size of 300 patients was chosen, as the primary variable 
and the 2 key secondary endpoints are to be tested in a confirmatory 
manner. 
 
 
 
 
 
 
 
Interim analysis and Multiplicity: 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

 
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Table 1 (Study Flow Chart): 177Lu-Edotreotide vs. Everolimus in GEP-NET (COMPETE Study) – 177Lu-Edotreotide Patients 
 
 
 
Treatment 
EOS
Early with-
drawalU
Post-
study 
FU
Examination / Evaluation
Dose 1
Dose 2
Dose 3
Dose 4
Month
0
1AAA
2AAA
3
4AAA
5AAA
6
7AAA
8AAA
9
10AAA 11AAA 12AA
15AA
18AA
21AA
24AA
27AA
30AA
Time point
Day
 -90 
to -1
 -28 
to -1
0
1
3
30
± 7
60    
± 7
90     
± 14
91
93
120
± 7
150
± 7
180    
± 14
181
183
210
± 7
240 ± 
7
270    
± 14
271
273
300 ± 
7
330 ± 
7
      
± 21
      
± 21
      
± 21
      
± 21
      
± 21
      
± 21
       
± 21
h*
Pre-
doseAA
Tx   
Dose 
1
0.5
±0.25
5
± 1
6
± 1
24
± 3
72-
96E
TxA, AA
Dose
2
24
± 3
72-
96E
TxA, AA
Dose
3
24
± 3
72-
96E
TxA, AA
Dose
4
24
± 3
72-
96E
Informed Consent
X
Review Inclusion / Exclusion Criteria
X
X
Randomisation
XT
General
Medical History
X
X
Physical Examination
X
X
X
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
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Haematology 
X
XB
XB
X
XB
XB
X
XB
XB
X
XB
XB
X
X
X
X
X
X
X
X
X
Serum ChemistryX
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
Clotting Parameters
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tumour MarkersC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy TestD
X
XD
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Current BiopsyF
X
Tumour HistologyG
X
EORTC QLQ-C30 and GI.NET21
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
Symptomatic Medication (SSA)H
X
XH
X
X
Adverse Events  / Baseline Findings
X
X
XY
XY
Overall Survival 
X
Antineoplastic Treatments
X
Imaging Inclusion, Outcome & Safety
Somatostatin Receptor Imaging (SRI)I
X
Morphological Imaging (MRI / CT)
XK
XK, L
X
X
X
XZZ
XZZ
XZZ
XZZ
XZZ
XZZ
X
XZZ
99mTc-MAG-3 Renogram 
XM
XM
(XM)
XM
XM
XM
X
X
Eligibility for continued PRRTMM
X
TreatmentZZZ 
Amino-Acid Solution InfusionN
X
X
X
X
177Lu-Edotreotide Infusion
X
X
X
X
177Lu Whole Body Planar Imaging
XZ
XO
XO
XO
XO
XP
XP
XP
XP
XP
XP
XP
XP
XP
177Lu Abdominal SPECT/CT ImagingQ
XR
XR
X
XR
X
X
X
Hospitalisation
X
X
X
X
X
X
X
X
*hours post last dose
Baseline
within 28 
days after 
withdrawal
2nd year
6 
monthly 
for 5 
years

 
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Table 1 – 177Lu-Edotreotide – (footnotes): 
 
 
 
 
(A) Pre- and post dosing procedures, as described for dose D1.
(AA) (Pre-dose) procedures (e.g. MRT / CT) may be performed within 7 days before visit. Investigations should be performed as close to PRRT as organisationally possible and as clinically appropriate. 
(AAA) Blood-sampling can be perfomed up to 72 hours prior to the visit according to local practice and as clinically appropriate. 
(B) Bi-weekly controls of haematology for 8 weeks following 177Lu-edotreotide administration,  to occur in week 2, 4, 6, 8 post dosing (GP acceptable).
(C) Tumour biomarkers in serum: chromogranin-A (CgA) in all patients; disease-specific homones, if positive at baseline work-up.
(D) Pregnancy test for all premenopausal female patients during screening. To be repeated, if dosing starts >14 days after screening. To be repeated monthly until EOS. 
(E) All scheduled evaluations may be performed 72 - 96 h (± 3 h) post infusion.
(F) Mandatory, unless prior tumour specimen (paraffin block) available. Biopsy sample to be sent to CPL before randomisation.
(G) Local histolopathology report to be sent to the CPL with the biopsy sample.
(I) SRI using PET/CT, SPECT/CT or planar imaging, as locally authorised (by 68Ga-edotreotide, 68Ga-DOTATATE, 111In-pentetreotide,or 99mTc-octreotide) within 4 months prior to randomisation.
(L) One native liver and contrast-enhanced liver and 3 regional (pelvis, abdomen, thorax) MRI or CT, not older than 28 days at the time of randomisation. Baseline method must be followed throughout the study period.
(Q) SPECT/CT in all patients @24 h p. inj. for verification of tumour targeting and 2D/3D hybrid dosimetry.
(R) Sub-study B (at selected sites): SPECT imaging serial at 0.5, 6, and 72 - 96 h in addition to 24 h scan, for full 3D dosimetry (complementary to serial planar imaging).
(U) In case of early withdrawal, all evaluations, as specified for EOS shall be performed, wherever possible.
(X) Hyperkalaemia is a known side effect of the Amino-Acid Solution. If K+ is elevated: additional clinical chemistry blood samples will be collected at the discretion of investigator
(Y) AEs ongoing at EOS have to be followed up until resolved or for a period up to a maximum of 30 days by the investigator.
      
      
D 1
D 2
D 3
D 7
post-infusion
0 
min
10 
min
30 
min
1h
3h
6h
24
± 3 h 
48   
± 3 h 
72   
±12h
168 
±12h
Urine 
X
X
X
X
X
Blood 
X
X
X
X
X
X
X
X
X
X
(O) Planar emission imaging, serial (4 time points) with calibration standard. Optional 5th time point 7 days post infusion.
(N) Nephroprotective amino acid solution has to be started 30-60 min. before 177Lu-Edotreotide infusion and should be administered for 4-6 h.
(M) 99mTc-MAG-3 renogram to be performed within 28 days prior to randomisation; 7 days prior to administering the cycle D3 (month 6) dose; and if the predicted absorbed kidney dose likely exceeds 23 Gy but not 29 Gy prior to dose D4 (month 9). To be performed 
within 7 days prior to month 12, 18, and 24 visits.
(H) Somatostatin agonists (SSA) for symptom control are allowed, if a) not exceeding the licensed posology and b) sufficient wash-out prior to 177Lu-edotreotide dosing is observed (24 h for immediate, 28 d for sustained release galenics).
Sampling Schedule Sub-study C
(ZZZ) Sub-study C (at selected sites in a subgroup of 20 patients): Urine samples for PK - urine will be collected from all voids beginning immediately at 0 min post-dose into 4 pooled samples in intervals from 0 min post-dose to 1 hour, and 1-6, 6-24 and 24-48 hours 
post-injection. Blood samples of 1 mL, each, will be drawn at 0 min, 10 min, 1 h, 3 h, 6 h, 24 h, 48 h, 3 d, and 7 d post end of infusion. Blood samples on D0 can be taken within ±5 min of the scheduled time, as long as the exact sampling times are recorded in the CRF. 
Sub-study C will be performed during any one of the four 177Lu-edotreotide treatment cycles (the choice of which of the four cycles to collect urine and blood samples for Sub-study C will be at the investigator’s discretion).
 Time
Day 0
(ZZ) MRI / CT to be performed within 7 days prior to month 12, 15, 18, 21, 24, and 27 visits. For early withdrawal, MRI / CT not to be repeated in case of progression.
(Z) Transmission scan and blank scan using either a Co-57 or Tc-99m sheet source or if available at the site whole body low dose CT scan. These scans can be performed up to 7 days prior to PRRT. For Tc-99m blank and transmission scan have to be performed 
together (one followed by the other) due to the short half-life of Tc-99m.
(P) Sub-study A (at selected sites): Full dosimetry imaging (see O + Z) to be repeated for doses D2 - D4, in order to a) validate kidney and tumour dose predictions (AD), based on cycle 1, and b) evaluate the possibility of single time point dosimetry estimations, based 
on cycle 1 information.
(MM) See Sections 5.4.1.2 and 5.4.3 of the protocol for details on dosing after Cycle 1.
(K) MRI / CT showing radiological tumour progression based on RECIST 1.1 as evidenced by two scans obtained within a maximum of 36 months prior to randomisation, with at least 90 days interval between them. The most recent scan should not be older than 90 
days at randomisation.
(T) 177Lu-edotreotide arm: Drug ordered at day of randomisation. The first dose of 177Lu-edotreotide should be administered within 21 days of randomisation. In the case of any delay, the site should check with the Sponsor via the site monitor and the reason for the 
delay should be documented accordingly.

 
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Table 2 (Study Flow Chart): 177Lu-Edotreotide vs. Everolimus in GEP-NET (COMPETE Study) – Everolimus Patients 
 
 
 
Examination / Evaluation
EOS
Early with-
drawalU
Post-
study FU
Month
0
1AAA
2AAA
3AA
4AAA
5AAA
6AA
7AAA
8AAA
9AA
10AAA
11AAA
12AA
15AA
18AA
21AA
24AA
27AA
30AA
Time point
Day
 -90 to  -
1
 -28 to  
-1
0
30    
± 7
60     
± 7
90 
± 14
120    
± 7
150    
± 7
180    
± 14
210    
± 7
240
± 7
270   
± 14
300    
± 7
330   
± 7
       
± 21
       
± 21
       
± 21
       
± 21
       
± 21
       
± 21
        
±21
within 28 
days after 
withdrawal
h*
Pre-
doseAA
0.5
±0.25
Informed Consent
X
Review Inclusion / Exclusion Criteria
X
X
Randomisation
XV
General
Medical History
X
X
Physical Examination
X
X
X
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
X
X
X
X
X
X
X
X
X
X
Haematology 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Chemistry 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clotting Parameters
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tumour MarkersC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy TestD
X
XD
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
X
X
X
X
Current BiopsyF
X
Tumour HistologyG
X
EORTC QLQ-C30 and GI.NET21
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
Symptomatic Medication (SSA)H
X
XH
X
X
Adverse Events  / Baseline Findings
X
X
XY
XY
Overall Survival 
X
Antineoplastic Treatments
X
Imaging Inclusion, Outcome & Safety
Somatostatin Receptor Imaging (SRI)I
X
Morphological Imaging (MRI / CT)
XK
XK, L
X
X
X
XZZ
XZZ
XZZ
XZZ
XZZ
XZZ
X
XZZ
99mTc-MAG-3 Renogram 
XM
X
XM
XM
XM
X
X
Comparator Arm
XS
X
Study Visits
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense of diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
177Lu-Edotreotide TherapyW
X
*hours post last dose
Everolimus AdministrationS
Treatment 1st year
Baseline
6 monthly 
for 5 years
Treatment 2nd year

 
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Table 2 – Everolimus – (footnotes): 
 
 
 
(AA) (Pre-dose) procedures (e.g. MRI / CT) may be performed within 7 days before visit. Investigations should be performed as close to dosing as organisationally possible and as clinically appropriate.  
(AAA) Blood-sampling can be perfomed up to 72 hours prior to the visit according to local practice and as clinically appropriate. 
(C) Tumour biomarkers in serum: chromogranin-A (CgA) in all patients; disease-specific hormones, if positive at baseline work-up.
(D) Pregnancy test for all premenopausal female patients during screening. To be repeated, if dosing starts > 14 days after screening. To be repeated monthly until EOS.
(F) Mandatory, unless prior tumour specimen (paraffin block) available. Biopsy sample to be sent to CPL before randomisation.
(G) Local histopathology report to be sent to the CPL with the biopsy sample.
(H) Somatostatin agonists (SSA) for symptom control are allowed, if not exceeding the licensed posology
(I) SRI using PET/CT, SPECT/CT or planar imaging, as institutionally available/locally acceptable (e.g. 68Ga-edotreotide, 68Ga-DOTATATE, 111In-pentetreotide, 99mTc-octreotide) within 4 months prior to randomisation.
(L) One native liver and contrast-enhanced liver and 3 regional (pelvis, abdomen, thorax) MRI or CT, not older than 28 days at the time of randomisation. Baseline method must be followed throughout the study period.
(S) Everolimus, 10 mg (per os, once daily) until diagnosis of progression. Dose may be modified according to protocol appendix 4.
(U) In case of early withdrawal, all evaluations, as specified for EOS shall be performed, wherever possible.
(W) 177Lu-Edotreotide therapy for patients (having progressed under everolimus therapy): Administration and follow-up as for study patients, until secondary progression.
(Y) AEs ongoing at EOS have to be followed up until resolved or for a period up to a maximum of 30 days by the investigator.
(ZZ) MRI / CT to be performed within 7 days prior to month 12, 15, 18, 21, 24, and 27 visits. For early withdrawal, MRI / CT not to be repeated in case of progression.
(V) If patient was randomised to everolimus, treatment should be initiated as soon as possible (preferably no later than 21 days after randomisation). The randomisation visit can then be taken as day 0 of treatment if all required pre-
dose examinations were performed on the same day.
(M) 99mTc-MAG-3 renogram to be performed within 28 days prior to randomisation; and within 7 days prior to month 12, 18, and 24 visits.
(K) MRI / CT showing radiological tumour progression based on RECIST 1.1 as evidenced by two scans obtained within a maximum of 36 months prior to randomisation, with at least 90 days interval between them. The most recent 
scan should not be older than 90 days at randomisation.

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Table of Contents 
Sponsor Approval Signature Page .................................................................................................. 3 
Principal Investigator Agreement Page ........................................................................................... 4 
Serious Adverse Event Reporting ................................................................................................... 5 
Synopsis ......................................................................................................................................... 6 
Table of Contents ......................................................................................................................... 26 
List of Tables, Figures, Equations and Attachments ..................................................................... 31 
List of Abbreviations ..................................................................................................................... 33 
Study Administrative Structure ...................................................................................................... 38 
1 
Introduction ............................................................................................................................. 40 
1.1 
Background ....................................................................................................................... 40 
1.2 
Rationale of the Study ....................................................................................................... 42 
1.3 
Benefit-Risk Assessment ................................................................................................... 43 
2 
Study Objectives ..................................................................................................................... 46 
3 
Overview of Methodology and Design ..................................................................................... 47 
3.1 
Study Design ..................................................................................................................... 47 
3.2 
Study Endpoints ................................................................................................................ 50 
3.3 
Justification of the Design .................................................................................................. 51 
3.4 
Justification of the Dose .................................................................................................... 52 
3.5 
Protocol Adherence ........................................................................................................... 53 
3.6 
Sub-studies (177Lu-Edotreotide patients only) .................................................................... 54 
3.6.1 Sub-study A: Repetitive Full Dosimetry Imaging (D1 – D4) .......................................... 54 
3.6.2 Sub-study B: 3D Dosimetry SPECT/CT Imaging .......................................................... 54 
3.6.3 Sub-study C: Pharmacokinetic Urine Analysis and Bone Marrow Dosimetry ................ 55 
4 
Study Population ..................................................................................................................... 56 
4.1 
Patient Population ............................................................................................................. 56 
4.2 
Eligibility ............................................................................................................................ 56 
4.2.1 Inclusion Criteria .......................................................................................................... 56 
4.2.2 Exclusion Criteria ......................................................................................................... 58 
4.3 
Recruitment ....................................................................................................................... 60 
4.4 
Withdrawal of Patients from Study Participation or Medication .......................................... 60 
4.4.1 Withdrawal ................................................................................................................... 60 
4.4.2 Withdrawal Procedures ................................................................................................ 61 
4.4.3 Replacement ............................................................................................................... 61 
4.5 
Patient Identification .......................................................................................................... 62 
4.6 
End of the Study ................................................................................................................ 62 
4.7 
Study Duration ................................................................................................................... 62 
5 
Study Drug .............................................................................................................................. 63 
5.1 
Identity .............................................................................................................................. 63 

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5.1.1 Chemical Properties of 177Lu-Edotreotide ..................................................................... 63 
5.1.2 Chemical Properties of Everolimus .............................................................................. 64 
5.1.3 Pharmaceutical Properties of 177Lu-Edotreotide ........................................................... 65 
5.1.4 Pharmaceutical Properties of Everolimus (Afinitor®) ..................................................... 65 
5.1.5 Storage and Handling .................................................................................................. 66 
5.2 
Treatment Assignment and Randomisation ....................................................................... 66 
5.3 
Blinding ............................................................................................................................. 66 
5.4 
Dosage and Administration................................................................................................ 67 
5.4.1 
177Lu-edotreotide Group ............................................................................................... 67 
5.4.1.1 
Absorbed Dose from 177Lu-Edotreotide PRRT to the Kidneys .............................. 67 
5.4.1.2 
Eligibility for Continued Administration of 177Lu-edotreotide after Cycle 1 ............. 68 
5.4.2 Everolimus Group ........................................................................................................ 68 
5.4.3 Dose-Modifying Toxicity ............................................................................................... 69 
5.4.3.1 
DMT under Everolimus ........................................................................................ 69 
5.4.3.2 
DMT during 177Lu-Edotreotide PRRT ................................................................... 69 
5.5 
Packaging and Labelling ................................................................................................... 70 
5.5.1 
177Lu-edotreotide .......................................................................................................... 71 
5.5.2 Everolimus (Afinitor®) ................................................................................................... 71 
5.6 
Drug Logistics and Accountability ...................................................................................... 71 
5.6.1 Storage, Dispensation and Return of 177Lu-Edotreotide ............................................... 71 
5.6.2 Storage, Dispensation and Return of Everolimus ......................................................... 71 
5.6.3 Drug Accountability ...................................................................................................... 72 
5.7 
Treatment Compliance ...................................................................................................... 72 
5.8 
Treatment of Overdose ...................................................................................................... 73 
6 
Therapies other than Study Drug ............................................................................................ 73 
6.1 
Prior and Concomitant Therapy ......................................................................................... 73 
6.1.1 Prohibited Medications ................................................................................................. 73 
6.1.2 Somatostatin Analogues .............................................................................................. 74 
6.1.3 Scheduled Nephroprotective Amino-Acid Solution for Patient Management ................ 75 
6.1.4 Antiemetic therapy ....................................................................................................... 76 
6.1.5 Medication Precautions ................................................................................................ 76 
6.1.5.1 
177Lu-edotreotide .................................................................................................. 76 
6.1.5.2 
Everolimus ........................................................................................................... 77 
6.2 
Post-Study Therapy ........................................................................................................... 77 
7 
Schedule of Evaluations and Visit Description ........................................................................ 78 
7.1 
Schedule of Evaluations .................................................................................................... 78 
7.2 
Screening Phase ............................................................................................................... 78 
7.2.1 Baseline ....................................................................................................................... 78 
7.3 
Treatment Phase ............................................................................................................... 80 
7.3.1 Month 0 ....................................................................................................................... 80 
7.3.1.1 
Day 0 ................................................................................................................... 80 

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7.3.1.2 
Day 1 (only 177Lu-edotreotide group) .................................................................... 82 
7.3.1.3 
Day 2 (only Sub-study C in 177Lu-edotreotide group) ............................................ 82 
7.3.1.4 
Day 3 (only 177Lu-edotreotide group) .................................................................... 82 
7.3.1.5 
Day 7: Sub-study C Only ..................................................................................... 83 
7.3.2 Month 1 and Month 2 ................................................................................................... 83 
7.3.3 Month 3 ....................................................................................................................... 84 
7.3.3.1 
Day 90 ................................................................................................................. 84 
7.3.3.2 
Day 91 (only 177Lu-edotreotide group) .................................................................. 86 
7.3.3.3 
Day 92 (only Sub-study C in 177Lu-edotreotide group) .......................................... 86 
7.3.3.4 
Day 93 (only 177Lu-edotreotide group) .................................................................. 86 
7.3.3.5 
Day 97: Sub-study C Only ................................................................................... 87 
7.3.4 Month 4 and Month 5 ................................................................................................... 87 
7.3.5 Month 6 ....................................................................................................................... 87 
7.3.6 Month 7 and Month 8 ................................................................................................... 87 
7.3.7 Month 9 ....................................................................................................................... 88 
7.3.8 Month 10 and Month 11 ............................................................................................... 88 
7.3.9 Second Year ................................................................................................................ 88 
7.3.10 End of Study (EOS) ..................................................................................................... 88 
7.3.11 Early Withdrawal Visit .................................................................................................. 89 
7.4 
Post-Study Evaluations ..................................................................................................... 90 
7.4.1 All Patients ................................................................................................................... 90 
7.4.2 
177Lu-edotreotide Therapy for Patients Progressing under Everolimus ......................... 90 
8 
Procedures and Variables ....................................................................................................... 90 
8.1 
Baseline Characteristics .................................................................................................... 91 
8.1.1 Demographic Characteristics ....................................................................................... 91 
8.1.2 Medical and Surgical History, Baseline Findings .......................................................... 91 
8.1.3 Prior and Concomitant Medication ............................................................................... 91 
8.1.4 Tumour Histology ......................................................................................................... 91 
8.2 
Efficacy.............................................................................................................................. 92 
8.2.1 Tumour Characterisation and Staging .......................................................................... 92 
8.2.1.1 
Somatostatin Receptor Imaging (SRI) .................................................................. 92 
8.2.1.2 
Morphological Imaging (MRI or CT) ..................................................................... 93 
8.2.1.3 
Tumour Markers .................................................................................................. 93 
8.2.2 
177Lu-edotreotide Biodistribution and Dosimetry ........................................................... 94 
8.2.2.1 
177Lu-edotreotide Whole Body Planar Scintigraphy .............................................. 94 
8.2.2.2 
177Lu-edotreotide Abdominal SPECT/CT .............................................................. 95 
8.2.2.3 
Serial 177Lu-edotreotide SPECT/CT, (Sub-study B, only) ..................................... 95 
8.2.2.4 
Pharmacokinetic Urine Analysis (Sub-study C, only) ........................................... 95 
8.2.2.5 
Bone Marrow Dosimetry (Sub-study C, only) ....................................................... 95 
8.2.3 Health-Related Quality of Life (HRQL) and Symptom Control ...................................... 96 
8.2.3.1 
EORTC QLQ-C30 ................................................................................................ 96 

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8.2.3.2 
EORTC QLQ-GI.NET21 ....................................................................................... 96 
8.2.4 Assessment of Progression-free Survival..................................................................... 96 
8.3 
Safety ................................................................................................................................ 97 
8.3.1 Baseline Findings ........................................................................................................ 97 
8.3.1.1 
Definition of Baseline Finding ............................................................................... 97 
8.3.1.2 
Categories, Assessments and Documentation of Baseline Findings .................... 98 
8.3.1.3 
Serious Baseline Findings ................................................................................... 99 
8.3.2 Adverse Events............................................................................................................ 99 
8.3.2.1 
Definition of Adverse Event .................................................................................. 99 
8.3.2.2 
Categories for Adverse Event Assessment .......................................................... 99 
8.3.2.3 
Assessments and Documentation of Adverse Events ........................................ 101 
8.3.2.4 
Expected Adverse Events .................................................................................. 102 
8.3.2.5 
Serious Adverse Events ..................................................................................... 104 
8.3.2.6 
Additional Provisions due to the Nature of the Underlying Disease .................... 105 
8.3.3 Physical Examination ................................................................................................. 106 
8.3.4 Vital Signs .................................................................................................................. 106 
8.3.5 Clinical Laboratory Tests ........................................................................................... 107 
8.3.6 Pregnancy Tests ........................................................................................................ 107 
8.3.7 12-Lead ECG ............................................................................................................. 108 
8.3.8 Renal Scintigraphy (99mTc-MAG3) .............................................................................. 108 
8.3.9 Kidney Function and GFR .......................................................................................... 108 
8.4 
Pharmacogenomics ......................................................................................................... 109 
8.5 
Total Volume of Blood ..................................................................................................... 109 
8.6 
Sample Shipment ............................................................................................................ 110 
8.6.1 Tumour Histology Samples ........................................................................................ 110 
8.6.2 Electronic File Transfer .............................................................................................. 110 
8.6.3 Other Samples ........................................................................................................... 110 
8.7 
Image Analyses ............................................................................................................... 110 
8.8 
Appropriateness of Procedures / Measurements ............................................................. 111 
9 
Statistical Methods and Determination of Sample Size ......................................................... 111 
9.1 
Randomisation ................................................................................................................ 111 
9.2 
List of Variables and Population Characteristics .............................................................. 112 
9.2.1 Primary Variable ........................................................................................................ 112 
9.2.2 Secondary Variable(s) ............................................................................................... 112 
9.2.2.1 
Key Secondary Variables ................................................................................... 112 
9.2.2.2 
Exploratory Efficacy Variables ........................................................................... 112 
9.2.2.3 
Safety and Tolerability Parameters .................................................................... 113 
9.2.2.4 
Health-Related Quality of Life (HRQL) ............................................................... 113 
9.2.2.5 
Dosimetry .......................................................................................................... 113 
9.2.2.6 
Pharmacokinetics (Sub-Study C) ....................................................................... 113 
9.2.3 Population Characteristics ......................................................................................... 114 

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9.2.3.1 
Primary Tumour Origin (GE-NET vs. P-NET) ..................................................... 114 
9.2.3.2 
Prior Medical Treatment (1st line vs. 2nd line) ...................................................... 114 
9.2.3.3 
Tumour Grade (G1 vs. G2), Ki-67, and KPS ...................................................... 114 
9.2.3.4 
Other Characteristics ......................................................................................... 114 
9.3 
Statistical and Analytical Plans ........................................................................................ 115 
9.3.1 General Considerations ............................................................................................. 115 
9.3.2 Interim Analysis and Multiple Testing ......................................................................... 116 
9.3.3 Analysis Sets ............................................................................................................. 116 
9.3.3.1 
Full Analysis Set (FAS) ...................................................................................... 116 
9.3.3.2 
Per Protocol set (PP) ......................................................................................... 117 
9.3.3.3 
Safety Analysis Set (SAF) .................................................................................. 117 
9.3.3.4 
Other Populations .............................................................................................. 117 
9.3.4 Statistical Analyses .................................................................................................... 117 
9.4 
Determination of Sample Size ......................................................................................... 118 
10 Data Handling and Quality Assurance .................................................................................. 121 
10.1 Data Recording ............................................................................................................... 121 
10.1.1 Case Report Form (CRF) ........................................................................................... 121 
10.1.2 Missing Data .............................................................................................................. 121 
10.1.3 Storage ...................................................................................................................... 121 
10.2 Monitoring ....................................................................................................................... 122 
10.3 Data Processing .............................................................................................................. 123 
10.4 Data Confidentiality ......................................................................................................... 123 
10.4.1 Documentation of Patients’ Participation .................................................................... 123 
10.4.2 Data Protection .......................................................................................................... 123 
10.5 Auditing ........................................................................................................................... 123 
10.6 Archiving ......................................................................................................................... 124 
11 Premature Termination of the Study ..................................................................................... 124 
11.1 Stopping Criteria .............................................................................................................. 125 
11.1.1 Stopping Criteria for the Entire Trial ........................................................................... 125 
11.1.2 Stopping Criteria for Individual Patients ..................................................................... 125 
11.2 Independent Data Safety Monitoring Board ..................................................................... 126 
12 Investigator’s Obligations and Regulatory Aspects ............................................................... 126 
12.1 Investigator’s Commitment .............................................................................................. 126 
12.2 Documentation ................................................................................................................ 127 
12.2.1 Approvals and Agreements ........................................................................................ 127 
12.2.2 Hospital Case Notes .................................................................................................. 127 
13 Ethical and Legal Aspects ..................................................................................................... 128 
13.1 Ethical and Legal Conduct of the Study ........................................................................... 128 
13.2 Patient Information and Consent ..................................................................................... 128 
13.3 Financial Disclosure ........................................................................................................ 129 
13.4 Publication Policy ............................................................................................................ 130 

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13.5 Compensation for Health Damage of Patients / Insurance............................................... 130 
14 Reference List ....................................................................................................................... 131 
Appendix 1: EORTC QLQ-C30 ................................................................................................... 136 
Appendix 2: EORTC QLQ-GI.NET21 .......................................................................................... 137 
Appendix 3: Karnofsky Performance Status (KPS) Scale ............................................................ 138 
Appendix 4: Afinitor Dose Adjustment Recommendations .......................................................... 139 
Appendix 5: Tumour Scoring....................................................................................................... 141 
 
List of Tables, Figures, Equations and Attachments 
Tables: 
Table 1 (Study Flow Chart): 177Lu-Edotreotide vs. Everolimus in GEP-NET (COMPETE Study) – 
177Lu-Edotreotide Patients ....................................................................................................... 22 
Table 2 (Study Flow Chart): 177Lu-Edotreotide vs. Everolimus in GEP-NET (COMPETE Study) – 
Everolimus Patients ................................................................................................................ 24 
Table 3: Criteria for Assessing the Prognosis of Endocrine Pancreatic Neoplasms ...................... 41 
Table 4: Sampling Schedule Sub-study C ..................................................................................... 55 
Table 5: Radiological Properties of Lutetium-177 .......................................................................... 63 
Table 6: 177Lu-Edotreotide Solution ............................................................................................... 65 
Table 7: Total Volume of Blood ................................................................................................... 109 
Table 8: Karnofsky Performance Status (KPS) Scale.................................................................. 138 
Table 9: Afinitor Dose Adjustment Recommendations ................................................................ 139 
 
Figures: 
Figure 1: Absorbed kidney dose from 7.5 ± 0.4 GBq 177Lu-edotreotide (Schuchhardt et al., 2013) 53 
Figure 2: Structural formula of 177Lu-edotreotide ........................................................................... 64 
Figure 3: Structural formula of everolimus (www.chemblink.com) ................................................. 64 
Figure 4: PFS for everolimus and 177Lu-edotreotide in NET ........................................................ 119 
Figure 5: 111In-pentetreotide-positive lesions ............................................................................... 141 
Figure 6: 111In-pentetreotide example of Liver Lesions ................................................................ 141 
Figure 7: 68Ga-Dotatate MIP ....................................................................................................... 142 
Figure 8: 68Ga-Dotatate examples. A) negative, B) and C) positive ............................................. 142 
Figure 9: 64Cu-Dotatate examples (B) 64Cu-DOTATATE maximum-intensity-projection image with 
arrows pointing at liver and lymph node metastases. Insert is fused PET/CT of peritoneal 
solitary tumour mass. (D) Axial CT and PET of liver revealing several small liver metastases.
 ............................................................................................................................................. 143 
Figure 10: 64Cu-Dotatate example PET/CT (left) and PET (right) scans of patient with intestinal NET 
and multiple metastases. ...................................................................................................... 143 
 

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Attachments: 
Appendix 1: EORTC QLQ-C30 ................................................................................................... 136 
Appendix 2: EORTC QLQ-GI.NET21 .......................................................................................... 137 
Appendix 3: Karnofsky Performance Status (KPS) Scale ............................................................ 138 
Appendix 4: Afinitor Dose Adjustment Recommendations .......................................................... 139 
Appendix 5: Tumour Scoring....................................................................................................... 141 

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List of Abbreviations 
177Lu-Edo 
177Lu-edotreotide 
3D 
Three-dimensional 
AAS 
Amino acid solution 
AD 
Absorbed dose 
ADR 
International Carriage of Dangerous Goods by Road 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
AP 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
BSA 
Body surface area 
CIM 
Clinical imaging manual 
CCL 
Creatinine clearance loss 
CgA 
Chromogranin A 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum serum concentration 
Cmin 
Minimum serum concentration 
CPS 
Central pathology services 
CPL 
Central pathology lab 
CR 
Complete response 
CRA 
Clinical research associate, monitor 
CRF 
Case report form 
CRO 
Clinical research organisation 
CRS 
Cytokine release syndrome 
CT 
Computed tomography 
CTCAE 
Common toxicity criteria – adverse events (version 4.03) 
CUP 
Cancer of unknown primary origin 
CYP2D6 
Cytochrome P450 (3A4) 
CYP3A4 
Cytochrome P450 (2D6) 
D1-4 
Dose 1 to 4 
DCR 
Disease control rate 

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DDC 
Duration of disease control 
DMT 
Dose-modifying toxicity 
DOTA 
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 
DOTATATE 
DOTA-octreotate 
DOTATOC 
Edotreotide 
EBRT 
External Beam Radiation Therapy 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EFR 
External Field Radiation 
EMA 
European Medicines Agency 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOS 
End of study 
EphMRA 
European pharmaceutical Market Research Association 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration (USA) 
FDG 
Fluorodeoxyglucose 
FOV 
Field of view 
FSH 
Follicle stimulating hormone 
GBq 
Gigabecquerel 
GE-NET 
Gastroenteric NET 
GEP-NET 
Gastroenteropancreatic NET 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
Gy 
Gray 
HBsAg 
Hepatitis B virus surface antigen 
HCV 
Hepatitis C virus 
HE 
Haematoxylin and eosin stain 
HES 
Hydroxyethyl starch 
HR 
Hazard ratio 
HIV 
Human immunodeficiency virus 
HPF 
High power field 
HRQL 
Health-related quality of life 
IATA 
International Air Transport Association 

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ICL 
Image core laboratory 
IEC 
Institutional Ethics Committee 
IDSMB 
Independent data safety monitoring board 
IMP 
Investigational medicinal product 
INN 
International non-proprietary name 
INR 
International normalised ratio 
IRB 
Institutional Review Board 
IRC 
Independent image review committee 
ISF 
Investigator's site file 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
Ki-67 
Antigen Ki-67 
KPS 
Karnofsky performance status 
MAG3 
Mercaptoacetyltriglycine 
Max 
Maximum 
MBq 
Megabecquerel 
MCH 
Mean corpuscular haemoglobin 
MCV 
Mean corpuscular volume 
Min 
Minimum 
mNET 
Metastasised neuroendocrine tumours 
mOS 
Median overall survival 
mPFS 
Median progression-free survival 
mP-NET 
Metastasised P-NET 
MRI 
Magnetic resonance imaging 
mTOR 
Mechanistic target of rapamycin 
n.c.a. 
Non carrier added 
NEC 
Neuro-endocrine carcinoma 
NET 
Neuro-endocrine tumours 
NF 
Non-functional 
NM 
Nuclear medicine 
n.s. 
not significant 
OA 
Octreotide acetate 
OR 
Overall morphological response 
ORR 
Objective response rate 
OS 
Overall survival 
p.i., p.inj. 
Post injection 

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%IA 
Percent injected activity 
PET 
Positron emission tomography 
PD 
Progressive disease 
PFS 
Progression-free survival 
PgP 
P-glycoprotein 
PI 
Principal investigator 
P-NET 
Pancreatic NET 
PP 
Per protocol 
PR 
Partial response 
PRRT 
Peptide receptor radionuclide therapy 
Q25 
25% quartile 
Q75 
75% quartile 
QLQ 
Quality of life questionnaire 
QOF 
Quality of life 
RCT 
Randomised, controlled trial 
RECIST 
Response criteria in solid tumours 
RFA 
Radiofrequency Ablation 
RP 
Reference product 
RR 
Response rate 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SEER 
Surveillance, epidemiology, and end results 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SPECT 
Single-photon emission computed tomography 
SPSS® 
Statistical package for social sciences 
SRI 
Somatostatin receptor imaging 
SSA 
Somatostatin agonist 
SSTR 
Somatostatin receptor 
TER 
Tubular extraction rate 
TLS 
Tumour lysis syndrome 
TMF 
Trial master file 
ToC 
Time of calibration 
TSH 
Thyroid stimulating hormone 

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ULN 
Upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
VIP 
Vasoactive intestinal peptide 

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Study Administrative Structure 
Responsibility 
Name 
Affiliation/Address 
Sponsor 
Dr. 
 
 
ITM Solucin GmbH  
Lichtenbergstrasse 1 
D-85748 Garching, Germany 
Phone: 
 
Fax: 
 
E-Mail: info-solucin@itm-radiopharma.com 
CRO 
Dr. 
 / 
, 
MD / 
 
(Countries: Austria, Germany, Italy, 
Netherlands, South Africa, and Switzerland) 
ABX-CRO advanced pharmaceutical  
services - Forschungsgesellschaft mbH 
Schössergasse 19 
D-01067 Dresden, Germany 
Phone: 
 
Fax: 
 
E-Mail: info@abx-cro.com 
 
(Countries: Australia, Belgium, Czech 
Republic, France, Poland, Spain, United 
Kingdom, and United States) 
PSI CRO AG 
Baarerstrasse 113 
6300 Zug, Switzerland 
Phone: 
 
Fax: 
 
E-mail: contact@psi-cro.com 
Pharmacovigilance 
Dr. 
 
ITM Oncologics GmbH 
Walther-von-Dyck-Strasse 4 
85748 Garching/Munich, Germany 
 
E-mail: SAE-reporting@itm-radiopharma.com  
Phone: 
 
Fax:  
 
Authors 
Dr. 
 
Prof. Dr. 
 
 
 
ABX-CRO advanced pharmaceutical 
services Forschungsgesellschaft mbH 
Phone: 
 
Fax: 
 
E-Mail: info@abx-cro.com 
 
 
 
 

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The principal investigator of each centre must sign the protocol signature sheet before patient 
recruitment may start at the respective centre. Likewise, all protocol amendments must be signed and 
dated by the principal investigator before coming into effect at the respective centre. 
A complete list of all participating centres and their investigators, as well as all required signature 
documents, will be maintained in the trial master file (TMF). 
 

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1 
Introduction 
1.1 
Background 
Neuroendocrine neoplasms arise from neuroendocrine cells present in specialised endocrine glands 
or as isolated endocrine cells in most tissues throughout the body. The current WHO 2010 
classification distinguishes between well-differentiated neuroendocrine tumours (NETs) and poorly 
differentiated neuroendocrine carcinomas (NECs) of small or large cell type (Rindi et al., 2010). The 
incidence of NETs has been rising over the past 30 years (Modlin et al., 2008), which is partly 
explained by improved diagnosis. About 72% of NETs arise in gastrointestinal structures, including 
the pancreas, which are collectively referred to as gastro-entero-pancreatic NETs (GEP-NETs). About 
25% of NETs are bronchopulmonary in origin, and less than 5 % arise from other sites (e.g. thymus, 
breast). Frequently, NETs are discovered late when already metastatic or locally advanced disease 
is present, and potentially curative surgical treatment is no longer possible. Common sites of 
metastasis are mesenteric lymph nodes and the liver via the portal vein. NETs may remain clinically 
silent until a significant liver tumour burden is present, or obstructive symptoms occur. If tumours 
produce endocrine hormones, they are referred to as functional NET. Functional tumours are 
associated with clinical syndromes, characteristic for the type of hormone released (e.g. carcinoid 
syndrome with flushing and diarrhoea in serotonin secreting tumours). Beyond surgery, therapeutic 
options for NETs include loco-regional therapies (bland embolisation, radio-embolisation, RFA, EFR), 
interferon, and chemotherapy, or molecular targeted agents, which address individual metabolic 
pathways. Most NETs strongly express somatostatin receptors (SSTRs), predominantly of the sst2 
subtype (Appetecchia et al., 2010), providing the basis of antisecretory and antiproliferative therapy 
with somatostatin agonists (SSA), such as octreotide or lanreotide (Rinke et al., 2009; Caplin et al., 
2014). Peptide receptor radionuclide therapy (PRRT), using therapeutically radio-labelled SSTR 
receptor ligands, directed against SSTRs is an innovative modality for NET treatment, which has 
shown highly promising outcomes, even in patients with advanced disease (Bodei et al, 2013). 
The largest group of GEP-NETs are found in the small intestine (carcinoids) and constitute 
approximately 50% of all GEP-NETs (Öberg et al., 2012). Of these carcinoids, approximately 30% 
are functional and present with the carcinoid syndrome, including flushing, diarrhoea and endocardial 
fibrosis. Neuroendocrine tumours of pancreatic origin (P-NETs) constitute approximately 30% of all 
GEP-NETs. 45-60% of P-NETs are non-functional, and 40–55% are functional (Öberg et al., 2012). 
Characteristic hormone-related syndromes include the Zollinger–Ellison syndrome (gastrin), 
hypoglycemia syndrome (insulin), glucagonoma syndrome (glucagon), in addition to which a large 
variety of very rare conditions exists, associated with the excessive production of VIP, somatostatin 
and other hormones. 
According to the United States (US)-American SEER database, the overall annual incidence of 
GEP-NETs is 3.65/100,000, which is subdivided into 0.33 for stomach, 1.08 for small intestine, 0.43 
for pancreas and 1.65 for colon and rectum (Lawrence et al., 2011). However, it should also be noted 
that considerable variations in incidence occur depending on country, race and gender (Lawrence et 
al., 2011, Öberg et al., 2012, Ramage et al., 2012). Non-functional GEP-NETs are usually diagnosed 
late in the course of the disease, and seem to have a slightly worse prognosis, compared to functional 

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tumours. When symptomatic, the most common presenting symptoms are abdominal pain (35-78%), 
weight loss (20–35%), anorexia and nausea (45%). The 5-year survival rate was found to be highest 
in rectal NETs at 89% and the lowest in P-NETs at 38% (Lawrence et al., 2011). The presence of 
distant metastases and the degree of differentiation are the most powerful predictors of poor survival 
(Falconi et al., 2012). Histologically, GEP-NETs are graded based on the number of mitoses per HPF 
(high power field), and the percentage of cells expressing the proliferation marker Ki-67 (Rindi et al. 
2006) into grades G1 (Ki-67 ≤2%), G2 (Ki-67 3-20%), and G3 (Ki-67 >20%). Histological criteria for 
assessing the prognosis of endocrine pancreatic neoplasms are shown in Table 3. Similar criteria 
apply to gastroenteric neuroendocrine tumours. 
 
Table 3: Criteria for Assessing the Prognosis of Endocrine Pancreatic Neoplasms 
According to Falconi et al., 2012 
Biological 
behaviour 
WHO 
classification 
Metastases Invasion Tumour 
size, cm 
Angio-
invasion 
Ki-67 
index [%] 
Benign 
NET G1 or G2 
- 
- 
≤ 2 
- 
Usually 
around 2 
Benign 
or 
low-grade 
malignant 
NET G1 or G2 
- 
- 
>2 
± 
Usually 
around 2 
Low-grade 
malignant 
NET G1 or G2 + 
+ 
any 
+ 
Usually 
>2 
High-grade 
malignant 
NEC or G3 
+ 
+ 
any 
+ 
>20 
 
The present protocol aims to investigate metastasised and/or locally advanced, inoperable GEP-NET 
of grade G1 and G2, with radiologically proven progression. 
Current treatment guidelines for metastasised GEP-NET published by ENETS (European 
Neuroendocrine Tumour Society), recommend as 1st line treatment for G1 midgut tumours 
somatostatin analogues (Pavel 2012). For P-NETs, a number of 1st line therapy options are presented, 
including streptozotocin-based chemotherapy in combination with 5-FU and/or doxorubicin (Jensen 
et al., 2012; Falconi et al., 2012; Pavel 2012). Streptozotocin is not generally licensed for the treatment 
of P-NET in the European Union (EU). In contrast, the mTOR inhibitor everolimus (Afinitor®, Novartis) 
and the tyrosine kinase inhibitor sunitinib, (Sutent®, Pfizer) have been licensed for treatment of P-NET 
in the EU and the USA. Most recently, everolimus has also been licensed for treatment of 
non-functional GE-NETs by both the US Food and Drug Administration (FDA) and European 
Medicines Agency (EMA). While everolimus has been quickly adopted clinically, sunitinib has 
remained a reserve medication, due to relatively poor tolerability. A further compound increasingly 
used for treatment of mP-NET – albeit off-label – is the chemotherapeutic agent temozolomide 
(Temodar®, MSD), which has shown outstanding tolerability and promising evidence of tumour control 
(Ekeblad et al., 2007). For non-resectable G1 P-NET tumours with demonstrated SSTR expression, 
treatment with long-acting somatostatin analogues (SSA), such as octreotide acetate (OA, 

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Sandostatin®, Novartis) or lanreotide (Somatuline®, Ipsen) is a further therapeutic alternative, which 
can alleviate hormone release symptoms, and provide some antiproliferative effect.  
PRRT with radiolabelled SSTR-ligands, such as 90Y-DOTATOC or 177Lu-DOTATATE has shown great 
promise in the treatment of NET (Bushnell et al. 2010; Kwekkeboom et al. 2008), with median 
progression-free survival (mPFS) of 18.2 and 33.0 months, and disease control rates (DCR, 
proportion of patients with stable disease, partial or complete response) of 74.4% and 65%, 
respectively. To date, however, a direct comparison of PRRT vs. medical therapy has not been 
performed. As GEP-NET disease is typically slowly progressing and chronic, patients undergo mostly 
sequential treatments with SSA, chemotherapy, and/or molecular targeted therapy (everolimus or 
sunitinib). The order and selection of individual agents varies considerably between institutions and 
patients. PRRT, where institutionally available, is traditionally performed rather late in the disease 
course, although its earlier use might be beneficial (Kwekkeboom et al. 2010).177Lu-edotreotide 
(synonym: 177Lu-DOTATOC) is an innovative PRRT agent, with favourable safety profile, and 
promising efficacy. Compared to 90Y-edotreotide, 177Lu-edotreotide PRRT in NET was found to be 
less haematotoxic, and associated with a longer mOS (45.5 vs. 35.9 months, n.s.), which was highly 
significant for patients with low tumour uptake (p < 0.001), extra hepatic (p < 0.012), and solitary 
metastases (p < 0.02) (Romer et al., 2014). Compared to other 177Lu-labelled somatostatin receptor 
ligands in clinical use, 177Lu-edotreotide has the lowest uptake/dose ratio delivered to normal organs 
and highest tumour-to-kidney ratio (Schuchardt et al., 2013), rendering it particularly promising as a 
PRRT agent for the treatment of NETs, considering both safety and efficacy. In patients with 
progressive, inoperable GEP-NETs treated with two or more cycles of 177Lu-edotreotide PRRT, a 
median PFS of 34.5 months and a disease control rate (DCR: SD, PR and CR) of 100.0% was 
observed in an academic study, conducted at the ENETS centre of excellence in Bad Berka, Germany 
(van Echteld et al., 2015; Baum et al., 2016). Based on these data, the EMA granted an Orphan Drug 
Designation to 177Lu-edotreotide for the treatment of GEP-NET. 
Therefore, 177Lu-edotreotide will be developed in the indication GEP-NET. Everolimus (Afinitor®) was 
selected as a comparator, based on the strength of scientific evidence of efficacy, and the high clinical 
acceptance this product has gained soon after marketing authorisation. However, everolimus 
received marketing authorisation for both functional and non-functional P-NETs but for GE-NETs only 
for non-functional tumours. Everolimus inhibits the so-called mechanistic target of rapamycin (mTOR), 
involved in the control of cell division and angiogenesis. Pharmacologically, everolimus acts by 
preventing tumour cell division and reducing the blood supply to tumours by inhibiting angiogenesis.  
Further details on the study drug 177Lu-edotreotide can be found in the investigator's brochure, 
whereas further details concerning the comparator everolimus (Afinitor®) are described in the local 
product information for the countries participating in this study (Afinitor®, current version of Summary 
of Product Characteristics [SmPC] for the EU and South Africa; US Prescribing Information [USPI] for 
the US; Information for Professionals for Switzerland; and Product Information for Australia).  
1.2 
Rationale of the Study 
Current ENETS guidelines recommend PRRT for 2nd line treatment in patients having failed on 
medical therapy (Jensen et al., 2012; Pavel et al., 2012). Although PRRT is considered an established 

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treatment modality in such cases, having shown impressive evidence of efficacy (PFS, OS, objective 
response rates) in non-comparative (single arm) studies, so far only one randomised prospective 
evaluation of PRRT has been performed with 177Lu-DOTATATE – the NETTER-1 study. The results 
of an interim analysis of the NETTER-1 study conducted at the primary endpoint (PFS) have very 
recently been published (Strosberg et al., 2017): Of the 229 patients with well-differentiated, 
metastatic midgut neuroendocrine tumours included in this study, 116 received 177Lu-Dotatate, and 
113 received octreotide LAR. At the data cut-off date for the primary analysis, the estimated rate of 
progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 
177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 
18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim 
analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group 
(P=0.004). With regard to safety, 177Lu-Dotatate was associated with low rates of grade 3 or 4 
hematologic toxic effects and, when administered together with a renal protective agent, showed no 
evidence of renal toxic effects during the observation period (median duration of follow-up, 
14 months). Based on the results of the NETTER-1 trial, 177Lu-Dotatate has recently received 
Marketing Authorisation in the EU and the USA as Lutathera® for the second-line treatment of 
unresectable or metastatic, progressive, somatostatin receptor positive gastroenteropancreatic 
neuroendocrine G1 and G2 tumours (GEP-NETs) in adults. 
However, the NETTER-1 study only enrolled patients with midgut neuroendocrine tumours, and 
patients with primaries in stomach, pancreas, descending colon and rectum were not included. 
Furthermore, the previously mentioned academic study, conducted at the ENETS centre of excellence 
in Bad Berka, Germany (van Echteld et al., 2015, Baum et al., 2016) showed an unprecedented 
objective response rate of 54% for inoperable GEP-NETs treated with two or more cycles of 177Lu-
edotreotide. 
The purpose of the present study, therefore, is to evaluate efficacy and safety of PRRT with 
177Lu-edotreotide in patients with metastatic GEP-NET, in comparison to established medical therapy 
using a prospective randomised controlled trial (RCT) design. As comparator drug, everolimus 
(Afinitor®), has been selected, a drug licensed for the treatment of unresectable or metastatic, well or 
moderately differentiated neuroendocrine tumours of pancreatic origin in adults with progressive 
disease and recently also for the treatment of unresectable or metastatic, well-differentiated (G1 or 
G2) non-functional neuroendocrine tumours of gastrointestinal origin. Everolimus has an innovative 
mode of action, high clinical acceptance, and a well-documented evidence of efficacy. This study will 
further be designed to allow a meaningful subgroup analysis of GE-NETs and P-NETs. In addition, 
by inclusion of both, 1st line and 2nd line GEP-NET patients, the issue of optimum timing of PRRT 
during the disease course will also be addressed by the trial.  
1.3 
Benefit-Risk Assessment 
The prognosis of GEP-NET patients is poor in most cases, since the disease is typically diagnosed 
at a late stage once the tumour has become non-resectable and/or has metastasised already (Modlin 
et al., 2008). For patients with metastasised P-NET (mP-NET), the observed 5-year survival rates are 
the lowest reported and vary between 25%-60% (Öberg et al., 2012),27-43% (Ramage et al., 2012) 
and 38% (Lawrence 2011), in spite of using all available treatment options, including surgery, 

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symptom control with SSA and/or chemotherapy. Everolimus (Afinitor®) and sunitinib (Sutent®) are 
two drugs currently licensed for treatment of P-NET in the EU and USA, based on a median PFS (vs. 
placebo) of 11.0 (vs. 4.6) (Yao et al., 2011) and 10.2 (vs. 5.4) (Blumenthal et al., 2012) months, 
respectively. Lanreotide (Somatuline®) has also been approved by the FDA for GEP-NET. Study 
results showed a median PFS of 18.0 months for placebo (Caplin et al., 2014) and recently a corrected 
median PFS of 30.8 months for lanreotide (Caplin et al., 2016), but none of the enrolled patients in 
this study was in progression. Most recently, everolimus (Afinitor®) was also licensed both in the USA 
and the EU for treatment of non-functional GE-NET and lung NET based on a median PFS of 
11.0 months vs. 3.9 months in placebo (Yao et al., 2016). 
Well-documented evidence of clinical safety and efficacy of 177Lu-edotreotide in patients with mNET 
is available from the academic study, mentioned above (van Echteld et al. 2015, Baum et al., 2016). 
Fifty-six (56) patients (27 female, 29 male, mean age 64.4 years) presenting with progressive NET 
disease, were administered 1 to 4 doses of 177Lu-edotreotide PRRT as sole treatment option until a 
new diagnosis of disease progression.  
For patients with metastasised GEP-NET, who received ≥ 2 177Lu-edotreotide cycles, a median PFS 
of 34.5 months was reported (van Echteld et al. 2015, Baum et al., 2016). It is, therefore assumed, 
that patients assigned to 177Lu-edotreotide treatment may experience a significant individual benefit, 
compared to those assigned to standard treatment.  
While everolimus treatment is chronic, acting by continuous inhibition of tumour and vascular growth, 
PRRT acts cumulatively by destroying sensitive tumour cells, similarly as fractionated EFR. For 
instance, in the Bad Berka academic study, most responding patients (34/37, 92%) showed their first 
response after the first PRRT cycle, but 5% of patients (2/37) required two, and one patient required 
three 177Lu-edotreotide cycles for induction of an initial response.  
In 65% (24 of 37) of patients the best response was observed after the first PRRT cycle. However, 
32% (12 of 37) of patients required 2 cycles for induction of their best response, while latency was 
more than 9 months from start of treatment in 7 of these patients and in 2 patients, latency was even 
more than 22 months. One patient required three 177Lu-edotreotide cycles for induction of the best 
response. Interestingly, 47% (9 of 19) of all objective responses (PR, CR) took more than nine months 
to develop from start of treatment. In 35% the best therapeutic response was observed only after their 
last PRRT cycle (late responders), without receiving further antineoplastic therapy. In addition to direct 
cytocidal effects of PRRT, mediated by lethal DNA double strand breaks, secondary antineoplastic 
effects may be induced, which can further improve the treatment outcome even months after the last 
PRRT cycle, without further specific treatment. 
177Lu-edotreotide PRRT will be administered as a maximum of four cycles of a 7.5 ± 0.7 GBq dose, 
referred to as dose 1 – dose 4 (D1 – D4), administered in 3-monthly intervals over a period of 
9 months. Although current guidelines on PRRT (Bodei et al., 2013; Zaknun et al., 2013; IAEA 2013) 
advise 200 mCi (=7.4 GBq) as maximum for a single dose, we have chosen to employ a 7.5 GBq 
dose based on SI-units. The advised number of cycles is three to five with a 6-12 weeks interval, from 
which we derived a maximum number of four cycles with a 3 months interval, based on the academic 
study, mentioned before (van Echteld et al. 2015, Baum et al., 2016). This dose and dose regimen 
were approved on several protocol discussion meetings with key opinion leaders. 

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Due to tubular re-absorption of radiolabelled peptide agents, radiation-induced kidney disease is the 
main safety concern for PRRT. Both, acute renal toxicity with increased serum creatinine and long-
term nephropathy with creatinine clearance loss (CCL) of 5 to more than 10% per year (Bodei et al., 
2008) may occur. Nephropathy is reported to be more pronounced in patients with renal risk factors 
(arterial hypertension, diabetes mellitus), pre-existing renal impairment or those who have received 
earlier nephrotoxic treatment modalities (chemotherapy, local EFR, prior PRRT) (Bodei et al., 2008). 
All patients in the above-mentioned academic study were pre-treated with a nephroprotective amino 
acid solution, administered IV starting 30 min to and lasting 3 – 4 h after the start of the PRRT infusion, 
according to current guidelines (Bodei et al., 2013; Zaknun et al., 2013; IAEA 2013). Such regimen 
has been shown to decrease the renal absorbed radiation dose by 50% without reducing the tumour 
uptake (Rolleman et al., 2010). Using this regimen, no clinically relevant nephrotoxicity following 
PRRT with 177Lu-edotreotide was observed, as evaluated by extended renal function testing 
(glomerular filtration rate [GFR], creatinine, tubular extraction rate [TER], K+ and BUN). 
In the context of the planned trial, a similar nephroprotective regimen will be used. In addition, patients 
with impaired renal function (GFR <60mL/min/1.73 m²), or ill-controlled renal risk factors will be 
excluded from participation. As a further safety measure, absorbed organ doses to the kidneys will in 
principle be restricted to ≤ 23 Gy, as per current guidelines on PRRT (Bodei et al., 2013; Zaknun et 
al., 2013; IAEA 2013). If the predicted absorbed dose to the kidneys likely exceeds 23 Gy upon 
administration of the next PRRT cycle, additional measurement of renal function must be performed. 
In case this pre-therapeutic TER (99mTc-MAG3 renal scintigraphy) is >50% of baseline, dosing can be 
continued. However, the absorbed dose is not allowed to exceed 29 Gy, as suggested by 
Konijnenberg et al. (2007).   
Patients assigned to comparator treatment with everolimus will receive licensed standard treatment. 
Potential side effects include among others anaemia, fatigue, diarrhoea, hyperglycaemia, and 
diabetes mellitus (see Afinitor®, current version of manufacturer's instruction and local product 
information for the countries participating in this study). The selected dose (10 mg/d) corresponds to 
manufacturer´s recommendations.  
PRRT with 177Lu-edotreotide has been administered in a relevant number of patients with NET in the 
context of the above-mentioned academic study. A promising impact on progression-free survival and 
objective response rate has been observed in these patients with advanced and progressive disease. 
At the same time, a safety profile favourable for an anti-cancer agent was established. For 
participating patients, the potential of an individual benefit is substantial, considering both an improved 
efficacy, and better safety and tolerability, compared to the licensed comparator medication 
everolimus. Furthermore, because of the expected substantial difference in PFS between 177Lu-
edotreotide PRRT and everolimus (Afinitor®) treatment, a 2:1 randomisation has been chosen, 
respectively. This allows a larger number of patients the direct potential benefits and low risks of 
177Lu-edotreotide PRRT. 
In summary, considering the expected favourable benefit-risk ratio for study participation of patients 
with progressive GEP-NET, the recommended 177Lu-edotreotide dosing, consisting of four cycles of 
7.5 ± 0.7 GBq, is justified to maximise therapeutic benefit, provided that individualised dosimetry 
shows the cumulative renal absorbed radiation dose not to exceed 23 Gy. Exceptionally, dosing up 

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to 29 Gy renal absorbed radiation dose is permitted, only if kidney function is not compromised and 
additional pre-therapeutic TER (99mTc-MAG3 renal scintigraphy) is proven to be >50% of baseline. 
In view of the expected benefit for patients with advanced cancer, the planned Phase 3 dosing 
regimen represents an optimum balance of risk (nephrotoxicity) and therapeutic benefit, in line with 
current guidelines and similar therapies under investigation.  
2 
Study Objectives 
Primary objective 
The primary objective is to demonstrate the efficacy of PRRT with 177Lu-edotreotide to prolong 
progression-free survival (PFS) in patients with inoperable, progressive, SSTR+ GEP-NET, compared 
to everolimus. 
Key secondary objectives 
The key secondary objectives of this study are: 
1. 
To assess objective response rates (ORR), defined as the proportion of patients achieving 
partial response (PR) or complete response (CR) as best outcome, after treatment with 
177Lu-edotreotide compared to everolimus  
2. 
To assess overall survival (OS) defined as the time from date of randomisation until death 
Exploratory secondary objectives 
The exploratory secondary objectives of this study are: 
3. 
To assess the duration of disease control (DDC), defined as the time of initial diagnosis of 
response (SD, PR or CR) until diagnosis of progression, after treatment with 
177Lu-edotreotide compared to everolimus 
4. 
To determine disease control rates (DCR), defined as the proportion of patients achieving 
stable disease (SD), PR or CR as best outcome 
5. 
To determine response rate (RR), considering CgA and specific hormones (where increased 
at baseline) 
6. 
To assess the safety and tolerability of 177Lu-edotreotide in GEP-NET patients 
7. 
To determine the health-related quality of life (HRQL) in GEP-NET patients during and after 
therapy (EORTC QLQ-C30 questionnaire) 
8. 
To evaluate symptomatic tumour response (EORTC GI.NET21 questionnaire) 

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9. 
To evaluate the impact of patient characteristics (time from primary diagnosis, time from 
diagnosis of progression, number of prior therapies (1st vs 2nd line), type of prior therapies, 
KPS at randomisation) on tumour response 
10. To evaluate the impact of tumour histology (histological entity, tumour grade, Ki-67 
expression, SSTR expression, functional state), as determined in primary or current tumour 
specimen, on tumour response 
Tertiary objectives (in 177Lu-edotreotide patients) 
1. 
To assess differences in tumour and kidney radiation dose estimates, obtained with 2D 
(planar) compared to hybrid (2D/3D), and 3D (SPECT) imaging 
2. 
To evaluate the value of pre-therapeutic SSTR imaging (SRI) to predict tumour response 
(globally/at lesion level) 
3. 
To evaluate the relationship between PRRT radiation dose (in Gy) and tumour response 
(globally/at lesion level) 
4. 
To assess metabolic stability and excretion pattern of 177Lu-edotreotide 
5. 
To assess bone marrow radiation dose 
3 
Overview of Methodology and Design 
3.1 
Study Design 
This will be a confirmatory, prospective, randomised, controlled, parallel group, open-label, multi-
centre phase III study to evaluate the efficacy and safety of 177Lu-edotreotide in comparison to 
molecular targeted therapy with everolimus in patients with inoperable, progressive, somatostatin 
receptor-positive (SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin (GEP-NET). 
In total, 300 GEP-NET patients will be randomised in a 2 : 1 fashion to receive either: 
• 
PRRT with 177Lu-edotreotide consisting of a maximum of four cycles (7.5 ± 0.7 GBq 
177Lu-edotreotide, each), administered as IV infusion at 3-monthly intervals for 9 months, or until 
diagnosis of progression (200 patients), or  
• 
10 mg everolimus (Afinitor®) daily, administered orally as a tablet (100 patients).  
The duration of study participation for the patients will be 30 months. Due to the extension of the 
duration of study participation from 24 months to 30 months, patients already in the post-study follow-
up will be contacted again if applicable and re-consented for performing the visits at 27 and/or 
30 months. The duration of the entire study is planned to be 90 months. Collection of survival data 
and information on further antineoplastic treatments as well as the development of secondary 

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malignancies will be continued for five years after EOS. To enable a meaningful subgroup analysis, 
randomisation will be stratified for primary tumour origin with ideally equal numbers of GE-NETs (150 
patients) and P-NETs (150 patients). Furthermore, a sufficient number of treatment-naive patients (1st 
line) and patients with previous therapies (2nd line) must be enrolled to allow conclusions on efficacy 
in each of the sub-populations. 
177Lu-edotreotide PRRT will be administered as a maximum of four cycles of a 7.5 ± 0.7 GBq dose 
referred to as dose 1 – dose 4 (D1 – D4), administered in 3-monthly intervals over a period of 
9 months. The administration of each dose may require a short-term hospitalisation of typically 3 days 
on a suitable radionuclide therapy ward. Individual hospitalisation requirements will be as specified 
per the locally applicable radiation safety regulations for each study site. Biodistribution of 
177Lu-edotreotide, and consequently the absorbed dose (AD) to kidneys may vary considerably 
between subjects. Therefore, following current guidelines, the absorbed organ doses to the kidneys 
will in principle be restricted to ≤ 23 Gy (Bodei et al., 2013; Zaknun et al., 2013; IAEA 2013).  
To this end, after administration of D1, patients will be subjected to sequential dosimetric whole body 
imaging at 0.5 (prior to voiding, preceded by a blank and a transmission scan or if available at the site 
whole body low dose CT scan), 6, 24, and 72–96 h p.i. using conventional planar scintigraphy, 
complemented by abdominal SPECT/CT imaging at 24 h (optional planar scintigraphy on day 7). 
Based on the first cycle, the cumulative AD to kidneys from the planned full treatment course of four 
doses of 7.5 ± 0.7 GBq 177Lu-edotreotide will be estimated. However, if the predicted absorbed dose 
to the kidneys likely exceeds 23 Gy upon administration of the next PRRT cycle, dosing can be 
continued up to a maximum of 29 Gy, provided that a pre-PRRT TER (99mTc-MAG3 renal scintigraphy) 
is >50% of the value at baseline (see Section 5.4.3). In selected patients, the accuracy of AD 
predictions made based on the first cycle will be verified by repeated dosimetry in cycles D2 – D4 
(Sub-study A). 
In addition, before receiving the next 177Lu-edotreotide treatment after cycle 1, all patients in the PRRT 
arm will be assessed for specific safety criteria during the pre-treatment evaluations on Day 90 post 
first cycle, including hematological as well as renal safety parameters. If the safety criteria are not 
met, the patients will not receive the next dose (see Section 5.4.1.2). 
177Lu-edotreotide dosimetry will be centrally analysed for the absorbed kidney and target tumour 
doses in a standardised fashion. Resulting mandatory prescriptions for additional 99mTc-MAG3 renal 
scintigraphy before continued administration of 177Lu-edotreotide doses D2 - D4, ensuring a safe 
kidney dose exposure, will be derived and communicated to the sites by the central lab. Dosimetry 
will be performed according to the current regulatory standard (conventional planar (2D) dosimetry), 
and according to the emerging clinical standard (2D/3D hybrid dosimetry) for a more accurate 
determination of the kidney dose. 
Quantitative SPECT reconstruction is a recent option to directly derive quantitative information on 
177Lu activity distribution in vivo, allowing to assess absorbed doses to kidneys (safety) and tumour 
(efficacy) with higher accuracy, compared to planar scintigraphy. In selected study sites, 
177Lu-edotreotide SPECT/CT (3D) will be performed at each time point in addition to planar 
scintigraphy (2D). Data will be quantitatively reconstructed, and dosimetrically analysed in 
comparison to planar (2D) and hybrid (2D/3D) dosimetry (Sub-study B). 

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To assess in-vivo stability of 177Lu-edotreotide, urine will be collected from all voids beginning 
immediately post-dose to 1 hour, and in intervals of 1-6, 6-24 and 24-48 hours post-injection in a 
subgroup of 20 patients at selected sites only. Urine will be analysed using gamma counting and 
radio-HPLC in order to investigate the radiochemical purity of the eliminated compound, as well as 
the excretion pattern of 177Lu-edotreotide (Sub-study C). In addition, bone marrow dosimetry will be 
assessed in Sub-study C by measuring radioactivity in blood samples at pre-defined intervals from 
0 minutes to 7 days post-injection of 177Lu-edotreotide.  
Following administration of each 177Lu-edotreotide dose (D1 – D4), blood has to be drawn for safety 
laboratory examinations (haematology) in 2-weekly intervals for 8 weeks. Where these time points 
will not coincide with formal study visits, blood may be drawn in local medical institutions, if a visit of 
the study site is not reasonably feasible.  
Everolimus: Patients randomised to everolimus therapy will undergo out-patient visits only. Patients 
will receive a standard dose of 10 mg daily, which may be reduced, where required for acceptable 
tolerability, according to manufacturer´s product information (see Appendix 4). 
Both study arms: Study visits will be monthly in the first 12 months, thereafter 3-monthly until end of 
study at month 30 or until progression (whatever occurs first). For symptom control, all patients are 
allowed to receive somatostatin analogues (SSA), as clinically indicated (best supportive care) in 
required doses, not to exceed licensed doses. In the 177Lu-edotreotide arm, clinically established 
wash-out periods prior to 177Lu-edotreotide dosing have to be considered (1 day for immediate 
release, and 28 days for sustained release SSA). 
Safety, tolerability and symptom control parameters, as well as tumour markers are captured at 
regular intervals. 
To assess efficacy, serial morphological imaging, comprising native liver and contrast-enhanced liver 
and 3 regional (pelvis, abdomen, thorax) MRI or CT (see Clinical Imaging Manual for details), is 
scheduled every three months, consistently using baseline methods. Evaluation of tumour response 
will be performed by local investigators using RECIST 1.1 criteria.  
In case of clinically suspected tumour progression, investigators may schedule appropriate diagnostic 
imaging at any time.  
Image analyses will also be conducted centrally. For establishment of PFS (primary endpoint) blinded 
reading in duplicate, with adjudication in case of discordance will be used. 
Patients who progressed under everolimus may be offered 177Lu-edotreotide therapy based on the 
personal judgement of the Investigator, if he/she considers it appropriate and likely to be beneficial 
for the individual patient (see Section 7.4.2).  
To further evaluate tumour response, the tumour marker Chromogranin A (Cg-A) will be determined 
at baseline, and then monthly until month 12, thereafter in 3-monthly intervals until diagnosis of 
progression or end of study. Cg-A represents a secretory protein present in dense-core vesicles of 
neuroendocrine (NE) cells. It is being expressed in most secretory, but also non-functional NET. Cg-A 
is the best circulating neuroendocrine marker available up to now for the management of differentiated 

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neuroendocrine malignancies irrespective of tumour location and functional status (Singh et Law, 
2012). 
The European Organisation for Research and Treatment of Cancer (EORTC) has issued an 
integrated system of quality of life questionnaires (QLQ) for assessing the health-related quality of life 
(HRQL) of cancer patients participating in international clinical trials. The QLQ-C30 and 
QLQ-GI.NET21 will be used in the current trial.  
QLQ-C30 is a copyrighted instrument, which has been translated and validated into 81 languages 
and is used in more than 3,000 studies worldwide. The first version of QLQ-C30 was released in 1993. 
Since then, several new versions have been developed and issued. Version 3.0, a 30-item 
questionnaire, is currently the standard version of the QLQ-C30, and should be used for all new 
studies unless compatibility to previous studies is intended. It is supplemented by disease specific 
modules for e.g. Breast, Lung, Head & Neck, Oesophageal, Ovarian, Gastric, Cervical cancer, 
Multiple Myeloma, Oesophago-Gastric, Prostate, Colorectal Liver Metastases, Colorectal and Brain 
cancer which are distributed from the EORTC Quality of Life Department. Other disease-specific 
modules are under development but not yet validated. 
The QLQ-C30 supplement QLQ-GI.NET21 is intended for use among patients with GI-related 
neuroendocrine tumours, who vary in disease stages and treatments. The module comprises 
21 questions assessing disease symptoms, side effects of treatment, body image, disease related 
worries, social functioning, communication, and sexuality (see Appendix 2). The module has been 
recently validated within an international multicentre study in 253 patients with gastrointestinal 
neuroendocrine tumours. All patients were requested to complete two quality of life questionnaires – 
the EORTC Core Quality of Life questionnaire (QLQ-C30) and the QLQ-GI.NET21 – at baseline, and 
at 3 and 6 months post-baseline; the psychometric properties of the questionnaire were then 
analysed. It was concluded that QLQ-GI.NET21 is a valid and responsive tool for assessing quality of 
life in the gut, pancreas and liver neuroendocrine tumours (Yadegarfar et al., 2013). The GI.NET21 
has been translated into several European languages. 
During treatment phase monthly QOL assessments will be performed as in the everolimus group the 
continuous daily treatment may lead to changes in quality of life which are not consistent to treatment 
intervals in the 177Lu-edotreotide group. 
3.2 
Study Endpoints 
The primary endpoint is progression-free survival (PFS). Diagnosis of progression will be established 
based on morphological imaging (MRI and/or CT) according to RECIST 1.1. Progression-free survival 
(PFS) will be determined as time elapsed between randomisation, and the date of first objective report 
of tumour progression (evaluated by RECIST criteria, 1.1), or death. Stratification will be made for 
primary tumour origin (GE-NET vs. P-NET) and prior medical therapy (1st line vs. 2nd line). Tumour 
grade (G1, G2), and baseline Karnofsky score will be used for further statistical subgroup analyses 
Secondary endpoints include parameters of morphological and biomarker tumour response, such as 
objective response rate (ORR), overall survival (OS) , disease control rates (DCR), and duration of 

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disease control (DDC), as well as safety, and health-related quality of life (HRQL). Furthermore, 
exploratory analyses will be performed on patient and tumour characteristics, as well as the degree 
of 177Lu-edotreotide uptake as possible predictors of PRRT efficacy.   
3.3 
Justification of the Design 
For the evaluation of a new treatment modality, a prospective, randomised, controlled trial (RCT) 
design is appropriate. Ideally, a double-blind setting should be implemented to minimise observational 
bias. Due to the nature (radioactive vs. non-radioactive) and the administration schemes of 
investigational and comparator drugs, a blinded design is not possible, as the treatments are 
substantially different. 177Lu-edotreotide therapy is administered in 3-monthly intervals at most four 
times as intravenous infusion with concurrent infusion of a nephroprotective amino acid solution. This 
therapy involves a short-term hospitalisation for each dose and several imaging procedures (for 
dosimetry and tumour targeting). In contrast, everolimus is a systemic therapy administered per os 
on an outpatient basis. 
While for pivotal phase III oncology trials “overall survival” (OS) is generally seen as the ideal primary 
outcome parameter (FDA, Guidance for Industry, 2007), “progression-free survival” (PFS) is widely 
accepted as alternative primary endpoint. Since GEP-NET patients typically are treated with various 
medications during their disease course, study participants are likely to undergo further treatments 
after study participation, rendering the interpretation of OS difficult. For this reason, PFS has been 
selected as primary endpoint, which requires appropriate randomisation, blinding and consistent 
definition of tumour progression criteria. 
To achieve blinding, although not feasible in the clinical setting, the diagnosis of progression (primary 
endpoint) will be independently confirmed by a centralised blinded read, in duplicate, with 
adjudication, as appropriate for a phase III study (Yao et al., 2011).  
Considering that licensed medications for the treatment of GEP-NET are available, a placebo-
controlled design as in earlier pivotal studies (Raymond et al., 2011; Yao et al., 2011) appears no 
longer adequate from an ethical and medical perspective. Also, products in current clinical use for 
treatment of GEP-NET, but not licensed (off-label use, e.g. temozolomide chemotherapy), are 
considered not adequate as comparators for a confirmatory study. The mTOR antagonist everolimus 
is currently the only product licensed worldwide for the treatment of inoperable, advanced low-grade 
and intermediate-grade GEP-NET, which is the indication 177Lu-edotreotide is being developed for. 
The license for GE-NET is limited to non-functional GE-NETs and granted in both the USA and EU. 
Consequently, everolimus (Afinitor®) was selected as the most suitable comparator. It will be 
administered using a standard dose of 10 mg/d, with the option of dose reduction in case of 
inadequate tolerability, according to the recommendations of the manufacturer (Appendix 4: Afinitor 
dose adjustment recommendations). 
An independent data safety monitoring board (IDSMB) will closely review safety data at regular 
intervals throughout the study. If there are any signs of safety issues, the IDSMB may suggest 
terminating the trial (see also Section 11 on premature termination of the study).  

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3.4 
Justification of the Dose 
The clinical dose regimen was selected based on biodistribution and dosimetry data from a subset of 
patients with neuroendocrine tumours, belonging to the same group of 140 patients of the Bad Berka 
retrospective study treated with 177Lu-edotreotide (Schuchardt et al., 2013; van Echteld et al., 2014; 
Baum et al., 2016), supported by detailed pharmacokinetics and biodistribution data of 86Y-edotreotide 
from Novartis Phase I clinical studies (Jamar et al., 2003; Barone et al., 2005). Furthermore the 
recommendations of the joint IAEA, EANM, and SNMMI practical guidance on peptide receptor 
radionuclide therapy (PRRNT) in neuroendocrine tumours (Zaknun et al., 2013) have been taken into 
consideration.  
The detailed examination of the pharmacokinetics and biodistribution of therapeutic radiolabelled 
edotreotide was performed in a Phase I, single-centre, open label, cross-over study of 24 GEP-NET 
patients (Jamar et al., 2003) and in a subset of 18 GEP-NET patients enrolled in a Phase-I multicentre 
study (Barone et al., 2005), using the positron emitting isotope yttrium-86 (86Y) and the inherent 
quantitative advantages of positron emission tomography (PET) imaging. 86Y-edotreotide is an 
appropriate surrogate to quantitatively predict the in vivo behaviour of the therapeutic compound, not 
only radiolabelled with chemically identical 90Y, but also when radiolabelled with chemically very 
similar 177Lu. Since Y(III) and Lu(III) belong to the same group of trivalent rare-earth elements with 
very similar chemical properties, Y(III) and Lu(III) reveal almost identical nine-coordinate structure 
and thermodynamic stability of the complexes with DOTA-chelator (Viola-Villegas & Doyle, 2009). 
Furthermore, the 86Y half-life of 14.74 h allows quantitative PET investigations up to 48 h p.i., which 
is adequate for the pharmacokinetics and biodistribution analysis of therapeutic 90Y- and 177Lu-
edotreotide. 
The main outcome of the Novartis Phase-I pharmacokinetics and biodistribution studies was a large 
variability in individual renal uptake. Kidney uptake and retention of 86Y-edotreotide varied between 
patients by a factor of 3 and indicated a wide range of absorbed doses during therapies, whereas 
body surface area only ranged between 1.50 and 2.06 m2. Given the known safety profile and dose 
limiting renal toxicity, the dosing of the therapeutic agent has been proposed based on the 
individualised dosimetry approach (Barone et al., 2005), rather than based on body mass. 
The same observation was reported in 59 patients treated with 177Lu-edotreotide and undergoing 
dosimetric evaluation by means of SPECT (Schuchardt et al., 2013). The mean kidney absorbed dose 
was 0.6 with a wide variation in range 0.3 – 1.6 mGy/MBq.  
Figure 1 shows a selection of 19 patients from the Bad Berka dosimetry data base, who received 
7.5 ± 0.4 GBq 177Lu-edotreotide (= 7.5 GBq ± 5%). These patients belong to the same group of 
140 patients of the above mentioned retrospective study. Similar to the results reported from Novartis 
Phase-I clinical trials, these data serve to support fixed dosing as opposed to body weight-guided 
dosing, since no correlation whatsoever is found between kidney absorbed dose and body weight for 
the same administered 177Lu-edotreotide dose. Furthermore, these data also serve to emphasise the 
importance of individual dosimetry-guided dosing, since we observe a 3-fold variation in absorbed 
kidney dose for the same administered 177Lu-edotreotide dose. 

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Figure 1: Absorbed kidney dose from 7.5 ± 0.4 GBq 177Lu-edotreotide 
(Schuchhardt et al., 2013) 
In summary, the selected 177Lu-edotreotide dosing is a regime of up to four cycles of a fixed 7.5 GBq 
dose per cycle, based on individual dosimetry not to exceed a 23 Gy cumulative renal absorbed 
radiation dose or maximally 29 Gy, provided that additional measurements of renal function 
(99mTc-MAG3 renal scintigraphy) are >50% of baseline. In addition, this clinical dose regimen is in line 
with the recommendations from recent literature and based on leading experts’ opinions of joint IAEA, 
EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in 
neuroendocrine tumours (Zaknun et al., 2013). 
3.5 
Protocol Adherence 
Strict adherence to all specifications laid down in this protocol is required for all aspects of the study 
conduct; the investigator may not modify or alter the procedures described in this protocol. If protocol 
modifications are necessary, all alterations that are substantial and not solely of an administrative 
nature require a formal protocol amendment which has to be approved by the Institutional Ethics 
Committee(s) IEC(s) / Institutional Review Board(s) IRB(s) and Competent Regulatory 
Agencies/Authorities according to national regulations before the amendments can be implemented 
and the study may continue (see Section 13.1 for the role of IECs / IRBs and Competent Regulatory 
Agencies/Authorities). 
If an investigator has deviated from the protocol in order to eliminate an immediate hazard to patients 
or for other inevitable medical reasons, the investigator shall document all such deviations, including 
the reasons thereof, and submit the document to the sponsor, the IEC(s) / IRB(s) and the relevant 
Competent Regulatory Agencies/Authorities if applicable, and according to national regulations. 
As an exception only during the COVID-19 pandemic, the Sponsor acknowledges that some 
organisational and/or logistical adjustments might be necessary at the investigational sites. Deviations 
from this protocol that might arise in case of exceptional circumstances must be documented and 
y = -0.8342x + 4277.8
R² = 0.0001
0
1000
2000
3000
4000
5000
6000
7000
0
20
40
60
80
100
120
Absorbed dose (mGy)
Body weight (kg)
Aborbed Kidney Dose from 7.5 ± 0.4 GBq 
177Lu-edotreotide (n = 19)

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discussed with the Sponsor without delay. Every effort should be made to ensure the continuity of this 
study as per this study protocol and to avoid delays, treatment discontinuation, missing assessments, 
and study dropout. 
3.6 
Sub-studies (177Lu-Edotreotide patients only) 
To obtain additional exploratory data, three sub-studies will be performed at selected sites with 
adequate technical capabilities. Patients will be informed about sub-studies during the informed 
consent process (see Section 13.2). Participation requires additional consent for each sub-study. 
3.6.1 
Sub-study A: Repetitive Full Dosimetry Imaging (D1 – D4) 
The total absorbed doses (AD) to kidneys and tumour from four cycles of 177Lu-edotreotide (D1 - D4) 
will be estimated, by linear extrapolation of the AD measured on D1 with 7.5 ± 0.7 GBq to the full dose 
of 30 GBq. Dosimetry will be measured, using serial planar and single time point SPECT imaging (see 
Section 8.2.2). To verify the accuracy of total AD estimations, based on a linear extrapolation of AD 
measured during D1, full dosimetric imaging will be repeated during subsequent cycles (D2 – D4) in 
a subgroup of approximately 20 patients, ready and able to undergo repetitive dosimetric imaging. 
For further details please refer to Clinical Imaging Manual.  
3.6.2 
Sub-study B: 3D Dosimetry SPECT/CT Imaging 
Traditionally, dosimetry imaging has been performed using serial planar scintigraphic imaging only 
(2D), which is still considered the standard reference methodology by regulatory authorities. Clinically, 
though, the combination of serial planar with single time point SPECT imaging (2D/3D hybrid imaging) 
has emerged as new standard with improved spatial resolution. Especially in the abdomen, where the 
superposition of critical organs (e.g. kidneys, intestine, liver) renders the anatomic attribution of 
activity to individual organs difficult, 2D/3D dosimetry has been found to be superior to 2D dosimetry.  
Full 3D dosimetry (3D), is based on serial SPECT/CT imaging only, which is quantitatively 
reconstructed yielding activity distributions of Bq/mL in the field of view (FOV). Serial planar imaging 
to capture the total adminstered and organ bound activities (% ID) is no longer required.  
In selected sites, with SPECT/CT systems, where serial 3D imaging is clinically established, 
abdominal SPECT images (1-2 bed positions, covering liver, kidneys, tumour, as appropriate) will be 
acquired in a subgroup of approximately 20 patients, in addition to the compulsory planar images at 
0.5, 6, 24, and 72 – 96 h p. i. of 177Lu-edotreotide. SPECT imaging will be performed after planar 
imaging.  
AD determined by 3D dosimetry, will be analysed in comparison to AD values obtained by planar (2D) 
and hybrid (2D/3D) dosimetry. For further details please refer to Clinical Imaging Manual. 

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3.6.3 
Sub-study C: Pharmacokinetic Urine Analysis and Bone Marrow Dosimetry 
Due to the prolonged imaging procedure, patients of Sub-studies A and B cannot be included in 
Sub-study C. Sub-study C will be performed during any one of the four 177Lu-edotreotide treatment 
cycles (the choice of which of the four cycles to collect urine and blood samples for Sub-study C will 
be at the investigator’s discretion). 
To assess in vivo stability of 177Lu-edotreotide, urine will be collected from all voids beginning 
immediately at 0 min post-dose into 4 pooled samples in intervals from 0 min post-dose to 1 hour, 
and 1-6, 6-24 and 24-48 hours post-injection in a subgroup of 20 patients at selected sites only (see 
Section 8.2.2.4).  
Urine will be analysed with gamma-counting and with radio-HPLC in order to investigate the 
radiochemical purity of the eliminated compound. 
As the radioactivity in blood was shown to be similar to that in bone marrow (Forrer et al., 2009), bone 
marrow dosimetry will be assessed by measuring radioactivity in blood samples at pre-defined 
intervals between 0 minutes and 7 days post-infusion of 177Lu-edotreotide in a subgroup of 20 patients 
at selected sites only.  
Blood samples of 1 mL, each will be drawn at a site on the lower arm below the amino acid infusion 
site, and opposite the arm receiving the infusion of 177Lu-edotreotide at 0 min, 10 min, 30 min, 1 h, 
3 h, 6 h, 24 h, 48 h, 3 d, and 7 d post-injection (see Table 4, and Section 8.2.2.5). Radioactivity in the 
blood samples will be measured using a well-type gamma-counter. 
The sampling schedule is featured in the footnotes of the flowchart in Table 1, as well as in Table 4, 
below: (All time points post-injection (p.i.) refer to post the start of injection.) 
Table 4: Sampling Schedule Sub-study C 
 
Sampling Schedule Sub-study C‡ 
Time 
Day 0* 
Day 1 
Day 2 
Day 3 
Day 7 
Post-injection 
0 min 
10 min 
30 min 
1 h 
3 h 
6h 
24±3h 
48±3h 
72±12h 
168±12h 
Urine 
X† 
 
 
X 
 
X 
X 
X 
 
 
Blood 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* Blood samples can be taken within ± 5 minutes of the scheduled time, as long as the exact sampling times are recorded in the CRF. 
† Urine will be collected from all voids beginning immediately at 0 min post-dose into 4 pooled samples in intervals from 0 min post-dose to 1 hour, 
and 1-6, 6-24 and 24-48 hours post-injection. 
‡ Sub-study C will be performed during any one of the four 177Lu-edotreotide treatment cycles (the choice of which of the four cycles to collect urine 
and blood samples for Sub-study C will be at the investigator’s discretion). 
 
In order to facilitate the patient recruitment in the regulatory required Sub-study C, 
 
 at the sites participating in Sub-study C and only at those sites: 
Following approval of this Study Protocol Amendment and activation of 
 
by the Sponsor, the patients who consent to participate in Sub-study C and who comply with all 

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protocol inclusion and exclusion criteria will directly be allocated to the PRRT arm (See Section 3.1) 
until a global cumulative number of 20 evaluable patients is reached for the Sub-study C. 
Aside from this 
 and the tests conducted for Sub-study C (see above), 
the treatment regimen and patient care management will remain identical to that implemented in the 
main study. However, 
 
 
 
After this 
 Sub-study C cohort is closed or if not activated or during the time this cohort 
is activated for the patients who consent to participate in the main study but not in the Sub-study C, 
the patients have the possibility to be randomised in the main study untill study termination provided 
they comply with all protocol inclusion and exclusion criteria. 
The sites not participating in the Sub-study C continue to only enroll patients using the randomization 
procedure of the main study. 
4 
Study Population 
4.1 
Patient Population 
It is planned to randomise 300 patients with histologically confirmed well-differentiated 
neuroendocrine tumours of gastroenteric or pancreatic origin (GEP-NET), which have inoperable, 
progressive, and somatostatin receptor positive (SSTR+) disease, as evidenced by somatostatin 
receptor imaging (SRI). To uniformly and consistently characterise the study population according to 
current classification systems, a central pathologist will confirm histological diagnoses, based on 
historical or current tumour specimens. 
To facilitate the patients recruitment in the Sub-study C, 
 
 at all sites participating in the Sub-study C until 20 evaluable patients are 
obtained globally. 
 
 
 
4.2 
Eligibility 
4.2.1 
Inclusion Criteria 
All patients must meet all of the following criteria: 
1. Written informed consent 
2. Male or female ≥18 years of age 

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3. Histologically confirmed diagnosis of well-differentiated neuroendocrine tumour of non-
functional gastroenteric origin (GE-NET) or both functional or non-functional pancreatic origin 
(P-NET), grade G1 or G2 (Ki-67 ≤20%), unresectable or metastatic, in a patient who is either 
treatment-naïve (1st line) or who has progressed under prior therapy (2nd line) 
4. Availability of existing biopsy specimen from primary tumour or metastasis or, if unavailable, 
willingness to undergo current biopsy for secondary central analysis 
5. Measurable disease per RECIST 1.1, on CT/MRI scans, defined as at least 1 lesion with ≥1 cm 
in longest diameter, and ≥2 radiological tumour lesions in total. A maximum of 5 target lesions 
visible on CT/MRI will be defined, thereof not more than 2 lesions per organ (Eisenhauer et 
al., 2009) 
6. Somatostatin receptor positive (SSTR+) disease, as evidenced by SSTR imaging (SRI) within 
4 months prior to randomisation, as locally authorized, by: 
• 
68Ga-based SSTR PET imaging (68Ga-edotreotide or 68Ga-DOTATATE), or 
• 
111In-pentetreotide SSTR SPECT/planar imaging, or 
• 
99mTc-octreotide SSTR SPECT/planar imaging 
• 
64Cu-based SSTR PET imaging (64Cu-DOTATATE) if approved according to local 
regulations 
All target lesions and ≥90% of non-target lesions need to be positive for SSTR; this relates to 
lesions of at least 15 mm in diameter acquired on SRI images with SPECT, and of at least 
10 mm in diameter acquired on SRI images with PET systems. 
7. The patient must have progressive disease based on RECIST 1.1 Criteria as evidenced by 
two morphological imaging examinations made with the same imaging method (either CT or 
MRI), within a maximum of 36 months prior to randomisation. The most recent scan must not 
be older than 90 days prior to randomisation date. The minimum interval between the two 
scans must be ≥90 days. 
8. Karnofsky performance status (KPS) scale ≥70 (see Appendix 3) 
9. Life expectancy allows the patient to participate in the study based on the investigator’s 
assessment 
10. Glomerular filtration rate (GFR, CKD-EPI) ≥60mL/min/1.73 m2 (see Section 8.3.9) 
11. For patients included in France only, verification and confirmation of their affiliation with a 
social security 
12. Patients with functional P-NETs who require SSA for symptom control may continue SSA 
treatment throughout the study, on condition that: 
a) they have been on a stable dose for at least three months prior to study enrollment  

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b) that progressive disease has been diagnosed while under such stable dose 
4.2.2 
Exclusion Criteria 
A patient will be excluded from participation in the trial if one or more of the following criteria are met: 
1. Known hypersensitivity to edotreotide or everolimus or any other Rapamycin derivative 
2. Known hypersensitivity to DOTA, lutetium-177, or any excipient of edotreotide or everolimus 
3. Known hypersensitivity to lysine, arginine, or any excipient of the nephroprotective amino acid 
solution 
4. Prior exposure to any peptide receptor radionuclide therapy (PRRT), including 
177Lu-edotreotide, 90Y-edotreotide or other SSTR-targeting agents (e.g. 177Lu-octreotate or 
high-dose 111In-pentetreotide) 
5. Prior therapy with mTOR inhibitors 
6. Prior EFR (external field radiation) to GEP-NET lesions within 90 days before randomisation 
or radioembolisation therapy (e.g. 90Y microspheres, 131I-lipiodol) with administration to the 
liver 
7. Prior therapy with chemotherapy, immunotherapy, interferon, chemo-embolisation, bland 
embolisation, cyclosporine-A within 4 weeks before randomisation; any new cancer treatment 
between screening and randomisation 
8. Therapy with an investigational compound and/or medical device within 30 days or 5 half-life 
periods (whichever is longer) prior to randomisation  
9. Subjects who have received a live vaccine up to 4 weeks prior to first dose  
10. Current therapy with any prohibited medication (see Section 6.1.1) 
11. Ongoing toxicity grade 2 from previous standard or investigational therapies (NCI-Common 
Terminology Criteria for Adverse Events [CTCAE] version 4.03) 
12. Indication for surgical lesion removal with curative potential 
13. Planned (for the period of study participation): chemotherapy, immunotherapy, radiation 
therapy, chemo-embolisation, bland embolisation, radio-embolisation, treatment with 
cyclosporine-A 
14. Neuroendocrine tumours, not meeting the inclusion criteria: 
• 
With known non-GEP-NET origin (e.g. pulmonary or gonadal primaries) 
• 
Functional GE-NET 
• 
 Explicit diagnosis of unknown primary (CUP) 

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• 
G3 neuroendocrine tumours and neuroendocrine carcinomas 
• 
NET for which no histological specimen for secondary histological analysis can be 
obtained 
15. Total hepatic tumour burden >70%  
16. Brain metastases 
17. Other malignancy within previous 5 years (except basal cell carcinomas and in situ squamous 
cell carcinomas of the skin) 
18. Serious non-malignant disease (e.g. psychiatric, infectious, autoimmune or metabolic), that 
may interfere with the objectives of the study or with the safety or compliance of the subject, 
as judged by the investigator 
19. Clinically relevant renal, hepatic, cardiovascular, or haematological organ dysfunction, 
potentially interfering with the safety of the study treatments, as follows: 
• 
Renal 
o Renal obstruction 
• 
Hepatic 
o Total bilirubin >1.5 x ULN 
o AST or ALT >2.5 x ULN  
o Alkaline phosphatase >5 x ULN 
o Albumin <3 g/dL, unless prothrombin time is within normal range 
• 
Cardiovascular 
o New York Heart Association classification III and IV 
o Uncontrolled hypertension 
• 
Haematopoietic 
o Platelets 80 × 109/L 
o Absolute neutrophil count (ANC) <1 x 109 cells/L 
20. Pregnant (see Section 8.3.6) or breast-feeding women. Female patients of childbearing 
potential or male patients with female partners of childbearing potential, unless willing to 
practice full and true sexual abstinence or who are surgically/permanently sterile (bilateral 
tubal occlusion, hysterectomy, or vasectomy), or female patients whose male partners have 
medically successful vasectomy (provided the partner is the sole sexual partner of the female 
patient of childbearing potential), or who are not willing to practice highly effective 
contraception in combination with a barrier method of contraception (e.g. condom). 
Contraception methods that are considered highly effective are: oral or non-oral (injected or 
implanted) non-oestrogen progesterone-based hormonal method; oral, intravaginal, or 

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transdermal combined oestrogen and progesterone-based hormonal method; and/or 
intrauterine device (IUD), and/or intrauterine hormone-releasing system (IUS). Sexual 
abstinence or the contraception methods described above must be followed throughout the 
entire study period and for 56 days after treatment in the everolimus group and, 66 days in the 
PRRT group (10 half-lives of 177Lu) after the last treatment cycle (see Section 8.3.1.1). 
21. Subjects not able to declare meaningful informed consent on their own (e.g. with legal 
guardian for mental disorders) or any other vulnerable population to that sense (e.g. persons 
institutionalised, incarcerated etc.) 
4.3 
Recruitment 
Potential patients for this study will be recruited by approximately 60 oncological centres in Europe, 
North America, South Africa and Australia specialised in endocrine oncology (endocrinology, 
gastroenterology, nuclear medicine), and with local access to or own experience in PRRT. Study sites 
will be interdisciplinary, consisting of an endocrine oncology sub-site, and a nuclear medicine sub-site. 
Study visits will be typically conducted at the recruiting sub-site, or as institutionally appropriate. 
Treatment visits for patients randomised to 177Lu-edotreotide will be performed in the collaborating 
nuclear medicine sub-site. Patients will be invited for study participation by the investigators in the 
context of specialised NET clinics. Interested patients will be provided with an information sheet and 
will undergo a detailed informed consent procedure prior to any study procedures (see Section 13.2). 
Recruitment will be continued until a sufficient number of patients has received at least one dose of 
PRRT treatment, or a sufficient number of events has been reached. 
4.4 
Withdrawal of Patients from Study Participation or Medication 
4.4.1 
Withdrawal 
Patients may decide to withdraw from the study at any time for any reason without prejudice to their 
further medical care. The investigator may withdraw a patient for any of the following reasons: 
• 
Adverse event: if patient is unwilling to continue because of an AE or if continued participation 
of the patient would be an unnecessary risk to the patient’s health, in the opinion of the 
investigator. 
• 
Non-compliance 
• 
Protocol deviation 
• 
Pregnancy 
• 
Lost to follow-up 
A female patient who becomes pregnant during the treatment phase of the study must be discontinued 
from study treatment. See Section 8.3.1.1 for follow-up procedures in the case of pregnancy. 

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4.4.2 
Withdrawal Procedures 
Although patients are not obliged to give their reason(s) for withdrawing prematurely from a trial, the 
investigator should make every effort to ascertain the reason(s) for withdrawal while fully respecting 
the patient’s rights. The investigator will make every effort to contact the patient and complete the 
EOS page on the case report form (CRF) and if possible the assessments outlined on EOS visit. 
An EOS CRF page is to be completed for every patient, whether or not the patient completed the 
study. The reason for any early discontinuation should be indicated on this form. The primary reason 
for a patient withdrawing prematurely should be selected from the following standard categories of 
early termination: 
• 
Safety Reason/Adverse Event: Clinical or laboratory events occurred that in the medical 
judgment of the investigator, for the best interest of the patient, are grounds for discontinuation. 
This includes serious and non-serious AEs regardless of relation to study medication. Criteria 
for dose-limiting toxicity are discussed in Section 5.4.3 and Table 9. 
• 
Protocol Violation: The patient’s findings or conduct failed to meet the protocol entry criteria or 
failed to adhere to the protocol requirements (e.g., drug non-compliance, failure to return for 
defined number of visits) as judged by the investigator or sponsor. The violation necessitated 
premature termination from the study. 
• 
Withdrawal of Consent: The patient desired to withdraw from further participation in the study in 
the absence of an investigator-determined medical need to withdraw. If the patient gave a 
reason for withdrawing, it should be recorded. 
• 
Lost to Follow-Up: The patient stopped coming for visits, and study personnel were unable to 
contact the patient (two unsuccessful phone contacts followed by registered letter and 
documentation in the source documents). 
The date of study drug administration must be documented. 
Appropriate follow-up of withdrawn patients will be performed, as required. 
Attempts to contact a patient who withdraws from the study or is lost to follow-up must be documented. 
Stopping rules for the entire study are described in Section 11. 
4.4.3 
Replacement 
Patients who drop out of the study before first treatment administration will be replaced. Additional 
enrolment will be performed for patients who have received study medication, but who do not have 
analysable efficacy data. As this is an open study, no specific replacement scheme is needed. 

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4.5 
Patient Identification 
All patients who give informed consent will be identified by a unique identification number (“patient 
number”) that consists of 5 digits in two parts: 
1. The site number is a 3-digit number that is provided by the sponsor prior to the start of 
recruitment. 
2. The screening number is a 2-digit number that is consecutively assigned by the site to each 
patient after informed consent. 
Example: The first patient screened by site “101” will receive patient number 101-01. 
Example: The third patient at site “112” will receive patient number 112-03. 
Investigational sites are required to keep a patient identification list, identifying their patients by name, 
date of birth, patient number and status (screen failure/completed study/withdrawn). This list will be 
reviewed by assigned monitors, but has to stay on site and will not be collected, in order to protect 
confidentiality.  
4.6 
End of the Study 
For regulatory purposes, the end of the study is defined as the last visit of the last patient or the last 
date of follow-up of toxicities, if required (whichever is later). 
The end of study for each individual patient is the visit at month 30, unless disease progression, 
withdrawal from the study, or death occurs earlier. 
4.7 
Study Duration 
After providing informed consent, subjects will be screened for study enrolment, for up to 90 days 
prior to the first study treatment. Once enrolled and randomised to treatment, subjects will stay in the 
study until disease progression is established per RECIST 1.1 criteria, an alternative treatment for 
GEP-NET is initiated, the subject is withdrawn from the study, or for 30 months, whichever occurs 
first.  
A subject randomised to everolimus (Afinitor®) who has disease progression must end study 
participation but may be offered 177Lu-edotreotide therapy based on the personal judgement of the 
Investigator, if he/she considers it appropriate and likely to be beneficial for the individual patient (see 
Section 7.4.2). 
The maximum duration of participation for individual subjects is 30 months. The observation time for 
overall survival will be 5 years (60 months) after EOS for all patients (see Section 7.4). 

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5 
Study Drug 
5.1 
Identity 
5.1.1 
Chemical Properties of 177Lu-Edotreotide 
The PRRT agent to be evaluated in the present study is 177Lu-edotreotide. Its chemical name is 
lutetium-177-Nα-[(4, 7, 10- triscarboxymethyl- 1, 4, 7, 10-tetraazacyclododec-1-yl)acetyl]-D-
phenylalanyl-L-hemicystyl-L-tyrosyl-D-tryptophyl- L-Lysyl- L-threonyl- L-hemicystyl- L-threoninol 
cyclic (2→7) disulphide. Synonyms are: 
• 
177Lu-DOTATOC, (DOTA(0)-Phe(1)-Tyr(3)) octreotide, and  
• 
177Lu-DOTA-Tyr3-octreotide.  
177Lu-edotreotide is radiolabelled with carrier-free lutetium-177 (177Lu), a synthetic, low-energy beta 
and gamma emitting isotope of lutetium, the last element in the lanthanide series of metallic elements. 
Carrier-free 177Lu is generated by neutron irradiation of the isotope ytterbium-176 (176Yb) and 
subsequent fractionation of 177Lu and 176Yb with cation chromatography. Key physical characteristics 
of 177Lu are summarised in Table 5.  
Table 5: Radiological Properties of Lutetium-177 
Physical 
half-life T½ 
Decay 
product 
Main β- 
emission 
Maximum 
range (β-) 
Main γ 
emission 
6.647 d 
177Hf 
498 keV 
1.7 mm 
208 keV 
113 keV 
 
The structural formula of 177Lu-edotreotide is shown in Figure 2. 

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Figure 2: Structural formula of 177Lu-edotreotide 
The chemical formula of 177Lu-edotreotide is Lu1C65H89N14O18S2. The molar weight is 1595.6 g/mol for 
177Lu-edotreotide and 1421.6 g/mol for edotreotide alone. 
5.1.2 
Chemical Properties of Everolimus 
As reference product (RP), the mTOR inhibitor everolimus (Afinitor®) will be used. The chemical name 
of everolimus is: 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)-2-
[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-
dimethoxy15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-
16,24,26,28-tetraene-2,3,10,14,20-pentone. 
Everolimus is a macrocyclic lactone. Its structural formula is shown in Figure 3. 
 
Figure 3: Structural formula of everolimus (www.chemblink.com) 
The molecular formula is C53H83NO14 and the molar weight is 958.2 g/mol. 

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5.1.3 
Pharmaceutical Properties of 177Lu-Edotreotide 
177Lu-edotreotide is administered intravenously. 
A description of 177Lu-edotreotide solution for infusion is shown in Table 6. 
Table 6: 177Lu-Edotreotide Solution 
Pharmaceutically active component 
177Lu-edotreotide 
Physical dose 
7.5 ± 0.7 GBq / cycle 
Substance dose 
150 µg edotreotide 
Primary unit dose container 
20 mL glass vial containing 16 – 20 mL of 
stabilised aqueous solution 
Appearance 
 
 
pH 
  
 
Bacterial Endotoxin 
EU/Dose 
Radionuclidic purity 
177Lu 
 % 
Sterility 
Sterile 
 
The labelled drug product is produced, tested and released under GMP conditions by a licensed 
radiopharmaceutical contract manufacturer as a sterile solution for injection/infusion, ready for use. 
The labelled drug product will be manufactured upon individual order and delivered directly to the 
study sites globally. 
5.1.4 
Pharmaceutical Properties of Everolimus (Afinitor®) 
Everolimus has been licensed for the treatment of several types of cancer including progressive 
neuroendocrine tumours of pancreatic origin (P-NET) and non-functional gastroenteric origin 
(GE-NET) with unresectable, locally advanced or metastatic disease. 
Afinitor® tablets are supplied for oral administration and contain 10 mg of everolimus. For patients not 
tolerating the regular dose of 10 mg, tablets containing 5 mg will also be available, to be administered 
according to the manufacturer´s instructions for dose reduction. The tablets also contain anhydrous 
lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and 
magnesium stearate as inactive ingredients. The tablets are white to slightly yellow, elongated with a 
bevelled edge and no score, and engraved with “UHE” on one side and “NVR” on the other.  

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Everolimus will be purchased from licensed commercial sources, and labelled by the central 
pharmacy, according to the requirements of the participating countries. Details will be described in 
the separate document Investigational Medicinal Product (IMP)-Management Plan. 
5.1.5 
Storage and Handling 
See Section 5.6. 
5.2 
Treatment Assignment and Randomisation 
All successfully screened patients will be randomised in a 2:1 fashion, to receive: 
a) 177Lu-edotreotide (at most four 177Lu-edotreotide doses, administered 3-monthly) or 
b) Everolimus (Afinitor®, administered daily). 
Randomisation will follow a confidential, pre-defined scheme under direct control of the Study Data 
Management. Details of treatment assignment procedure, from the initial request down to the delivery 
of the requested IMP will be described in the IMP-Management Plan. 
Stratified randomisation, using four randomisation lists, will be used to ensure in both study arms a 
balanced frequency of GE-NET patients vs. P-NET patients and a balanced frequency of patients 
naive to medical treatment (1st line patients) vs. patients who have received prior medical therapies 
(2nd line patients). Prior therapies may include chemotherapy, SSA, targeted therapy (e.g. sunitinib), 
and others; the types of prior therapies will have to be recorded in the CRF (see also Section 9.2.3.2). 
Furthermore, inclusion of an equal number of GE-NET and P-NET will be attempted, but any ratio will 
also be acceptable as long as it allows meaningful subgroup analysis. 
Randomisation should be performed as soon as all necessary information for patient eligibility from 
screening assessments is available. Start of treatment should commence as soon as possible after 
randomisation, e.g. on the day of randomisation (everolimus group). In the 177Lu-edotreotide group, 
the study drug needs to be ordered on the day of randomisation. The first dose of 177Lu-edotreotide 
should be administered within 21 days of randomisation. In case of any delay, the site should check 
with the Sponsor via the site monitor and the reason for delay should be documented accordingly. 
5.3 
Blinding 
Not applicable, since this is an open label study. 
For blinded Image Data Analysis please refer to Section 8.7. 

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5.4 
Dosage and Administration 
5.4.1 
177Lu-edotreotide Group 
Patients assigned to 177Lu-edotreotide treatment will undergo at most four cycles of 7.5 ± 0.7 GBq 
177Lu-edotreotide, each containing a mass dose of 150 µg edotreotide. The cumulative 
177Lu-edotreotide dose will be up to 30 GBq with treatment cycles every 3 months.  
177Lu-edotreotide will be administered as a slow intravenous infusion over 10 – 20 min, via a flexible 
cannula into the cubital vein of the non-dominant arm (i.e. left arm in right-handers and vice versa). 
Concomitantly to the administration of 177Lu-edotreotide patients will receive a nephroprotective amino 
acid solution (starting 30 – 60 min before IMP, and lasting 4 - 6 h) as described in Section 6.1.3. 
In most regulatory environments, 
177Lu-edotreotide administration requires a short-term 
hospitalisation in a radionuclide therapy ward for radiation protection reasons, in order to minimise 
irradiation of others, and in order to collect radioactive excretions. During cycle 1 (D1), patients will 
undergo planar scintigraphy and SPECT/CT imaging (see Section 8.2.2), to determine the absorbed 
dose (AD) to kidneys and tumour from 177Lu-edotreotide from this first cycle (D1). AD to kidneys will 
be determined centrally by image core laboratory (ICL), to ensure methodological uniformity across 
all sites. Dosimetry prescription information will be returned to the sites by the central ICL in a timely 
manner, sufficiently in advance before the subsequent cycle.  
Patients randomised to the 177Lu-edotreotide group experiencing progressive disease under treatment 
must stop study participation. 
5.4.1.1 
Absorbed Dose from 177Lu-Edotreotide PRRT to the Kidneys 
Traditionally, an absorbed dose (AD) to the kidneys, not exceeding 23 Gy has been recommended to 
effectively avoid radiation-induced toxicity to the kidneys (IAEA PRRNT guideline 2013). Current 
dosimetric studies and clinical observations demonstrate, however, that an AD of 23 Gy does not 
correlate with kidney toxicity in PRRT, and that radiation tolerance of the kidneys for PRRT is actually 
higher than 23 Gy (Barone et al., 2005; Strosberg et al., 2017). Absorbed doses to kidneys have been 
described to vary considerably between patients, while at the same time variation of AD does not 
predictably correlate with body weight (Barone et al., 2005; Schuchardt et al., 2013, Strosberg et al., 
2017) (see Section 3.4).  
For safety reasons, therefore, AD to kidneys will be measured in all PRRT patients after their 1st PRRT 
cycle in this study. The absorbed dose to the kidneys (in Gy/GBq) is calculated based on AD to 
kidneys from 177Lu-edotreotide activity (in GBq) administered during the first cycle. From this, the 
cumulative AD to kidneys (in Gy) can be estimated for the cumulative activity dose (GBq) administered 
during the study, individually for each patient. If it can be anticipated that according to the individual 
AD per GBq of 177Lu-edotreotide, the traditional limit of a total of 23 Gy would be exceeded in a 
subsequent treatment cycle, no further treatment cycle will be administered, unless a) clinically 
relevant tubular renal dysfunction (see below) can be excluded, and b) the investigator considers it in 
the best interest of the patient to undergo a next cycle.  

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A PRRT cycle leading to transgression of an AD to kidneys of >23 Gy may only be administered on 
condition that a) the TER (99mTc-MAG3 renal scintigraphy) determined before this cycle, is >50% of 
the value at baseline (a value not associated with GFR changes), and b) and that the resulting AD to 
kidney will not exceed a maximum of 29 Gy (Konijnenberg et al., 2007; Bodei et al., 2013; Barone et 
al., 2005; Strosberg et al., 2017). 
5.4.1.2 
Eligibility for Continued Administration of 177Lu-edotreotide after Cycle 1 
Prior to receiving further 177Lu-edotreotide administration, subsequent to cycle 1, the following general 
eligibility criteria should be met for safety reasons in all patients in the PRRT arm, the latest by day 
90 (±14) calculated from the date of the first 177Lu-edotreotide cycle, to be determined during the pre-
treatment evaluations, in the investigator’s opinion:  
• 
Hb concentration ≥5.0 mmol/L (≥8.0 g/dL); WBC ≥2 x 109/L (2000/mm3); platelets ≥75 x 109/L 
(75 x 103/mm3). 
• 
Total bilirubin ≤3 x ULN. 
• 
Serum albumin >3.0 g/dL, or serum albumin ≤3.0 g/dL, but normal prothrombin time. 
• 
KPS ≥60. 
• 
Serum creatinine ≤150 μmol/L (≤1.7 mg/dL) and eGFR (estimated GFR) ≥50 mL/min/1.73 m². 
In all cases, where the eGFR is ≥ 50 mL/min/1.73m² and ≤60 mL/min/1.73m², the eGFR needs 
to be confirmed by a non-radioactive plasma clearance method (e.g. collection of 24 h urine 
for creatinine clearance determination), prior to administration of the subsequent 
177Lu-edotreotide cycle. In cases where eGFR is >60 mL/min/1.73m², no confirmation by a 
non-radioactive plasma clearance method is required. GFR will be calculated using the 
recommended CKD-EPI formula* (Levey et al., 2009). 
*GFR = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black], where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for 
females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the 
maximum of Scr/κ or 1. 
5.4.2 
Everolimus Group 
Patients assigned to RP receive a standard dose of 10 mg everolimus (Afinitor®) per os once daily at 
the same time every day. Reduction of dose is permitted according to the recommendations of the 
manufacturer (see Appendix 4). Everolimus needs to be administered either consistently with food or 
consistently without food and should be swallowed in whole with a glass of water. 
Patients randomised to everolimus experiencing progressive disease under treatment must stop 
study participation but may be offered 177Lu-edotreotide therapy based on the personal judgement of 
the Investigator, if he/she considers it appropriate and likely to be beneficial for the individual patient 
(see Section 7.4.2). The administration of this individual treatment requires the patient's consent. 
Administration, assessments and follow-up should be according to the schedule described for the 
177Lu-edotreotide arm of the study. 

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5.4.3 
Dose-Modifying Toxicity 
As different types of toxicities are likely to occur under Everolimus and 177Lu-edotreotide PRRT, 
specific dose-modifying toxicity criteria are to be used for each of the study treatments. In general, 
the evaluation of patients for potential dose modifying toxicities (DMT) is defined according to NCI 
CTCAE v 4.03.  
5.4.3.1 
DMT under Everolimus 
Dose reductions in the everolimus group are to be done according to manufacturer’s 
recommendations (see Appendix 4). 
5.4.3.2 
DMT during 177Lu-Edotreotide PRRT 
Dose modifying toxicity (DMT) during 177Lu-edotreotide treatment is defined as any of the following 
conditions which are ongoing on day 90 following the preceding PRRT cycle (i.e. at the time of the 
next scheduled PRRT cycle, as established during the respective pre-treatment evaluations):  
• 
Grade 2 CTCAE or above toxicity for platelet count 
• 
Grade 4 CTCAE lymphopenia 
• 
Grade 3 CTCAE or above toxicity for any other haematological parameter  
• 
40% increase over baseline in serum creatinine  
• 
decrease of over 40% in creatinine clearance from baseline 
• 
any other Grade 4 CTCAE toxicity considered at least possibly related to study drug, 
regardless of duration, with the exception of liver enzymes (ASAT, ALAT, AP), which will not 
be used to define DMT. 
Patients experiencing DMT from 177Lu-edotreotide treatment may receive subsequent PRRT cycles, 
provided that toxicity has subsided below the values defined above by week 16 following the non-
tolerated PRRT administration.  
With regard to renal DMT, further PRRT cycles may only be administered, if the following additional 
conditions are met by week 16: 
• 
Serum creatinine level must be classified CTCAE Grade 0,  
• 
Calculated creatinine clearance must have improved to within 20% from baseline (i.e. at least 
80% of initial value) 
• 
The GFR is at least ≥ 50 ml/min/1.73 m². A GFR value below 50 ml/min/1.73 m² will preclude 
further administration of 177Lu-edotreotide. 

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In patients with renal DMT, the eGFR (estimated GFR), needs to be confirmed by a non-radioactive 
plasma clearance method (e.g. 24 h creatine collection in urine), prior to administration of further 
administration of 177Lu-edotreotide, in all cases, where the eGFR is ≥50 ml/min/1.73m² and 
≤60 mL/min/1.73m² at 16 weeks. In cases where eGFR is >60 mL/min/1.73m² at 16 weeks, no 
confirmation by a non-radioactive plasma clearance method is required. 
As only standard 177Lu-edotreotide doses of 7.5 GBq ± 0.7 GBq are used in this study, dose 
modification will not be achieved by reducing the next planned dose, but by delaying the next 
treatment cycle up to a maximum of 4 weeks (week 16 (+ 2). In such a situation, subsequent PRRT 
cycles and evaluations (except for evaluation of tumour response based on morphological imaging 
RECIST 1.1) will be performed in intervals of 90 (±14) days, calculated from the delayed PRRT cycle. 
In case toxicity has not recovered by week 16, a patient cannot receive further PRRT cycles, but will 
remain in the study. 
Following the second occurrence of DMT, the patient is excluded from further treatment, but will 
remain in the study. 
5.5 
Packaging and Labelling 
177Lu-edotreotide will be supplied in vials for injection in appropriate packaging. 
Everolimus will be delivered as commercially available blisters which will be specially labelled for the 
use in this clinical trial. 
The outer packaging of all study drugs will contain label(s) which will include the following minimum 
information: 
• 
Name and address of sponsor 
• 
Study number 
• 
Investigator identification 
• 
Name of study drug and formulation 
• 
Dosage strength 
• 
Batch number 
• 
Patient number 
• 
Expiry date (or retest date) 
• 
Storage instructions 
• 
“For Clinical Trial Use only”. 
A system of medication numbering in accordance with all requirements of Good Manufacturing 
Practice (GMP) and any other applicable regulatory requirement will be used for all study drugs. This 
will ensure that for each patient, any dose of study drug can be identified and traced back to the 

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original bulk ware of the active ingredients. Lists linking all numbering levels will be maintained by the 
institutions in charge of study drug packaging. 
5.5.1 
177Lu-edotreotide 
177Lu-edotreotide will be delivered in 20 mL injection vials, labelled according to pharmaceutical 
requirements, governing investigational medicines, as described above. In addition, the vial will bear 
a radioactive warning symbol. The vial will be shipped in a lead-shielded transport container, bearing 
a radioactive warning symbol in accordance with radioactive pharmaceutical requirements. The 
labelled lead shield is packaged with absorbent material to minimise radioactive spill in case of vial 
damage within special packaging designed to conform to all applicable agreements concerning 
International Air Transport Association (IATA) and International Carriage of Dangerous Goods by 
Road (ADR) regulations and requirements for shipment of radioactive materials. 
5.5.2 
Everolimus (Afinitor®) 
Commercial drug product will be purchased from the manufacturer (Novartis Pharma Stein AG; Stein, 
Switzerland) or a licensed pharmaceutical wholesaler, able to provide lot documentation and will be 
labelled according to the requirements as described above. 
Tablets will be available with the following strengths: 10 mg and 5 mg. 
5.6 
Drug Logistics and Accountability 
5.6.1 
Storage, Dispensation and Return of 177Lu-Edotreotide 
177Lu-edotreotide will be shipped at ambient temperature, should be stored without freezing, and 
should be used by the expiration date and time printed on the label. 177Lu-edotreotide contains 
radioactive material and should only be handled by personnel trained in the use of radioactive 
isotopes with proper shielding and monitoring. Receipt and use of 177Lu-edotreotide is limited to 
institutions holding an appropriate handling permit by their competent national or regional authority. 
Storage, handling and destruction must be performed according to local guidelines regarding 
radioactive waste management. Details are outlined in the IMP management plan. 
5.6.2 
Storage, Dispensation and Return of Everolimus 
Everolimus (Afinitor®) is shipped at and should be stored not above 25°C, and should be used by the 
expiration date printed on the label. Everolimus for study purposes should be stored in a locked 
cabinet (separate from other medication for clinical use). As an exception only during the COVID-19 
pandemic, sites are allowed to ship everolimus directly to the patients. 
Unless the site has a specific Standard Operating Procedure (SOP) for reconciliation of unused or 
remaining everolimus, in the absence of sites’ SOP for reconciliation, unused or remaining everolimus 

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will be kept at the site until reconciliation and approval of the site CRA to return it to the CRO. Details 
are outlined in the IMP management plan. 
5.6.3 
Drug Accountability 
The investigator (or pharmacist, whatever applicable in certain countries) will confirm receipt of the 
study drug in writing and will use the study drug only within the framework of this clinical study and in 
accordance with this study protocol. He/she will keep a record of the study drug dispensed. 
Receipt, distribution and return of the study drug must be properly documented on the forms provided 
by the sponsor giving at least the following information: study protocol number, sender, receiver, date, 
mode of transport, quantity, batch number, expiration date and retest date, if applicable. 
5.7 
Treatment Compliance 
A record of the number of 177Lu-edotreotide doses and everolimus tablets dispensed to and taken by 
each subject must be maintained and reconciled with study treatment and compliance records. Details 
of each study drug administration will be recorded in appropriate source documents and then reported 
in the CRF. 
• 
177Lu-edotreotide: 
177Lu-edotreotide will be administered by study personnel at the trial site only. In any case of 
interruption of 177Lu-edotreotide infusion, the infused and discarded amounts will be recorded. 
177Lu-edotreotide is to be ordered on the day of randomisation. The first dose of 
177Lu-edotreotide should be administered within 21 days of randomisation. In case of any 
delay, the site should check with the Sponsor via the site monitor and the reason for delay 
should be documented accordingly.  
• 
Everolimus: 
Subjects will be asked to maintain a dosing diary to record their daily administration of 
everolimus. At each visit, the subject should return the dosing diary. An evaluation of subject 
compliance with study treatments taken will be performed. The investigator will make every 
effort to bring non-compliant subjects into compliance. Compliance with dosing will be 
assessed through querying the subject during site visits and will be documented in the source 
documents and in the CRF, including treatment start and stop dates, dates for treatment 
delays and/or dose reductions. 
The following deviations are defined as major protocol deviations, leading to exclusion from the PP 
set (see Section 9.3.3): 
• 
177Lu-edotreotide arm:  
o Subjects with incomplete 177Lu-edotreotide infusion, in which less than 50% of the total 
pre-scribed activity (GBq) based on initially dosimetry assessment was injected. 
o Subjects in whom a dose was administered more than 30 days outside the per protocol 
date. 

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• 
Everolimus arm:  
o Subjects missing more than 14 doses, within a visit interval of 30 days (with exception 
of treatment interruptions due to toxicity, see Section 5.4.3.1). 
Regardless whether a patient is compliant or non-compliant, the investigator must make every effort 
to perform all investigations according to the protocol for the entire duration of study participation.  
5.8 
Treatment of Overdose 
• 
177Lu-edotreotide: 
177Lu-edotreotide has a very favourable safety profile (see Section 1.3). 
The risk of overdosing is minimal in this trial, as individual doses will be prepared centrally by 
a radiopharmaceutical contract manufacturer. Nevertheless, if accidental overdosing of 
radio-labelled product should occur, it will result in increased radioactive tissue exposure, with 
kidney and bone marrow as the critical organs. 
In the event of an overdose of 177Lu-edotreotide, no specific treatments are available, and the 
patient should be treated at the discretion of the investigator. 
• 
Everolimus: 
Reported experience with overdose in humans is very limited. Single doses of up to 70 mg 
have been given with acceptable acute tolerability (EU: SmPC, Afinitor®, current version). 
General supportive measures should be initiated in all cases of overdose. 
6 
Therapies other than Study Drug 
6.1 
Prior and Concomitant Therapy 
Prior medications (up to 4 weeks prior to the screening visit) and all medications taken from baseline 
until EOS (including herbal products) must be recorded in the patient’s file. The indication for each 
drug, generic name, dosage form, strength, dose, frequency of dosing, route of administration, start 
date and, if applicable, stop date should also be recorded in the CRF. All medications will be encoded 
according to WHO-DD classification. 
6.1.1 
Prohibited Medications 
Patients will not be permitted to enter the study if they have received any of the following therapies: 
• 
Prior exposure to any PRRT, including 177Lu-edotreotide, 90Y-edotreotide or other SSTR-
targeting agents (e.g. 177Lu-octreotate or high-dose 111In-pentetreotide) 
• 
Prior mTOR inhibitor therapy 

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• 
Prior EFR (external field radiation) to GEP-NET lesions or radioembolisation therapy (e.g. 90Y 
microsphere, 131I-lipiodol) administration to the liver 
• 
Prior therapy with an investigational compound and/or medical device within 30 days or 
5 half-life periods (whichever is longer) prior to randomisation. 
• 
Any new cancer treatment between screening and randomisation 
The following therapies are prohibited from 4 weeks before randomisation until the end of the study: 
chemotherapy, 
immunotherapy, 
interferon, 
radiation 
therapy, 
chemo-embolisation, 
bland 
embolisation, radioembolisation, cyclosporine-A, or any other cancer therapy. In the event that any 
prohibited medication is given to a patient during the study, any such medication needs to be recorded 
in the CRF. The patient will then be excluded from further participation.  
Subjects in the everolimus group must not receive live vaccines during the study and for eight weeks 
after final dose. Potent inhibitors of CYP3A4 and PgP, and potent inducers of CYP3A4 are also 
prohibited for everolimus patients (see Section 6.1.5.2).  
6.1.2 
Somatostatin Analogues 
Somatostatin analogues are currently standard therapies for NETs. Somatuline® (Lanreotide) and 
Sandostatin® LAR (octreotide) are both licensed for the treatment of specific types of GEP-NETs. To 
prevent evaluation bias and simultaneously allow adequate symptomatic treatment for functional 
tumours, the following rules apply: 
• 
Patients with non-functional NETs who have experienced progressive disease under SSA 
treatment for their tumours (i.e. inefficacy of SSA to control tumour growth) will have to 
discontinue their SSA therapy prior to randomisation.  
• 
Patients with functional P-NETs who require SSA for symptom control may continue SSA 
treatment throughout the study, on condition that: 
a) they have been on a stable dose for at least three months prior to study enrolment 
b) that progressive disease has been diagnosed while under such stable dose, and  
c) they will remain on a stable dose during study participation.  
The doses for symptomatic treatment must not exceed 30 mg Octreotide/Sandostatin LAR 
every 4 weeks, or 120 mg Lanreotide/Somatuline every 4 weeks, respectively (maximum 
doses according to label). The morphological MRI/CT scan demonstrating progression during 
screening will be obtained after establishment of a stable dose of SSAs in functional P-NET 
patients, and preferably before the next dose of long-acting SSA is due (trough). 
• 
Patients with primarily functional GE-NETs are excluded from the study. However, if a patient 
with a primarily non-functional tumour develops a hormone-release (e.g. carcinoid) syndrome 
in the course of the study, he/she may receive SSA for symptom control using a stable dose 
to be maintained throughout study participation, not exceeding Octreotide/Sandostatin LAR 
every 4 weeks, or 120 mg Lanreotide/Somatuline every 4 weeks, respectively (maximum 
doses according to label).  

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• 
Patients on stable doses of SSA who develop exacerbation of symptoms due to clinical 
fluctuation of a hormone-release (e.g. carcinoid) syndrome during the study, may receive SSA 
rescue medication, as clinically appropriate, at the discretion of the investigator. Rescue 
medication type, dosing, duration, and clinical symptomatology will be recorded in detail. Such 
patients will remain in the study and receive further study treatments as scheduled. 
Subcutaneous, short-acting Somatostatin Analogue injections may be used as rescue 
medication, in accordance with the manufacturer’s prescribing information.   
Concomitant SSA use will be recorded throughout the study. Data of all patients receiving any SSA 
while on study will be statistically analysed for a possible impact on the primary endpoint (sensitivity 
analysis). 
6.1.3 
Scheduled Nephroprotective Amino-Acid Solution for Patient Management 
Nephroprotective AAS aims to reduce the risk of acute and chronic radiation nephropathy, by 
inhibiting undesired renal 177Lu-edotreotide uptake, thereby allowing administration of higher 
therapeutic doses to the tumour. Efficient nephroprotection, therefore, does increase the therapeutic 
index of PRRT. To ensure comparable safety and efficacy of a given therapeutic dose across sites in 
the present study, a standardised nephroprotection protocol will be used, which is based on the 
concomitant administration of an amino acid solution (AAS) according to the recommendations of 
different international Societies of Nuclear Medicine for the management of PRRT in NET (Bodei et 
al., 2013). 
No commercially available amino acid solution, optimised for nephroprotection in PRRT exists. 
Available products vary considerably in their composition in different countries. For the study, 
therefore, a standardised amino acid solution optimised for PRRT will be used. 
The AAS to be used in this study will contain a mixture of 25 g lysine-HCl and 25 g arginine-HCl 
diluted in 2000 mL of electrolyte solution, infused over 4 - 6 h, starting 30 – 60 min before PRRT. The 
AAS should preferably be co-infused with the radiopeptide via a three-way stop cock.  
Amino acid infusion causes elevation of serum potassium levels due to induction of a shift of 
potassium ions from cells to the extracellular department. This shift can lead to significant 
hyperkalaemia in up to 19% of patients (Giovacchini et al., 2011). In this trial potassium levels are 
monitored at pre-dose, 4 - 6 h, and 24 h post 177Lu-edotreotide infusion. If hyperkalaemia >6.0 mmol/l 
occurs, additional monitoring and/or therapeutic measures should be undertaken. Severe 
hyperkalaemia can lead to cardiac arrhythmias and subsequently circulatory arrest. Non-specific 
clinical signs include malaise, palpitations, muscle weakness and mild hyperventilation. Treatment 
options are e.g. IV calcium, IV loop diuretics (e.g. furosemide), inhaled salbutamol, and oral sodium 
polystyrene sulfonate/sorbitol.  
Please note that the AAS should not be co-administered with plasma expanders, e.g. 
gelofusine or HES.  

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6.1.4 
Antiemetic therapy 
Amino acid infusion is frequently associated with nausea and vomiting (see Section 8.3.2.4). For this 
reason, administration of a standard antiemetic regimen prior to amino acid infusion is recommended 
according to current international guidelines (Bodei et al., 2013) If an antiemetic is given on the day 
of dosing, it should be recorded in the patient’s records and transcribed onto the CRF form. 
6.1.5 
Medication Precautions 
6.1.5.1 
177Lu-edotreotide 
PRRT may potentially induce hormonal dysregulation or interact with other medications, by virtue of 
its pharmacological effects on GEP-NET cells, especially in the following situations (see 
Section 8.3.2.4): 
• 
Diabetes mellitus: Blood glucose levels should be monitored and anti-diabetic treatment 
adjusted accordingly, where needed. 
• 
Gastritis 
• 
Diarrhoea 
• 
Gastroesophageal reflux 
• 
Pain 
• 
Nausea 
Medical administration of radioactive therapies such as 177Lu-edotreotide is guided by national 
radiation safety regulations, differing extensively between countries. Excretion limits acceptable for 
discharge will be defined by the investigators in compliance with the local regulations. The 
requirement of hospitalisation will be approximately for 3 days in most countries, but can be adapted 
at the discretion of the investigator, as appropriate. 
The following safety precautions for patients apply during and after 177Lu-edotreotide administration: 
• 
Good hydration is recommended if not otherwise contraindicated. 
• 
Subjects should be advised to observe rigorous hygiene in order to avoid risk of 
contamination of others using the same toilet facility. 
• 
A double toilet flush is recommended. 
• 
Subjects should wash their hands thoroughly every time after using the toilet. 
It must be noted that if the predicted absorbed dose to the kidneys is likely to exceed 23 Gy upon 
administration of the next PRRT cycle, dosing can be continued up to a maximum of 29 Gy, provided 
that a pre-PRRT TER (99mTc-MAG3 renal scintigraphy) is >50% of the value at baseline (see Section 
5.4.1.1 and 5.4.3.2) and the criteria for continued administration of study drug are fulfilled (see Section 
5.4.1.2). 

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Patients should be carefully monitored for side effects. Pre-existing co-morbidities (e.g. pre-existing 
nephropathy and diabetes mellitus) must be assessed and appropriate monitoring and prophylactic 
measures are to be applied according to local standard of care. 
Tumour lysis syndrome (TLS) was previously reported in patients receiving 177Lu PRRT. Patients 
should be monitored for the development of TLS or cytokine release syndrome (CRS). In case of 
suspected TLS or CRS development, 177Lu-edotreotide treatment must be discontinued and 
symptomatic treatment is to be given immediately according to local standard of care. 
If hypersensitivity or anaphylactic reaction occurs, treatment with 177Lu-edotreotide must be 
discontinued and appropriate treatment is to be given according to local standard of care. 
6.1.5.2 
Everolimus 
Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore, 
absorption and subsequent elimination of everolimus may be influenced by products that affect 
CYP3A4 and/or PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor 
of CYP2D6. 
For detailed information on known and theoretical interactions with selected inhibitors and inducers 
of CYP3A4 and PgP, see SmPC of everolimus. 
CYP3A4 and PgP inhibitors increasing everolimus concentrations 
Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by 
decreasing metabolism or the efflux of everolimus from intestinal cells. 
CYP3A4 and PgP inducers decreasing everolimus concentrations 
Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by 
increasing metabolism or the efflux of everolimus from intestinal cells. 
Agents whose plasma concentration may be altered by everolimus 
Based on in vitro results, the systemic concentrations obtained after oral daily doses of 10 mg make 
inhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the gut 
cannot be excluded. An interaction study in healthy subjects demonstrated that co-administration of 
an oral dose of midazolam, a sensitive CYP3A substrate probe, with everolimus resulted in a 25% 
increase in midazolam Cmax and a 30% increase in midazolam AUC (0-inf). The effect is likely to be 
due to inhibition of intestinal CYP3A4 by everolimus. Hence everolimus may affect the bioavailability 
of orally co-administered CYP3A4 substrates. However, a clinically relevant effect on the exposure of 
systemically administered CYP3A4 substrates is not expected (EU: SmPC, Afinitor®, current version). 
6.2 
Post-Study Therapy 
After withdrawal or EOS, patients will be treated according to clinical practice at the discretion of the 
investigator following completion of this study. This includes treatment of the tumour disease as well 
as any conditions that may arise during the trial (see also Section 7.4.2). 

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For French patients: please refer to the rollover study. 
7 
Schedule of Evaluations and Visit Description 
7.1 
Schedule of Evaluations 
A detailed schedule of evaluations is shown in Table 1 and Table 2. 
If more than one procedure is scheduled at the same time, the assessments will be performed in an 
order as clinically appropriate. 
As an exception only during the COVID-19 pandemic, if a patient is unable to attend his/her 
institutional site visit per the protocol schedule, blood samples may be collected and tested in the 
patient’s local centre in a laboratory certified as per local requirements. However, the physical 
examination, vital signs, and electrocardiogram (ECG) may be postponed to the next scheduled site 
visit. Any of these deviations from the protocol-specified schedule will be considered a minor protocol 
deviation. The principal investigator (or delegate) will follow up on the patient’s status as needed. 
Protocol measures introduced because of the COVID-19 outbreak are temporary (see also 
Section 5.6.2), and will be considered revoked as soon as there is a consensus that the period of the 
current public health crisis has passed. 
7.2 
Screening Phase 
Screening is to take place between 90 days and 1 day before treatment (day -1). Screening 
evaluations can be divided; all necessary results need to be available prior to randomisation. 
7.2.1 
Baseline  
After signing the informed consent form, patients will undergo the following screening investigations 
and procedures: 
• 
Review of inclusion/exclusion criteria 
• 
Medical history (not older than 28 days at the time of randomisation) 
• 
Physical examination (not older than 28 days at the time of randomisation) 
• 
Vital signs (not older than 28 days at the time of randomisation) 
• 
Clinical laboratory tests (not older than 28 days at the time of randomisation) 
o Haematology 
o Serum chemistry and clotting parameters 
o Urinalysis 

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• 
Tumour serum biomarker tests (not older than 28 days at the time of randomisation) 
• 
Pregnancy test (not older than 28 days at the time of randomisation) 
• 
12-Lead ECG (not older than 28 days at the time of randomisation) 
• 
EORTC QLQ-C30 and GI.NET21 (not older than 28 days at the time of randomisation) 
• 
Current biopsy (mandatory, unless prior tumour specimen is available, see Section 8.1.4) 
• 
Tumour histology (see Section 8.1.4) 
• 
Concomitant medications and SSA medications assessment (over a period of 28 days before 
randomisation) 
• 
SSTR imaging (SRI), not older than 4 months must be available or has to be performed, by 
either: 
o preferably 68Ga-based SSTR PET imaging (68Ga-edotreotide or 68Ga-DOTATATE), or, 
if unavailable, 
o 
111In-pentetreotide or 99mTc-octreotide SSTR SPECT/planar imaging 
• 
Morphological imaging: native liver and contrast-enhanced liver and 3 regional (pelvis, 
abdomen, thorax) MRI or CT, must be available (performed within 28 days prior to 
randomisation) or has to be repeated as baseline MRI/CT 
• 
99mTc-MAG3 renal scintigraphy (performed within 28 days prior to randomisation) 
If the patient meets all of the selection criteria, he/she will be randomly assigned to one of both 
treatment groups.  
177Lu-edotreotide is to be ordered on the day of randomisation. The first dose of 177Lu-edotreotide 
should be administered within 21 days of randomisation. In case of any delay, the site should check 
with the Sponsor via the site monitor and the reason for delay should be documented accordingly. 
If randomisation reveals assignment to the everolimus arm, treatment should be initiated as soon as 
possible (preferably no later than 21 days after randomisation). The randomisation visit can then be 
taken as day 0 of treatment if all required pre-dose examinations were performed on the same day. 
If a patient is a screen failure, the following information is to be collected in the electronic case report 
for (eCRF): 
• 
Date of informed consent 
• 
Date of the screening visit 
• 
Demography (see Section 8.1.1) 
• 
Inclusion/exclusion criterion number not met 
• 
Serious adverse event, if applicable 
• 
EOS page of eCRF is to be completed with reason “Screen Failure” 

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7.3 
Treatment Phase 
Adverse events and concomitant medication are to be reported continuously from Day 0 until end of 
study. AEs ongoing at EOS have to be followed up until resolved or for a period up to a maximum of 
30 days by the investigator (see Section 8.3.2.3). Pregnancy tests are to be performed monthly in all 
female patients from the start of treatment until EOS.  
7.3.1 
Month 0 
7.3.1.1 
Day 0 
The following examinations and procedures will be performed on day 0: 
Pre-dose: 
Only 177Lu-edotreotide group: 
• 
Hospital admission (according to discretion of investigator and local regulations) 
• 
Transmission scan and blank scan using either a Co-57 or Tc-99m sheet source or if available 
at the site whole body low dose CT scan. These scans can be performed up to 7 days prior to 
day 0. For Tc-99m, blank and transmission scan have to be performed together (one followed 
by the other) due to the short half-life of Tc-99m, but both scans can also be performed up to 
7 days prior to day 0. For Co-57, blank and transmission scan can be acquired on different 
days within the defined period.  
Only for everolimus group: 
• 
Ambulatory visit, beginning pre-dose and ending approximately 3 h post-dose when all 
examinations and procedures are completed for day 0. 
Both treatment groups: 
• 
Physical examination 
• 
Vital signs 
• 
Clinical laboratory tests 
o Haematology 
o Serum chemistry and clotting parameters 
o Urinalysis 
• 
Tumour serum biomarker tests 
• 
Pregnancy test (if baseline pregnancy test was performed more than 14 days ago) 
• 
12-Lead ECG 
• 
Concomitant medications and SSA medications continuously 

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• 
Adverse events 
Pre-dose procedures may be performed within 7 days before Day 0 for both treatment groups. 
Investigations should be performed as close to PRRT or dosing as possible and as clinically 
appropriate. 
Treatment 
177Lu-edotreotide group: 
• 
Pre-medication with amino acid solution (see Section 6.1.3) 
• 
Infusion/injection of undiluted 177Lu-edotreotide dose 1 (D1) over 10 to 20 min according to 
locally established practice 
Everolimus group: 
• 
Start with everolimus administration, 10 mg p.o. 
Post-Treatment (only 177Lu-edotreotide group): 
Assessments: 
• 
Vital signs immediately after end of infusion and 6 h ± 1 h post start of infusion 
• 
Serum chemistry 5 h ± 1 h post start of infusion 
• 
Concomitant medications and SSA medications continuously 
• 
Adverse events continuously 
Imaging: 
• 
177Lu whole body planar imaging immediately after vital signs assessment (approx. 0.5 h 
± 0.25 h) and 6 h (± 1 h) post start of infusion 
• 
Sub-study B: Serial 3D SPECT/CT Imaging only: 177Lu abdominal SPECT/CT 0.5 ± 0.25 h and 
6 h ± 1 h post start of infusion 
Post-imaging urine and blood samples (Sub-study C only) 
The following samples will be collected only if Sub-study C is performed during the first 
177Lu-edotreotide treatment cycle: 
• 
Urine will be collected from all voids beginning immediately post-dose to 1 hour, and in 
intervals of 1-6 and 6-24 hours post-injection 
• 
Blood samples of 1 mL, each will be drawn from a site on the lower arm below the amino acid 
infusion site, and opposite the arm receiving the infusion of 177Lu-edotreotide at 0 min, 10 min, 
30 min, 1 h, 3 h, and 6 h post-injection (see Section 8.2.2.5). 
Post-Treatment (only Everolimus group): 

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• 
Vital signs 0.5 h ± 0.25 h after everolimus administration 
• 
Concomitant medications and SSA medications continuously 
• 
Adverse events continuously 
• 
Patients receive compliance diary 
7.3.1.2 
Day 1 (only 177Lu-edotreotide group) 
Prior to Imaging:  
• 
Vital signs 24 h ± 3 h post start of infusion 
• 
Serum chemistry 24 h ± 3 h post start of infusion 
• 
Concomitant medications and SSA medications continuously 
• 
Adverse events continuously 
Imaging: 
• 
177Lu whole body planar imaging 24 h ± 3 h post start of infusion 
• 
177Lu abdominal SPECT/CT imaging 24 h ± 3 h post start of infusion 
Post-imaging urine and blood samples (Sub-study C only) 
The following samples will be collected only if Sub-study C is performed during the first 
177Lu-edotreotide treatment cycle: 
• 
Urine sampling interval from 6-24 hours post-dose ends and next sampling interval from 24-48 
hours post-dose starts. 
• 
Blood sample for dosimetry will be taken at 24 h ± 3 h post-injection. 
7.3.1.3 
Day 2 (only Sub-study C in 177Lu-edotreotide group) 
The following samples will be collected only if Sub-study C is performed during the first 
177Lu-edotreotide treatment cycle: 
• 
Urine sampling ends at 48 h (± 3 h) post start of infusion 
• 
Blood sample for dosimetry will be taken at 48 h ± 3 h post-injection 
7.3.1.4 
Day 3 (only 177Lu-edotreotide group) 
Prior to Imaging: 
• 
Vital signs 72 – 96 h (± 3 h) post start of infusion 
• 
12-lead ECG 72 - 96 h (± 3 h) post start of infusion 
• 
Concomitant medications and SSA medications continuously 
• 
Adverse events continuously 

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Patients randomised to 177Lu-edotreotide group will receive bi-weekly haematology controls for 
8 weeks following 177Lu-edotreotide administration at week 2, 4, 6, 8 post-PRRT (general practitioner 
acceptable). 
Imaging: 
• 
177Lu whole body planar imaging 72 - 96 h (± 3 h) post start of infusion  
• 
Sub-study B: Serial 3D SPECT/CT Imaging only: 177Lu abdominal SPECT/CT imaging–
72 - 96 h (± 3 h) post start of infusion (same time as planar imaging) 
• 
Discharge of patients in the morning after day 3 or later, according to discretion of 
investigator and local regulations. 
Optional 177Lu whole body planar and – for Sub-study B – SPECT/CT imaging 7 days (± 2 d) post 
start of infusion may be performed at investigator’s discretion. 
The following sample will be collected only if Sub-study C is performed during the first 
177Lu-edotreotide treatment cycle: 1mL blood sample for dosimetry will be taken 72 ± 12 h post-
injection. 
7.3.1.5 
Day 7: Sub-study C Only 
The following sample will be collected only if Sub-study C is performed during the first 
177Lu-edotreotide treatment cycle: 1 mL blood sample for dosimetry will be taken 7 days ± 12 h 
post-injection. 
7.3.2 
Month 1 and Month 2 
The visits have to be performed at day 30 and 60 with ± 7 days window calculated from day 0. 
The following examinations and procedures will be performed in all patients: 
• 
Physical examination 
• 
Vital signs 
• 
Clinical laboratory tests  
o Haematology 
o Serum chemistry and clotting parameters 
o Urinalysis 
• 
Tumour serum biomarker tests 
• 
Pregnancy test 
• 
EORTC QLQ-C30 and GI.NET21 
• 
Concomitant medications and SSA medications continuously 
• 
Adverse events 

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• 
Everolimus patients receive their compliance diary 
Blood-sampling can be performed up to 72 hours prior to the visit according to local practice and as 
clinically appropriate. 
7.3.3 
Month 3 
It must be noted that if the predicted absorbed dose to the kidneys in patients receiving 
177Lu-edotreotide is likely to exceed 23 Gy upon administration of the next PRRT cycle, dosing can 
be continued up to a maximum of 29 Gy, provided that a pre-PRRT TER (99mTc-MAG3 renal 
scintigraphy) is >50% of the value at baseline (see Sections 3.1, 5.4.1.1, and 5.4.3.2) and the criteria 
for continued administration of study drug are fulfilled (see Section 5.4.1.2). 
7.3.3.1 
Day 90 
Visit may be performed ±14 days calculated from day 0, whereby days 91 and 93 will be calculated 
from the actual day 90 visit date. Pre-dose procedures may be performed within 7 days before the 
Day 90 visit for both treatment groups. Investigations should be performed as close to PRRT or dosing 
as possible and as clinically appropriate. 
The following examinations and procedures will be performed: 
Pre-dose: 
Only 177Lu-edotreotide group: 
• 
Hospital admission (according to discretion of investigator and local regulations) 
• 
Sub-study A: Repeated Full Dosimetry Imaging only: Transmission scan and blank scan or 
if available at the site whole body low dose CT scan. For further details see Day 0 
(Section 7.3.1.1). 
Only for everolimus group: 
• 
Ambulatory visit, beginning pre-dose and ending approximately 3 h post-dose when all 
examinations and procedures are completed for day 90 
Both treatment groups: 
• 
Physical examination 
• 
Vital signs 
• 
Clinical laboratory tests 
o Haematology 
o Serum chemistry and clotting parameters 
o Urinalysis 
• 
Tumour serum biomarker tests 

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• 
Pregnancy test 
• 
12-Lead ECG 
• 
EORTC QLQ-C30 and GI.NET21 
• 
Concomitant medications and SSA medications continuously 
• 
Adverse events 
• 
Evaluation of tumour response: native liver and contrast-enhanced liver and 3 regional 
(pelvis, abdomen, thorax) MRI or CT, baseline method to be adhered to 
Treatment: 
177Lu-edotreotide group: 
• 
Pre-medication with amino acid solution (see Section 6.1.3) 
• 
Infusion/injection of undiluted 177Lu-edotreotide (dose D 2) over 10 to 20 min according to 
locally established practice 
Everolimus group: 
• 
Continuation of everolimus administration, 10 mg orally once daily 
• 
Everolimus patients receive their diary 
Post-Treatment (only 177Lu-edotreotide group): 
Prior to Imaging:  
• 
Vital signs immediately after end of infusion and 6 h ± 1 h post start of infusion 
• 
Serum chemistry 5 h ± 1 h post start of infusion 
• 
Concomitant medications and SSA medications continuously 
• 
Adverse events continuously 
Imaging: 
• 
Sub-study A: Repeated Full Dosimetry Imaging only: 177Lu whole body planar imaging 
immediately after vital signs assessment (approx. 0.5 h ± 0.25 h) and 6 h ± 1 h post start of 
infusion 
Post-imaging urine and blood samples (Sub-study C only) 
The following samples will be collected only if Sub-study C is performed during the second 
177Lu-edotreotide treatment cycle: 
• 
Urine will be collected from all voids beginning immediately post-dose to 1 hour, and in 
intervals of 1-6 and 6-24 hours post-injection 
• 
Blood samples of 1 mL, each will be drawn from a site on the lower arm below the amino acid 
infusion site, and opposite the arm receiving the infusion of 177Lu-edotreotide at 0 min, 10 min, 
30 min, 1 h, 3 h, and 6 h post-injection (see Section 8.2.2.5). 

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7.3.3.2 
Day 91 (only 177Lu-edotreotide group) 
Prior to Imaging: 
• 
Vital signs 24 h ± 3 h post start of infusion 
• 
Blood sample serum chemistry 24 h ± 3 h post start of infusion 
• 
Concomitant medications and SSA medications continuously 
• 
Adverse events continuously 
Imaging: 
• 
Sub-study A: Repeated Full Dosimetry Imaging only: 177Lu whole body planar imaging 24 h 
± 3 h post start of infusion.  
• 
177Lu abdominal SPECT/CT imaging 24 h ± 3 h post start of infusion 
Post-imaging urine and blood samples (Sub-study C only) 
The following samples will be collected only if Sub-study C is performed during the second 
177Lu-edotreotide treatment cycle: 
• 
Urine sampling interval from 6-24 hours post-dose ends and next sampling interval from 
24-48 hours post-dose starts 
• 
Blood sample for dosimetry will be taken at 24 h ± 3 h post-injection 
7.3.3.3 
Day 92 (only Sub-study C in 177Lu-edotreotide group) 
The following samples will be collected only if Sub-study C is performed during the second 
177Lu-edotreotide treatment cycle: 
• 
Urine sampling ends at 48 h (± 3 h) post start of infusion 
• 
Blood sample for dosimetry will be taken at 48 h ± 3 h post-injection 
7.3.3.4 
Day 93 (only 177Lu-edotreotide group) 
Prior to Imaging: 
• 
Vital signs 72 - 96 h (± 3 h) post start of infusion 
• 
12-Lead ECG 72 - 96 h (± 3 h) post start of infusion 
• 
Concomitant medications and SSA medications continuously 
• 
Adverse events continuously 
Patients randomised to 177Lu-edotreotide group will receive bi-weekly safety controls for 8 weeks 
following 177Lu-edotreotide administration including haematology. 

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Imaging: 
• 
Sub-study A: Repeated Full Dosimetry Imaging only: 177Lu whole body planar imaging 
72-96 h post start of infusion 
• 
Discharge of patients in the morning after day 93 or later, according to discretion of 
investigator and local regulations 
An optional 177Lu whole body planar imaging for Sub-study A 7 days post end of infusion may be 
performed at investigator’s discretion. 
The following sample will be collected only if Sub-study C is performed during the second 
177Lu-edotreotide treatment cycle: 1 mL blood sample for dosimetry will be taken 72 h ± 12 h 
post-injection. 
7.3.3.5 
Day 97: Sub-study C Only 
The following sample will be collected only if Sub-study C is performed during the second 
177Lu-edotreotide treatment cycle: 1 mL blood sample for dosimetry will be taken 7 days ± 12 h 
post-injection. 
7.3.4 
Month 4 and Month 5  
The visits have to be performed at day 120 and 150 with ± 7 days window calculated from day 0. 
The examinations and procedures to be performed are identical to month 1. 
7.3.5 
Month 6  
The visit has to be performed at day 180 with ± 14 days window calculated from day 0. Days 181 and 
183 will be calculated from the actual day 180 visit date. 
All patients will undergo a 99mTc-MAG3 renal scintigraphy.  
All further examinations and procedures to be performed at month 6 are identical to month 3. Pre-dose 
procedures may be performed within 7 days before Day 180 for both treatment groups. Investigations 
should be performed as close to PRRT or dosing as possible and as clinically appropriate.  
If Sub-study C is to be performed during the third 177Lu-edotreotide treatment cycle, the urine and 
blood samples for Sub-study C are to be collected as described for month 3. 
7.3.6 
Month 7 and Month 8  
The visits have to be performed at day 210 and 240 with ± 7 days window calculated from day 0 
The examinations and procedures to be performed are identical to month 1. 

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7.3.7 
Month 9 
The visit has to be performed at day 270 with ± 14 days window calculated from day 0. Days 271 and 
273 will be calculated from the actual day 270 visit date. 
Patients randomised to 177Lu-edotreotide will receive dose D4 at day 270 provided that the kidney 
function allows administration (see Sections 3.1 and 5.4.3.2).  
All further examinations and procedures to be performed at month 9 are identical to month 3. Pre-dose 
procedures may be performed within 7 days before Day 270 for both treatment groups. Investigations 
should be performed as close to PRRT or dosing as possible and as clinically appropriate. 
If Sub-study C is to be performed during the fourth 177Lu-edotreotide treatment cycle, the urine and 
blood samples for Sub-study C are to be collected as described for month 3. 
7.3.8 
Month 10 and Month 11 
The visits have to be performed at day 300 and 330 with ± 7 days window calculated from day 0. 
The examinations and procedures to be performed are identical to month 1. 
7.3.9 
Second Year 
During the second year of the study, patients in the everolimus arm continue on everolimus, while 
patients in the 177Lu-edotreotide arm will not receive further PRRT treatment until diagnosis of 
progression. Study visits during the 2nd year take place on an out-patient basis in 3-monthly intervals 
(12, 15, 18, 21, 24, and 27 months after day 0, with ± 21 day time window). For the management of 
patients impacted by the follow-up extension, see Section 3.1. Examinations comprise physical 
examination, vital signs, blood sampling for laboratory and tumour markers, pregnancy test, EORTC 
QLQ questionnaire, recording of AEs and concomitant medication, morphological MRI/CT imaging at 
every second year visit, as well as 12-lead ECG and 99mTc-MAG3 renal scintigraphy at months 12, 
18, and 24 only. Morphological MRI/CT imaging and 99mTc-MAG3 renal scintigraphy should be 
performed within 7 days prior to the study visit, in order for the results to be available at the time of 
the visit. Pregnancy tests for the following months without visits at the study centre will be handed out 
to the patients at every visit. Blood-sampling can be performed up to 72 hours prior to each visit 
according to local practice and as clinically appropriate. Pregnancy tests are to be repeated monthly 
during year 2 until EOS. Everolimus patients continue to receive their patient diary at every visit. 
7.3.10 
End of Study (EOS) 
The EOS visit will be performed 30 months from day 0, or after establishment of definitive disease 
progression, whatever occurs earlier (see Section 8.2.4). Study patients who experience disease 
progression established prior to the next planned visit are required to complete the EOS visit. For the 
management of patients impacted by the follow-up extension, see Section 3.1. 
The following examinations and procedures will be performed: 
• 
Physical examination 

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• 
Vital signs 
• 
Clinical laboratory tests 
o Haematology 
o Serum chemistry and clotting parameters 
o Urinalysis 
• 
Tumour serum biomarker tests 
• 
Pregnancy test 
• 
12-Lead ECG  
• 
EORTC QLQ-C30 and GI.NET21 
• 
Concomitant medications and SSA medications 
• 
Adverse events 
• 
MRI (CT) evidencing radiological tumour progression by RECIST 1.1: native liver and contrast-
enhanced liver and 3 regional (pelvis, abdomen, thorax) MRI or CT, baseline method to be 
adhered to - not to be repeated in case of progression 
• 
99mTc-MAG3 renal scintigraphy 
7.3.11 
Early Withdrawal Visit 
In case of early withdrawal, the EOS visit is to be performed within 28 days after discontinuation. If 
the visit cannot be completely performed for any reason, the investigator must make every attempt to 
complete at least all safety-relevant evaluations: 
• 
Physical examination 
• 
Vital signs 
• 
Pregnancy test 
• 
Clinical laboratory tests 
o Haematology 
o Serum chemistry and clotting parameters 
o Urinalysis 
• 
12-Lead ECG 
• 
Concomitant medications and SSA medications 
• 
Adverse events 
• 
99mTc-MAG3 renal scintigraphy 
The reason for withdrawal must be noted in patient's file, where known. 

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7.4 
Post-Study Evaluations 
7.4.1 
All Patients 
As this is an oncological study with overall survival and other progression parameters as secondary 
endpoints, survival information and progression status, as well as further cancer treatments and the 
development of late toxicities, including renal toxicity and secondary malignancies will be collected 
from all randomised patients (including drop-outs, non-compliant patients, other), in compliance with 
local legal regulations for five years after end of study for each patient. The sites will contact their 
patients at 6-monthly (± 1 month) intervals (i.e. at 6, 12, 18, 24, etc. months after EOS/Early 
withdrawal) and check the survival status and tumour progression of their patients. 
For the management of patients impacted by the follow-up extension, see Section 3.1. 
7.4.2 
177Lu-edotreotide Therapy for Patients Progressing under Everolimus 
Study patients experiencing disease progression under everolimus have to perform EOS visit and 
terminate study participation. Subsequently, a patient who progressed under everolimus may be 
offered 177Lu-edotreotide therapy based on the personal judgement of the Investigator/treating 
physician, if he/she considers it to be appropriate and beneficial for the individual patient. In these 
cases, the investigator can request from the sponsor the provision of study drug to individual patients 
on a "named patient” basis, as a bona fide unsolicited order, formulated in accordance with the 
specifications of an authorised healthcare professional and for use by an individual patient under his 
or her direct personal responsibility as a special needs request.  
The administration of this individual treatment requires the patient's consent. 99mTc-MAG3 renal 
scintigraphy should be repeated if it was performed more than six months prior to the start of individual 
post-study 177Lu-edotreotide therapy. 
8 
Procedures and Variables 
Patients will provide written informed consent before any study-related procedures can be performed 
(see Section 13.2). 
The schedule of assessments is provided in Table 1 and Table 2. 
Unless otherwise specified, all examinations and procedures will be performed by the investigator or 
authorised study personnel. An additional visit can be scheduled at any time if the investigator 
considers it to be necessary. This applies especially, when there is clinical suspicion of disease 
progression. In this situation, the investigator will schedule all necessary clinical investigations, 
irrespective of the study schedule. 
Patient-related events and activities, including specific instructions, procedures, concomitant 
medications, dispensing of study drug, and descriptions of AEs are to be recorded in the appropriate 

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source documents. Any findings and information resulting from the below described procedures will 
be recorded in the CRF (see Section 10.1). 
8.1 
Baseline Characteristics 
8.1.1 
Demographic Characteristics 
The following demographic characteristics will be recorded: 
• 
Date of birth or age, depending on local requirements on data protection 
• 
Weight, height, ethnic origin, gender 
8.1.2 
Medical and Surgical History, Baseline Findings 
Medical/surgical history and medical conditions present before randomisation will be recorded at the 
screening visits. 
Detailed instructions on the differentiation between (i) medical / surgical history and (ii) baseline 
findings can be found in Section 8.3.1.1. 
8.1.3 
Prior and Concomitant Medication 
Prior and concomitant medication will be recorded at screening and throughout the study, until the 
End-Of-Study visit (see Section 6). 
8.1.4 
Tumour Histology 
Only patients with histologically proven, metastasised or unresectable, well-differentiated 
neuroendocrine tumours of gastroenteric or pancreatic origin (GEP-NET) are eligible for this study. In 
case of GE-NET, clinical evidence of non-functionality needs to be provided. Central histological 
re-assessment will be made at baseline using tissue specimens from primary diagnosis or, where 
unavailable, from a current biopsy. 
During screening, a histopathology report of the primary tumour and/or a current tissue specimen, 
specifying the histological diagnosis, needs to be available. A pseudonymised copy of such report(s) 
will be collected for the TMF by the monitor for each randomised patient. 
Histological diagnosis will be centrally verified for consistency with the current WHO classification 5 
(Fletcher et al., 2013). For this purpose, paraffin-embedded blocks or suitable slide-mounted tissue 
samples obtained during previous interventions will be retrieved from the site pathology and sent to 
the Central Pathology Laboratory (CPL) University of Bern, Institute of Pathology, Prof. Dr. Aurel 
Perren. If no prior sample is available, a fresh tumour sample must be obtained to verify diagnosis 
(inclusion criterion).  

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The Central Pathology Laboratory will assess: 
• 
Histological entity 
• 
Tumour grade 
• 
Mitoses per high power field (HPF) 
• 
Ki-67 expression 
• 
SSTR expression 
• 
Chromogranin (CgA) immune reactivity 
Argyrophilia or hormone expression will not be assessed. 
Only patients with a histology of well-differentiated GEP-NET, as confirmed by the CPL will be 
included in the per protocol analysis.  
To avoid that central pathology review capacity delays enrolment of patients, randomisation and start 
of treatment may be performed, once availability of paraffin-embedded blocks or suitable slide-
mounted tissue samples is confirmed at the study site. 
In case the results obtained by the CPL cannot confirm the presence of GEP-NET of tumour grade 
G1 or G2, the corresponding patients may remain in the study, but will be included only in the safety 
analysis. If in the everolimus arm, it will be at the discretion of the treating physician to offer continued 
treatment off-label. The treating physician may also offer 177Lu-edotreotide therapy if he/she considers 
it to be appropriate and beneficial for the individual patient. 
8.2 
Efficacy 
8.2.1 
Tumour Characterisation and Staging 
8.2.1.1 
Somatostatin Receptor Imaging (SRI) 
To clinically establish somatostatin receptor (SSTR) expression at baseline, patients undergo 
somatostatin receptor imaging (SRI) according to local guidelines, preferably with 68Ga-based 
PET/CT (e.g. 68Ga-edotreotide (68Ga-DOTATOC) or 68Ga-DOTATATE). Where 68Ga-based PET/CT 
is not available, 111In-pentetreotide (OctreoScan®) or 99mTc-octreotide SPECT/CT imaging, less 
preferably planar or SPECT only imaging may be used.  
Wherever 
possible, 
SRI 
tomographic 
hybrid 
imaging 
(PET/CT; 
SPECT/CT), 
providing 
three-dimensional information should be performed to alleviate the identification the target lesions, 
pre-defined per RECIST 1.1. (based on CT/MRI) on the SRI scan. Planar or “SPECT-only-SRI” should 
only be performed, where tomographic hybrid imaging is not established, as registration/ identification 
of target lesions with SRI-positive lesions is not easily possible.   
All target lesions (up to 5) and ≥90% of non-target lesions need to show adequate tracer uptake, 
defined as being “clearly differentiable from background” (SSTR positive). This criterion relevant for 

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eligibility will be assessed by the local investigator. Criteria for SRI scoring are presented in 
Appendix 5: Tumour Scoring. 
Subsequently, image analysis will be centrally verified by the ICL, see Section 8.7. Any differences 
between local and central assessment will be reported. 
8.2.1.2 
Morphological Imaging (MRI or CT) 
Morphological imaging by MRI / CT will be used a) for the establishment of the radiologically confirmed 
progressive disease (key inclusion criterion), and b) for the determination of the primary endpoint 
(PFS).  
Two MRI or CT scans obtained using the same method within a maximum of 36 months prior to 
randomisation, with at least 90 days interval between them, need to demonstrate progressive disease, 
as per RECIST 1.1. criteria. The most recent scan must not be older than 90 days at randomisation. 
The minimum interval between two scans must be ≥90 days. 
At baseline, one native liver and contrast-enhanced liver and 3 regional (pelvis, abdomen, thorax) 
MRI or CT, must be available (performed within 28 days prior to randomisation) or has to be repeated 
as baseline MRI / CT. Where established, combined imaging (e.g. abdominal MRI / thoracic CT) can 
be used. The baseline imaging method has to be used consistently throughout the whole study period. 
Tumour lesions in the body, and tumour burden in the liver at baseline will be documented, as far as 
visible on morphological imaging (performed within 28 days prior to randomisation). Tumour burden 
will be assessed semi-quantitatively/visually. According to RECIST 1.1., a maximum of 5 target 
lesions, visible on morphological imaging will be defined, in descending order of size. Per organ, only 
2 target lesions may be defined. All other lesions are defined as non-traget lesions. Only after 
definition of target lesions on CT / MRI, SSTR expression of target and non-target lesions will be 
assessed, using SRI (see Section 8.2.1.1).  
For follow-up, native liver and contrast-enhanced liver and 3 regional (pelvis, abdomen, thorax) MRIs 
or CTs will be obtained from all patients in 3-monthly intervals, starting at month 3, until diagnosis of 
progression or end of study. Additional MRI / CT scans may be performed at any other time if, in the 
investigator’s clinical judgment, progressive disease is suspected. Diagnosis of progression will be 
made by the local investigator at the point of time when radiological progression criteria, according to 
RECIST (Eisenhauer et al., 2009) are first met. The RECIST 1.1 and the SRI evaluations performed 
locally at the study sites will be centrally verified by the ICL (see Section 8.7). For the primary endpoint 
PFS, the central ICL will perform blinded readings in duplicate, with adjudication in case of 
discordance will be used. 
8.2.1.3 
Tumour Markers 
Chromogranin A (CgA) will be determined at baseline, and then monthly until month 12, thereafter in 
3-monthly intervals until diagnosis of progression or end of study. 

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CgA serum concentrations will be considered for the assessment of response to therapy (see 
Section 8.2.4). In patients with an elevated baseline CgA, changes in CgA serum concentrations could 
be classified in analogy to published classifications (Bajetta et al., 1993) as follows: Complete 
biomarker response (CR): return to normal range; partial biomarker response (PR): decrease ≥50% 
from baseline, biomarker stable disease (SD): An increase by <25% or decrease by <50% from 
baseline; biomarker progressive disease (PD): increase in CgA by ≥25% from baseline, or compared 
to prior examination, in patients, where an initial improvement following therapy has been observed. 
In addition, specific hormones related to clinical symptoms (e.g. gastrin, insulin, etc.) will be 
determined in patients, if showing elevated levels at baseline work-up. Response could be graded in 
analogy to CgA, where merited. 
8.2.2 
177Lu-edotreotide Biodistribution and Dosimetry 
Biodistribution and dosimetry of 177Lu-edotreotide will be determined using traditional, current, and 
innovative methods, in order to comply with regulatory expectations (planar 2D), correspond to the 
current clinical standard (2D/3D hybrid), and to evaluate innovative dosimetry methods (3D) currently 
under investigation at leading research institutions. These innovative methods may considerably 
reduce the effort for acquisition and analysis in the future, thereby greatly facilitating clinical dosimetry.  
Dosimetry will be used, a) to determine the AD to kidney, the organ with highest dose exposure in 
PRRT (safety dosimetry), and b) to determine the AD to tumour lesions, as basis for establishing a 
dose response relationship, based on the Gy dose achieved in a tumour, rather than based on a Bq 
dose administered to the patient, as is the current practise. Dosimetry evaluations will be centrally 
analysed (ICL, see Section 8.7), using a) the MIRD methodology, which is based on a standard 
phantom to describe the spatial relationship between organs, and b) the Voxel-S methodology, which 
considers individual activity distribution of the patient, allowing a more precise description of doses to 
tumours. 
8.2.2.1 
177Lu-edotreotide Whole Body Planar Scintigraphy 
177Lu-edotreotide whole body 2D planar images will be performed in anterior and posterior projection, 
in conjunction with transmission/blank scan using 57Co or 99mTc sheet source or if available at the site 
whole body low dose CT scan for attenuation correction (pre-dose) and an external calibration source. 
Serial scans will be obtained at four points of time after first dosing (D1, day 0) of 177Lu-edotreotide: 
0.5 h (prior to voiding), 6 h, 24 h and 72-96 h post-infusion. An additional 177Lu whole body planar 
imaging 7 days post infusion may be performed at investigator’s discretion. 
Scintigraphy results will be used to determine 177Lu-edotreotide traditional 2D dosimetry (reference 
method), with emphasis to kidney (safety) and target tumours (efficacy). 
In selected patients, the accuracy of AD predictions made based on the first cycle will be verified by 
repeated dosimetry in cycles D2 – D4 (Sub-study A: verification of the accuracy of AD extrapolation 
based on AD determined after D1). 

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8.2.2.2 
177Lu-edotreotide Abdominal SPECT/CT 
Abdominal SPECT/CT scans, covering kidneys and liver will be acquired in a supine position (usually 
1 - 2 bed positions), 24 h after each infusion of 177Lu-edotreotide (D1 - D4). The scan following D1 will 
be quantitatively reconstructed, to yield absolute activity concentrations (Bq/ml) for 2D/3D hybrid 
dosimetry. The scans from D2 – D4 will be analysed qualitatively only, to demonstrate tumour 
targeting of 177Lu-edotreotide. In subjects participating in Sub-study A, quantitative reconstruction will 
be made for all cycles (D1 – D4). 
After the first dosing (D1) a SPECT/CT scan will be performed. CT-derived information data from this 
scan will be used for attenuation and scatter correction. 
a) Tumour targeting 
Tumour targeting will be assessed by demonstration of 177Lu-edotreotide binding inside or in 
the vicinity of the target lesion, seen on structural imaging using SPECT/CT acquired 24 h 
post-infusion. 
b) 2D/3D hybrid dosimetry 
To take superimposition and self-absorption of abdominal organs into consideration, 
quantitatively reconstructed abdominal SPECT images (Bq/mL) from a single time point 
(24 h p. i.) of the first dose (D1) will be used to correct 2D planar dosimetry results 
(reference method), with emphasis to kidney and target tumours.  
8.2.2.3 
Serial 177Lu-edotreotide SPECT/CT, (Sub-study B, only) 
At sites, where 3D dosimetry is performed as routine, or research methodology, serial SPECT/CT 
imaging covering kidneys and tumour will be acquired in a supine position (usually 2 bed positions), 
in addition to the mandatory planar acquisitions (see Section 8.2.2.1). SPECT/CT images will be 
acquired subsequent to planar images and quantitatively reconstructed as described under 
Section 8.2.2.2. 
8.2.2.4 
Pharmacokinetic Urine Analysis (Sub-study C, only) 
At selected sites, urine will be collected after any one of the 4 administrations of 177Lu-edotreotide 
from all voids of patients in the 177Lu-edotreotide arm, beginning immediately post-dose (0 min) to 
1 hour, and in intervals of 1-6, 6-24 and 24-48 hours post-injection in a subgroup of 20 patients, to 
assess in-vivo stability of 177Lu-edotreotide. Volume and radioactivity content of these voids should 
be recorded up to 48 hours. Radioactivity concentrations will be measured with a calibrated well-type 
gamma-counter. Urine will be analysed using radio-HPLC in order to investigate the radiochemical 
purity of the eliminated compound. 
8.2.2.5 
Bone Marrow Dosimetry (Sub-study C, only) 
As the radioactivity in blood was shown to be similar to that in bone marrow (Forrer et al., 2009), bone 
marrow dosimetry will be assessed by measuring radioactivity in blood samples at 0 min, 10 min, 

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30 min, 1 h, 3 h, 6 h, 24 h, 48 h, 3 d, and 7 d post injection during any one of the 4 administrations of 
177Lu-edotreotide in a subgroup of 20 patients in the 177Lu-edotreotide arm at selected sites only. 
8.2.3 
Health-Related Quality of Life (HRQL) and Symptom Control 
To evaluate HRQL, self-rating questionnaires will have to be completed by the patient at baseline, 
and then monthly until month 12, thereafter in 3-monthly intervals until diagnosis of progression or 
end of study. Completion will be made prior to the administration of study medication, if applicable for 
this visit. 
8.2.3.1 
EORTC QLQ-C30 
The QLQ-C30 questionnaire (version 3.0, in local language) will be used for the assessment of the 
general health state. It will not be considered for the diagnosis of progression or symptomatic tumour 
response (see Section 9.2.2). 
8.2.3.2 
EORTC QLQ-GI.NET21 
The QLQ-GI.NET21 questionnaire (in local language) will be used for the assessment of symptomatic 
response to therapy, as well as for the diagnosis of symptomatic progression (see Section 9.2.2). In 
patients with elevated baseline GI.NET21 score, changes in the score will be classified as follows: 
Complete symptomatic response (CRS): normalisation of score; partial response (PRS): decrease 
≥50% from baseline score; symptomatically stable disease (SDS): An increase by <25% or decrease 
by <50% from baseline scores. Symptomatic progression (PDS) will be defined as an increase in the 
GI.NET21 score of ≥25% from baseline, or compared to prior examination, in patients, where an initial 
improvement following therapy has been observed. 
8.2.4 
Assessment of Progression-free Survival 
Primary endpoint 
The primary endpoint is progression-free survival (PFS), determined as time elapsed between 
randomisation and the date of first objective report of tumour progression (evaluated by RECIST 
criteria, 1.1), or death. Diagnosis of progression will be established based on radiological information 
from morphological imaging (MRI / CT) using RECIST 1.1 (Eisenhauer et al. 2009). Status of disease 
will be defined as one of the following options: Complete response (CR), partial response (PR), stable 
disease (SD), or progressive disease (PD).  
In addition to the evaluation by local investigators pseudonymised images will be transferred to the 
ICL (see Section 8.7), and analysed by independent radiologists not involved in the study in a blinded 
fashion in duplicate, with adjudication in case of discordance. In case of discordance reads, a third 
independent radiologist will act as an adjudicator.  
A detailed description of the process of image handling, analysis and documentation will be outlined 
in a separate document, the image review charter (IRC).   

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8.3 
Safety 
8.3.1 
Baseline Findings 
8.3.1.1 
Definition of Baseline Finding 
Definition of a baseline finding 
A baseline finding is defined as any untoward medical condition in a study patient who has signed the 
informed consent form but not yet received the first dose of the study drug. This includes conditions 
stabilised by treatment. By definition, a baseline finding cannot be causally related to study drug; 
however, it may be causally related to the study (e.g., caused by study-conduct-related 
investigations). 
Differentiation between medical / surgical history and baseline findings 
Conditions which started before signature of informed consent and for which no symptoms or 
treatment are present until the first administration of study drug (e.g., seasonal allergy without acute 
complaints) are recorded as medical / surgical history. 
Conditions which started before signature of informed consent and for which new or worsening 
symptoms or further treatment are present between signature of informed consent and first 
administration of study drug (e.g., allergic pollinosis) are recorded as baseline findings. 
Differentiation between baseline findings and adverse events 
Conditions (e.g., abnormal physical examination findings, symptoms, diseases, laboratory, ECG) 
present before the first administration of study drug will be documented as baseline findings. 
Conditions which started or deteriorated after the first administration of study drug will be documented 
as adverse events. 
Pregnancy  
Following the existing international guidelines on embryo-foetal Risk Mitigation and Risk Assessment 
of Medicinal and Investigational Medicinal Products on Human Reproduction and Lactation and in 
consideration with the absence of adequate data from the use of the reference study drug in pregnant 
women and its effects including known embryotoxicity and fetal toxicity as well as considering the 
known risks of radiation exposure to the embryo or foetus from therapeutic procedures with the 
administration of radioactive pharmaceuticals, highly effective contraceptive methods that can 
achieve a failure of less than 1% per year when used consistently and correctly are considered to be 
used in this study. Female patients of childbearing potential as well as male patients having female 
partners of childbearing potential, unless surgically/permanently sterile (bilateral tubal occlusion, 
hysterectomy, or vasectomy), will be excluded from participation in the study unless they are willing 
to: practice full and true sexual abstinence, or use highly effective contraception in combination with 
a barrier method of contraception (e.g. condom). Contraception methods that are considered highly 
effective are: oral or non-oral (injected or implanted) non-oestrogen progesterone-based hormonal 

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method; oral, intravaginal, or transdermal combined oestrogen and progesterone-based hormonal 
method; and/or IUD, and/or IUS. Sexual abstinence or the contraception methods described above 
must be followed throughout the entire study period and for 56 days after treatment in the everolimus 
group and 66 days in the PRRT group (10 half-lives of 177Lu) after the last treatment cycle. True 
abstinence may be practised if this is in line with the preferred and usual lifestyle of the subject. 
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. A partner who has a medically successful vasectomy is a highly effective birth control 
method provided the partner is the sole sexual partner of the female patient of childbearing potential. 
Pregnancy is rather unlikely due to study design and presents an exclusion criterion for this study. 
Adequate pregnancy testing will be performed at regular intervals throughout the study (see Section 
8.3.6). Should it nevertheless emerge, it will not be classified as an SAE except in cases where it can 
be shown that the effectiveness of the contraception was affected by the IMP/RP. A female patient 
who becomes pregnant during the treatment phase of the study must be discontinued from study 
treatment. All pregnancy cases (pregnant patient or a male patient who has impregnated a partner) 
except those emerging after 80 days (66 days per exclusion criteria and 14 days additional waiting 
period) after the last treatment cycle in the PRRT group and 70 days (56 days per exclusion criteria 
and 14 days additional waiting period) after treatment in the everolimus group, will be monitored and 
followed up in regular intervals in order to identify adverse events especially fulfilling the criteria for 
an SAE. If a pregnant patient or a male patient who has impregnated a partner withdraws from the 
study during the pregnancy, the pregnant patient/partner will be monitored and followed up on at 
regular intervals in order to identify adverse events especially fulfilling the criteria for an SAE until the 
end of the pregnancy. A pregnant patient will not have any further radiation-related follow-up 
assessments or other follow-up assessments that may interfere with the pregnancy, determined by 
investigator discretion. 
8.3.1.2 
Categories, Assessments and Documentation of Baseline Findings 
The date and time of the first acute occurrence of the event is documented as the onset. 
If the baseline finding is "continuing" into the treatment phase, no AE is to be recorded if, after start 
of study treatment, the event has the same or milder pattern and intensity/severity. If the finding 
worsens in terms of either the pattern or intensity/severity after study drug administration, the event 
must be documented as an AE. 
If the event is concluded, this should be recorded in the CRF ("resolved"). If the event vanishes but 
re-occurs during treatment, an AE with a start date of its re-occurrence should be entered. 
All baseline findings will be assessed and documented by the investigator according to the following 
categories: 
• 
Seriousness: for each baseline finding, the seriousness must be determined according to the 
criteria given in Section 8.3.2.5. If serious, the baseline finding has to be handled in the same 
way as an SAE. 
• 
Intensity/Severity 

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• 
Specific drug treatment 
• 
Specific non-drug treatment 
• 
Causal relationship to study conduct 
• 
Outcome 
The intensity/severity of an event, the causal relationship to study conduct, and the outcome of the 
baseline finding should be classified according to the same categories used for AEs, as specified in 
Section 8.3.2. 
8.3.1.3 
Serious Baseline Findings 
Baseline findings will be regarded as serious if they meet the criteria used for defining serious adverse 
events (SAEs) (see Section 8.3.2.5). 
Serious baseline findings will be reported on the SAE form described in Section 8.3.2.5. 
8.3.2 
Adverse Events 
8.3.2.1 
Definition of Adverse Event 
The definition below follow International Conference on Harmonisation (ICH) – Good Clinical Practice 
(GCP) (see also ICH Guideline for Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting): 
Adverse event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product. 
By definition, for this study, all AEs are regarded as 'treatment emergent', i.e., not seen before 
treatment or, if already present before treatment, worsened after start of treatment. See 
Section 8.3.2.6 for exemptions. 
8.3.2.2 
Categories for Adverse Event Assessment 
All AEs will be assessed and documented by the investigator according to the categories detailed 
below. NCI-CTCAE version 4.03 will be used for this purpose. 
Seriousness 
For each AE, the seriousness must be determined according to the criteria given in Section 8.3.2.5. 

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Intensity/severity 
The intensity of an AE is classified according to NCI-CTCAE version 4.03, taking into account the 
possible range of the intensity of the event (see Section 8.3.2.3). 
• 
NCI-CTCAE Grade 1 (mild) 
• 
NCI-CTCAE Grade 2 (moderate) 
• 
NCI-CTCAE Grade 3 (severe) 
• 
NCI-CTCAE Grade 4 (life-threatening) 
• 
NCI-CTCAE Grade 5 (fatal) 
An AE should be documented with the applicable diagnosis, if possible (rather than as a symptom, 
sign, or laboratory finding). 
Main pattern 
The main pattern of the AE is to be documented as follows: 
Every drug administration: 
Events that occur in a clear time relationship to every study drug 
administration 
Intermittent: 
Regular or irregular repeating events that are clearly of the same 
kind and same cause, but not clearly time related to study drug 
administration 
Continuous: 
Events that are continuously present within the whole time period 
which is covered by the form, but not clearly time related to study 
drug administration 
Other: 
All other patterns, need to be specified in the following text field 
 
 
Study drug action 
Any potential study drug action to resolve the AEs is to be documented as follows 
• 
Drug withdrawn 
• 
Dose reduced 
• 
Dose not changed 
• 
Other action (stopped: definitely, temporarily with exact dates ) 

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Drug treatment 
Non-drug treatment 
Causal relationship to study drug 
The assessment of a possible causal relationship between the AE and the administration of the study 
drug is based on the following question: 
“Is there a reasonable likelihood that the event was caused by the study drug?” 
Possible answers are: 
• 
Related (plausible time relationship to the administration of IMP/RP. No plausible explanation 
by underlying/concurrent disease or other drugs/events),  
• 
Possible (plausible time relationship to the administration of IMP/RP, but the AE can be also 
plausibly explained by the underlying/concurrent disease or other medicinal products/events),  
• 
Unlikely (unlikely temporal relationship to the administration of IMP/RP. Other medicinal 
products, events, and the underlying/concurrent disease provide a plausible explanation)  
• 
Not related (clear evidence that the AE is not connected to the IMP/RP administration) 
• 
Not assessable (no evaluation possible based on present data, additional clarification and 
follow-up necessary) 
Causal relationship to study conduct 
The assessment of a possible causal relationship between the AE and the study conduct other than 
the relationship to study drug is based on the following question: 
“Is there a reasonable likelihood that the event was caused by the study conduct?” 
• 
Possible answers are “related”, “not related”, “not assessable.”  
Outcome 
The outcome of the AE is to be documented as follows: 
• 
recovered 
• 
recovered with sequelae, with additional details  
• 
ongoing  
• 
fatal 
• 
unknown 
8.3.2.3 
Assessments and Documentation of Adverse Events 
All adverse events which occur up to EOS, both those observed by study site personnel and those 
spontaneously reported by study patients, must be recorded on the ‘adverse event’ page(s) in the 

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CRF regardless of causality. AEs ongoing at EOS have to be followed up until resolved or for a period 
up to a maximum of 30 days by the investigator. 
If an adverse event fulfils any of the criteria for a SAE, both the adverse event pages of the CRF and 
the Serious Adverse Event Form must be completed. SAEs are recorded for the entire duration of the 
study. For details of how to report SAEs see Section 8.3.2.5. 
For both Serious and Non-serious AEs, documentation must be supported by an entry in the patient’s 
hospital notes. Required information includes: the type of adverse event, seriousness of the event, 
start date, date of resolution, actions required, outcome, and an assessment of its relationship to 
study drug and an estimate of its severity (using NCI-CTCAE, version 4.03). NCI-CTCAE severity will 
be marked in the SAE Report Form using the numeric grades: grade 1 (mild), grade 2 (moderate), 
grade 3 (severe), grade 4 (life-threatening) and grade 5 (fatal). 
All abnormal laboratory results, which are considered to be clinically relevant by the investigator, 
should also be recorded as adverse events. If an abnormal laboratory result meets any of the criteria 
for a SAE, this must also be reported on a Serious Adverse Event Form. 
An AE should be documented with the applicable diagnosis, if possible (rather than as a symptom, 
sign, or laboratory finding). 
All adverse events that meet the criteria for serious require the completion of a SAE Report Form, in 
addition to being recorded on the AE pages of the patients’ CRF. This applies to all SAEs, whether or 
not they were considered to be related to study treatment. 
8.3.2.4 
Expected Adverse Events 
Expected disease-related AEs 
Neuroendocrine tumour disease has a serious cluster of symptoms. Common disease-related events 
are: 
• 
Gastrointestinal hormone disorders including potential symptoms, e.g. hypoglycaemia, 
hyperglycaemia, gastritis, steatorrhea, cholecystolithiasis, weight loss, anorexia 
• 
Skin irritations and sore skin 
• 
Obstructive symptoms and vomiting 
• 
Diarrhoea 
• 
Indigestion 
• 
Abdominal pain or back pain 
• 
Gastroesophageal reflux 
• 
Nausea 
Expected conduct-related AEs 
The use of an indwelling cannula for the purpose of blood sampling and administration of study drug 
may be accompanied by mild bruising and also, in rare cases, by transient inflammation of the vessel 

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wall. After initial irritation, the presence of an indwelling cannula is usually painless and hardly 
noticeable. The same applies to single vein punctures for blood sampling. 
Patients may also experience discomfort from the imaging facilities, e.g. back pain, claustrophobia, 
headache, chill, and others. 
Expected AEs related to the nephroprotective amino acid solution 
Amino acid infusion may cause elevation of serum potassium levels by inducing a shift of potassium 
ions from cells to the extracellular department. This shift can lead to significant hyperkalemia in up to 
19% of patients (Giovacchini et al., 2011), leading to malaise, palpitations, muscle weakness and mild 
hyperventilation. Generalised flushing, fever, nausea and vomiting have also been reported during 
infusions of amino acid solutions. Prevention and treatment of these symptoms are described in 
Sections 6.1.3 and 6.1.4. 
Expected AEs related to an investigational drug 
Please refer to the IB (Section 6.8.2 Undesirable Effects Related to 177Lu-edotreotide) for 
177Lu-edotreotide.  
Patients should be carefully monitored for side effects. Pre-existing co-morbidities (e.g. pre-existing 
nephropathy and diabetes mellitus) must be assessed and appropriate monitoring and prophylactic 
measures are to be applied according to local standard of care. 
TLS was previously reported in patients receiving 177Lu PRRT. Patients should be monitored for the 
development of TLS or CRS. In case of suspected TLS or CRS development, 177Lu-edotreotide 
treatment must be discontinued and symptomatic treatment is to be given immediately according to 
local standard of care. 
If hypersensitivity or anaphylactic reaction occurs, treatment with 177Lu-edotreotide must be 
discontinued and appropriate treatment is to be given according to local standard of care. 
Please refer to the local product information for the countries participating in the study for everolimus. 
Expected Adverse Drug Reactions 
The definition below follows ICH-GCP (see also ICH Guideline for Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting): 
Adverse drug reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as 
the therapeutic dose(s) may not be established, all noxious and unintended responses to a medicinal 
product related to any dose should be considered as ADR. The phrase “responses to a medicinal 
product” means that a causal relationship between a medicinal product and an AE is at least a 
reasonable possibility, i.e., the relationship cannot be ruled out. 

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Regarding marketed medicinal products: a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for 
modification of physiological function. 
Unexpected Adverse Drug Reactions 
An unexpected adverse drug reaction is defined as any adverse drug experience, the nature, 
specificity or severity of which is not consistent with the applicable product information (e.g. 
investigator’s brochure for an unapproved investigational product or Summary of Product 
Characteristics for an approved product). “Unexpected” as used in this definition refers to an adverse 
drug experience that has not been previously observed and included in the product information, rather 
than from the perspective of such experience not being anticipated from the pharmacological 
properties of the investigational product. Any unexpected adverse drug reaction, as of formal criteria 
of an SAE may not be met, (see above), has to be reported by the investigator immediately after 
informing the sponsor, using an SAE form. 
8.3.2.5 
Serious Adverse Events 
Definition of Serious Adverse Events 
Definition 
The following SAE definition is based on ICH guidelines and the final rule issued by the FDA and 
effective 06-Apr-1998. It is to be applied to both, AEs (defined in Section 8.3.2.1) and baseline findings 
(defined in Section 8.3.1.1). 
An SAE is classified as any untoward medical occurrence that at any dose 
• 
Results in death, or 
• 
Is life threatening, or 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation, or 
• 
Results in persistent or significant disability / incapacity, or 
• 
Is a congenital anomaly / birth defect, or 
• 
Is a medically important event or reaction. 
The term ‘life threatening’ in the definition refers to an event in which the patient was at risk of death 
at the time of the event, it does not refer to an event which hypothetically might have caused death if 
it were more severe. 
Medical and scientific judgment should be exercised in deciding whether it is appropriate to report an 
AE as serious also in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalisation but may jeopardise the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered serious. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
inpatient hospitalisation; or development of drug dependency or drug abuse. 

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Actions and reporting obligations in case of serious adverse events 
All adverse events that meet the criteria for serious require the completion of a SAE Report Form, in 
addition to being recorded on the AE pages of the patients’ CRF. This applies to all SAEs, whether or 
not they were considered to be related to study treatment. 
SAEs must be reported within 24 hours, once the investigator or other study site personnel are 
aware of the event. An initial written report should be prepared using the SAE Report Form and sent 
to the sponsor preferably per email (SAE-reporting@itm-radiopharma.com) or (in case of email 
system failure) per fax (+49 89 329 8986 6068). This report should provide a detailed description of 
the SAE. Any other relevant documents such as anonymised copies of hospital records may also be 
attached, if available. If it is not possible to notify the sponsor by email or fax within 24 hours, an initial 
notification to your assigned clinical research associate (CRA) should be made by telephone, to 
include the following information: 
• 
Identification of the investigator and centre 
• 
Patient number  
• 
Confirmation of study medication given, with date and dose 
• 
Concomitant medication and indication for using such medication 
• 
Information on the event, including date and time of onset of symptoms, severity, resolution (if 
applicable), date of death or other outcome (as applicable) 
• 
Relationship with study medication in the investigator’s opinion 
Toxic death should be reported immediately to the sponsor using the SAE Report Form. Also death 
as a result of progression of disease (no relatedness to study medication) needs to be reported using 
the SAE Report Form (option “not related” in the SAE reporting form section “relatedness to study 
medication”). A detailed description of the cause of death should be provided. Autopsy reports, if 
available, should also be sent to the sponsor as soon as they become available. Any additional 
information which becomes known to the investigator should be provided in a follow-up report. The 
severity of SAEs will be graded according to NCI-CTCAE 4.03 (see Section 8.3.2.3). SAEs must be 
followed up until a definite outcome can be documented, the event has resolved or stabilised, or the 
event is diagnosed as a chronic condition. 
Also all pregnancy cases must be reported within 24 hours on the corresponding Pregnancy Form, 
once the investigator or other study site personnel are aware of the pregnancy.  
The Sponsor is obliged to report SAEs and SUSARs to the respective authority within the statutory 
reporting period. The reporting is delegated by the sponsor to the Pharmacovigilance representative 
(see page 5). 
8.3.2.6 
Additional Provisions due to the Nature of the Underlying Disease 
Progression-free interval is the primary endpoint of this study. Tumour progression will be considered 
not to be an SAE within the scope of this study. However, death or other serious adverse events 
linked to disease progression/tumour progression will be considered as SAEs. If these serious 

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adverse events are linked to the disease progression/tumour progression, a diligent evaluation of the 
IMP/RP impact (see Section 8.3.2.2) through the reporter is necessary before the relatedness is 
classified as “unlikely” or “not related”.  
The SAE cases where the relatedness was classified as either “not related” or “unlikely” will be treated 
by the sponsor as not related to the IMP/RP and thus will not underlie the provisions of the expedited 
reporting of SUSARs (the latter does not affect the local provisions to submit local fatal SAEs if 
required and applicable).  
The SAE cases where no relationship to the IMP/RP was stated will be treated as “possible” and a 
follow-up with the reporter will be initiated.  
The SAE cases where the relationship was stated as “not assessable” will be treated as “unlikely” and 
a follow-up with the reporter will be initiated.  
8.3.3 
Physical Examination 
A physical examination will be performed at each study visit from baseline visit(s) until end of study. 
It consists of general appearance, orientation to time, space and person, cardio-pulmonary 
auscultation, manual abdominal examination, and further investigation of any abnormal system, as 
appropriate. 
Physical examination will be performed prior to dosing of study medication. 
All pertinent findings will be recorded in the subject’s study records and transcribed to the appropriate 
pages of the CRF. 
8.3.4 
Vital Signs 
Body temperature, supine blood pressure and heart rate will be measured at baseline visit(s) and at 
each study visit. 
Body temperature: The same location as for first measurement will be used throughout the entire 
study. 
Supine blood pressure and heart rate: Both parameters will be measured on the non-dominant arm 
after 5 minutes of supine rest. 
Vital signs will be measured for all subjects at the points of time given in Table 1 and Table 2. 
Subjects randomised into the 177Lu-edotreotide group will have additional vital signs collected prior to 
177Lu-edotreotide infusion, immediately after end of infusion (approx. 0.5 h) and at 6, 24, 48, 72-96 
hours post start of infusion. 
Locations of measurements and results will be recorded in the patient's file. 

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8.3.5 
Clinical Laboratory Tests 
Blood and urine samples for clinical laboratory parameters will be collected for all subjects at the 
points of time given in Table 1 and Table 2. 
Laboratory assessments will be performed by the institutional or local laboratories. Because of the 
potential for radioactivity in some blood and urine samples, the local laboratory must adhere to their 
SOPs and/or any guidance and regulations for handling radioactive substances. 
177Lu-edotreotide arm ONLY: at study site wherever possible. If not logistically feasible, inter-visit lab 
samples can be taken by a medical general practitioner (GP) in the vicinity of the patient’s home.  
Samples will be tested for the following parameters: 
Haematology: haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular 
haemoglobin (MCH), white blood cell count (total and differential: leukocytes, neutrophils, eosinophils, 
basophils, lymphocytes, monocytes), red blood cells, platelets. 
Biochemistry: sodium, potassium, chloride, calcium, glucose, creatinine, urea, albumin, total bilirubin, 
aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (AP), gamma-
glutamyl transferase (GGT), lipase, amylase, total protein. 
Clotting parameters: prothrombin time (quick), reagent-independent prothrombin ratio (international 
normalised ratio; INR), activated partial thromboplastin time (aPTT). 
Urinalysis (dipstick accepted): specific gravity, pH, protein, glucose, blood, leukocytes, ketones, 
nitrite, albumin, creatinine. Alpha-1-microglobulin will also be tested in urine but only in centres with 
adequate technical equipment and an established test method.  
Tumour marker: Chromogranin-A, further markers (see Section 8.2.1.3). 
The investigator will sign each laboratory printout and assess clinical significance. Clinically significant 
values have to be highlighted as “c.s.” (clinically significant). The printouts will be included in the 
patient’s file. 
8.3.6 
Pregnancy Tests 
A serum or urine β-HCG pregnancy test will be performed for all female patients of childbearing 
potential at baseline, within 28 days prior to first study treatment. 
Post-menopausal status (for female patients <60 years of age) must be proven by one of the following: 
• 
History of hysterectomy 
• 
Last spontaneous bleeding at least 1 year prior to informed consent and negative β-HCG 
• 
Serum estradiol <20 pg/mL and FSH >40 IU/L  
During the course of the study, pregnancy tests will be repeated monthly until end of study in female 
patients of childbearing potential. At the first dosing visit (D0), a pregnancy test does not need to be 

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performed if the baseline pregnancy test result is not older than 14 days. Since after month 12 and 
during the 2nd year (months 12-27), visits are performed in three monthly intervals, female patients of 
childbearing potential will be provided with pregnancy test strips for the performance of pregnancy 
tests at home during months: 13, 14, 16, 17, 19, 20, 22, 23, 25, and 26. The study sites/Investigators 
will collect and register information on the outcome of the tests via telephone contacts.  
A female patient who becomes pregnant during the treatment phase of the study must be discontinued 
from study treatment. SAE reporting/pregnancy reporting and pregnancy monitoring and follow-up will 
be performed as described in Sections 8.3.1.1 – pregnancy – and 8.3.2.5. 
8.3.7 
12-Lead ECG 
A 12-Lead ECG will be recorded after 5 minutes supine rest at the following points of time: 
• 
At baseline, within 28 days prior to first study treatment 
• 
Study visits of treatment phase (months 0 - 11): at 0, 3, 6, 9 months 
• 
Study visits of 2nd year (months 12 - 24): at 12, 18, and 24 months 
• 
At EOS visit 
Subjects randomised into the 177Lu-edotreotide group will have additional ECGs at 72 h after each 
dose administration. 
Rhythm, RR-, HR-, PR-, QT-, QTc- and QRS-intervals will be assessed at each point of time that a 
12-lead ECG is recorded. The ECG printout will be included in the patient’s file, and the investigator 
will comment on whether the results are normal, abnormal (not clinically significant) or abnormal 
(clinically significant). 
8.3.8 
Renal Scintigraphy (99mTc-MAG3) 
Within 28 days prior to randomisation, each subject will undergo 99mTc-MAG3 (99mTc-mercapto-
acetyltri-glycine) renal scintigraphy, to assess the baseline tubular extraction rate (TER) of the kidneys 
and evaluate the kidney functionality from renogram and sequence images. Follow-up 99mTc-MAG3 
renal scintigraphy will be performed in 6-monthly intervals in both groups: at month 6, 12, 18, 24, and 
30. For the 177Lu-edotreotide arm, the month 6 99mTc-MAG3 renal scintigraphy has to be performed 
within 7 days before administration of the cycle D3 dose of study drug. In case an additional 
99mTc-MAG3 renal scintigraphy is prescribed to allow dosing up to 29 Gy to the kidney, it also has to 
be performed before dosing of study drug (see Section 3.1).  
The renal scintigraphy will be performed as clinically established, but in accordance with the details 
defined in the Clinical Imaging Manual (CIM). 
8.3.9 
Kidney Function and GFR 
Kidney function will be monitored assessing 
• 
Quantitative TER (see Section 8.3.8) determined at baseline, and thereafter in 6-monthly 
intervals 

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• 
GFR calculated from serum creatinine, determined at baseline, thereafter in 3-monthly 
intervals. 
• 
The calculated GFR will be determined centrally for consistency. Body weight, and height, as 
well as sex and age will be recorded in the CRF. 
• 
Kidney volume (abdominal MRI/CT, baseline, 3-monthly interval). 
• 
GFR will be calculated using the recommended CKD-EPI formula (Levey et al., 2009) 
8.4 
Pharmacogenomics 
Not applicable. 
8.5 
Total Volume of Blood 
Blood volumes drawn for safety evaluations correspond to those used in clinical routine for patients 
with GEP-NET. In addition, blood for tumour marker analyses will be drawn. 
Total volume of samples will not exceed 50 mL / month. They are summarised in Table 7. 
Patients in Sub-study C will also have a total of 11 mL of blood taken for dosimetry within 7 days. 
Table 7: Total Volume of Blood 
Sample 
Volume per 
Sample [mL] 
Number of 
Samples 
Total Volume 
[mL] 
Haematology 
Screening 
Months 0-11 
2nd year, EOS 
 
3 
3 
3 
 
1 
20 x 1 
7 x 1 
 
3 
60 
21 
Biochemistry A 
Screening 
Months 0-11 
2nd year, EOS 
 
7.5 
7.5 
7.5 
 
1 
20 x 1 
7 x 1 
 
7.5 
150 
52.5 
Clotting parameters 
Screening 
Months 0-11 
2nd year, EOS 
 
3 
3 
3 
 
1 
12 x 1 
7 x 1 
 
3 
36 
21 
TER by 99mTc-MAG3 renal 
scintigraphy 
Screening 
Month 6 (optional M 9) 
Months 12, 18, 24 
EOS 
 
 
7.5 
7.5 
7.5 
7.5 
 
 
1 
1 (x1) 
1 x 3 
1 
 
 
7.5 
7.5 (7.5) 
22.5 
7.5 
Overall TOTAL 
 
83 
399.0 (406.5) 
A including tumour markers; including pregnancy test (if not performed from urine) 

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8.6 
Sample Shipment 
8.6.1 
Tumour Histology Samples 
For central histological investigations, mounted tissue specimens will be shipped to the following 
Central Pathology Laboratory (CPL) in ambient temperature with a sample shipment log: 
 
Address 
University Bern 
Institute of Pathology  
Murtenstrasse 31 
CH-3010 Bern, Switzerland 
Contact Person 
Prof. 
 
Telephone 
 
Fax 
 
E-Mail 
 
 
The samples will be examined for quality and completeness, and receipt will be documented. 
8.6.2 
Electronic File Transfer 
Where possible, all image data are transferred using ABX-DIRECT® software as described in the 
Clinical Imaging Manual. If ABX-DIRECT® is not available, image data will be transferred via DVD by 
pick up postal service. 
8.6.3 
Other Samples 
Samples for analysis of chromogranin A (and other tumour marker samples, if applicable; see 
Section 8.2.1.3), pregnancy status and clinical laboratory will be analysed in the institutional 
laboratories of each site according to local specifications. 
8.7 
Image Analyses 
Image acquisition, processing, analysis, and format of reporting will follow standardised procedures 
that are defined in separate documents (Clinical Imaging Manual, Image Review Charter). 
Primary image analysis (e.g. determination of target lesion dimensions of individual time points), as 
well as secondary image analysis (e.g. RECIST 1.1 classification, considering earlier reference time 
points) will be performed by a central ICL whose readers are blind to the treatment group.  

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Reading of morphological imaging (MRI/CT) for determination of progression-free survival (PFS, 
primary endpoint) will be in duplicate, with adjudication in case of discordance. 
All secondary image analyses will be made by a single reader at the central ICL, only. 
Results of image analysis will be transferred in a suitable alphanumeric format to the Study Data 
Management in batches.  
8.8 
Appropriateness of Procedures / Measurements 
The purpose of this study is the evaluation of efficacy and safety of 177Lu-edotreotide in the treatment 
of inoperable, progressive, somatostatin receptor-positive GEP-NET in comparison to everolimus, the 
only medication currently licensed in the target indication advanced low- and intermediate-grade NET 
of pancreatic or gastroenteric origin. Comprehensive characterisation of survival endpoints 
(progression-free survival and overall survival), taking into consideration objective response (RECIST 
1.1), biomarker response (tumour markers), and symptomatic response (HRQL questionnaires), 
corresponds to current standards in oncological efficacy evaluation. 
Standard safety evaluations (laboratory, ECG) as well as treatment-specific evaluations (99mTc-MAG3 
renal scintigraphy) are included. 
Serial planar scintigraphic imaging (2D) is considered the traditional standard method for the 
evaluation of radiation dosimetry, expected by regulatory agencies. Hybrid dosimetry (2D/3D), based 
on serial planar and single time point SPECT/CT imaging, is the emerging clinical standard, allowing 
to investigate absorbed doses to kidneys (safety) and tumour (efficacy) more accurately, due to a 
higher spatial resolution and more precise delineation of organ-bound activity, compared to 2D 
dosimetry (see Section 8.2.2). 
This approach is considered to be adequate for verifying the therapeutic index of 177Lu-edotreotide 
PRRT in greater detail. 
9 
Statistical Methods and Determination of Sample Size 
9.1 
Randomisation 
Randomisation will be stratified using four independent randomisation lists to control for primary 
tumour origin (GE-NET vs. P-NET) and for prior medical therapy (1st line vs. 2nd line) as critical 
baseline co-variates (see Section 9.2.3). A central web-based randomisation system will be used. 

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9.2 
List of Variables and Population Characteristics 
For the main analyses of variables based on tumour response, centrally assessed RECIST 1.1 will 
be used. Local RECIST 1.1 assessment can be used for sensitivity analyses, if deemed relevant. 
9.2.1 
Primary Variable 
Progression-free survival 
Progression-free survival will be determined starting from randomisation until the date of an event 
(PD by RECIST 1.1 or death). For the primary analysis, any withdrawal (or drop-out) before EOS visit 
will be censored. Patients who have not shown progression at the end of the study will also be 
censored.  
9.2.2 
Secondary Variable(s) 
9.2.2.1 
Key Secondary Variables 
a) Objective response rate (ORR), defined as the percentage of patients, achieving (based on 
RECIST 1.1) a partial response (PR) or complete response (CR) as best outcome 
b) Overall survival (OS), will be calculated starting from the date of randomisation until the date 
of death. OS will be determined based on all available evidence, including study visits, 
follow-up telephone calls, subsequent medical reports, or the report of death, as appropriate. 
OS will be followed up for 5 years (60 months) after EOS.  
9.2.2.2 
Exploratory Efficacy Variables 
c) Percentage of patients progression-free at 2 years after randomisation in either treatment arm 
(% 2y-PFS) 
d) Disease control rate (DCR), considers – in contrast to the ORR – the percentage of patients, 
achieving partial reponse (PR), complete response (CR), and stable disease (SD) as best 
outcome 
e) Duration of disease control (DDC), will be calculated only in patients who achieve CR, PR or 
SD as the period from the time point of first establishment of SD (or better) until a new 
diagnosis of morphological progression per RECIST 1.1 criteria 
f) Similarly, duration of response (DoR), will be calculated only in patients who achieve CR or 
PR as the period from the time point of first establishment of PR (or better) until a new 
diagnosis of morphological progression per RECIST 1.1 criteria 
g) Association between RECIST 1.1 tumour response and CgA and/or specific hormone levels 
will be explored. If relevant, percentage of patients experiencing a biomarker tumour response 
(CgA, specific hormones), classified as SD, PR, CR, and PD, can be investigated, as well as 
the duration of such response 

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9.2.2.3 
Safety and Tolerability Parameters 
a) Measured tubular extraction rate (TER), percentage depart from baseline value 
b) Calculated glomerular filtration rate (GFR), percentage depart from baseline value 
c) Renal volume (Vkidney), percentage depart from baseline value 
d) Frequency of occurrence and severity of abnormal findings in safety investigations (vital signs, 
12-lead ECG, clinical laboratory, adverse events) 
9.2.2.4 
Health-Related Quality of Life (HRQL) 
a) Maximum HRQL improvement (EORTC QLQ-C30 and GI.NET21 questionnaires) total scores, 
relative to baseline 
b) Duration of maximum HRQL improvement 
c) Time to HRQL deterioration, defined as the time from randomisation to first HRQL 
deterioration 
9.2.2.5 
Dosimetry 
Full dosimetry assessments of target organs and tumour lesions will be reported including time to 
activity curves. 
Cumulative absorbed dose (in Gy) of 177Lu-edotreotide to target tumour lesions and kidneys, will be 
estimated from dosimetry after first 177Lu-edotreotide cycle (D1) considering prospective total 177Lu-
edotreotide dose prescriptions from D1 – D4 (assuming dose linearity). 
In Sub-study A patients, the cumulative absorbed dose to kidneys and to tumour lesions extrapolated 
from absorbed dose estimated at D1 will be compared with the cumulative absorbed dose measured 
at the different administration times (i.e. D1 to D4). 
In Sub-study B patients, absorbed dose (in Gy) determined by 3D dosimetry, will be analysed in 
comparison to absorbed dose values obtained by planar (2D) and hybrid (2D/3D) dosimetry. 
In Sub-study C patients, bone marrow absorbed dose (in Gy) will be extrapolated from blood 
radioactivity. 
9.2.2.6 
Pharmacokinetics (Sub-Study C) 
a) Urine radioactivity in percentage of injected activity (%IA) at pre-defined intervals within 48 
hours post-injection to assess excretion pattern 
b) Blood radioactivity in %IA at pre-defined time points within 7 days post-injection to assess 
clearance pattern 
c) Radiochemical purity assessed through HPLC of urine samples collected within 48 hours 
post-injection 

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9.2.3 
Population Characteristics 
9.2.3.1 
Primary Tumour Origin (GE-NET vs. P-NET) 
In this trial patients with histologically confirmed diagnosis of well-differentiated neuro-endocrine 
tumour of non-functional gastroenteric origin (GE-NET) or both functional or non-functional pancreatic 
origin (P-NET) will be eligible. Therefore, stratified randomisation will be used to ensure a balanced 
frequency of GE-NET and P-NET patients in both treatment arms. To enable an optimal subgroup 
analysis, ideally equal numbers of GE-NET and P-NET should be recruited. 
9.2.3.2 
Prior Medical Treatment (1st line vs. 2nd line) 
In the present trial both, treatment-naive (1st line), and patients who have progressed under prior 
medical therapy (2nd line) will be eligible. Since prior medical treatment status is expected to be a 
relevant baseline co-variate, stratified randomisation will be used, to ensure a balanced frequency of 
1st line and 2nd line subjects in both treatment arms. 
In addition, the evaluation of prior medical treatment in patients receiving second line therapy will be 
differentiated into chemotherapy, SSA, targeted therapy (e.g. sunitinib), and others. 
9.2.3.3 
Tumour Grade (G1 vs. G2), Ki-67, and KPS 
Tumour grade, Ki-67, and baseline clinical status, determined using the Karnofsky Performance Score 
(KPS) are suspected to be further relevant baseline co-variates, which should be investigated at the 
time of analysis. 
9.2.3.4 
Other Characteristics 
Summary tables and/or listings will be provided for demographics and other baseline characteristics, 
including: 
• 
Age, ethnic origin, sex, physical exam 
• 
Medical/surgical history at baseline, 
• 
Prior and concomitant medication 
• 
Time from primary diagnosis, time from diagnosis of progression, number and type of 
prior therapies for condition, site(s) of metastases 
• 
Histological entity, functional state 
All variables of population characteristics will be confirmed by non-parametric statistical testing for 
both treatment groups to check their comparability at baseline (except for detailed physical 
examination, medications, and medical/surgical history). If there should be major differences between 
the treatment groups, their impact on analysis will be investigated including with stratified methods, if 
deemed appropriate. 

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In addition, appropriate methods (stratification, multivariate analyses, subgroup analyses) will be used 
to assess the impact of patient and tumour characteristics and tumour histology on tumour response 
as foreseen in the exploratory study objectives. 
9.3 
Statistical and Analytical Plans 
9.3.1 
General Considerations 
The primary objective of this trial is to demonstrate the efficacy of PRRT with 177Lu-edotreotide to 
prolong progression-free survival (PFS) in patients with inoperable, progressive, SSTR+ GEP-NET, 
compared to everolimus. 
The primary variable progression-free survival (PFS) will be analysed using confirmatory statistics. All 
survival data will be analysed using the Kaplan-Meier method, which takes into account the impact of 
censored observations and the Log-rank test. Likewise, the secondary variable overall survival (OS) 
and PFS, adjusted for the co-variates primary tumour origin, prior medical treatment, tumour grade 
and baseline KPS, will be compared using exploratory statistics. Further statistical stratified tests will 
not be made. Instead, the influence of other baseline and/or intercurrent factors such as, but not 
limited to, concomitant SSA treatment and treatment switch will be investigated by sensitivity 
analyses. 
The main analysis of OS may take into consideration treatment switches if a high proportion (e.g. 
>33%) of patients in the everolimus arm received subsequent PRRT treatment. 
All secondary variables will be analysed descriptively by treatment group. All continuous and ordinal 
parameters will be summarised using standard summary statistics as appropriate (n, mean, standard 
deviation, median, minimum, maximum, 25th percentile, and 75th percentile). Summary statistics for 
ordinal and categorical variables will include frequency counts and percentages. 95% confidence 
interval will be calculated where relevant. Non-parametric methods will be used for comparison 
between study groups or subgroups (Mann-Whitney U test), changes within groups (Wilcoxon test) 
or percentages (Fisher’s exact test or Chi2 test). The influence of censored data will be evaluated by 
using Kaplan-Meier, log-rank test and Cox model analysis when appropriate. 
A statistical power of at least P = 0.8, and a significance level of p < 0.05 (two-sided) are envisaged. 
All data will be listed and summarised. 
Adverse events prior to the first treatment will be captured for all enrolled patients and reported 
separately from treatment emergent AEs, as baseline findings. 
Patient assignment to the analysis sets, specified in Section 9.3.3, will be performed and listed prior 
to any analysis taking place. 

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9.3.2 
Interim Analysis and Multiple Testing 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.3.3 
Analysis Sets 
9.3.3.1 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) will be used for all efficacy analyses and is defined as all patients who 
are randomised to treatment; patients in this population will be analysed according to the treatment 
to which they were randomised. All available data for PFS and survival will be collected and analysed 
for these patients. For FAS patients who have inadequate data post-baseline to assess efficacy 
according to the criteria for response or who dropped out before EOS, follow-up will be censored for 

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analysis of PFS on the date of the last adequate tumour assessment prior to withdrawal (see the 
Statistical Analysis Plan [SAP] for more details). 
The confirmatory analysis of the primary and the 2 key secondary endpoints will be based on the 
FAS. 
9.3.3.2 
Per Protocol set (PP) 
In order to determine if any bias results from including untreated patients or patients lost to follow-up 
in the primary FAS analysis, an additional analysis will be conducted on patients who are protocol-
compliant: the Per Protocol set (PPS). Patients with major protocol violations determined before 
statistical analysis will be excluded from this population. Major protocol violations are defined as those 
that could impact the efficacy or safety evaluations and will be specified in the SAP. For the study 
arms the following deviations are defined as major protocol deviations, leading to exclusion from the 
PPS: 
• 
177Lu-edotreotide arm:  
o Subjects with incomplete 177Lu-edotreotide infusion, in which less than 50% of the total 
pre-scribed activity (GBq) based on initially dosimetry assessment was injected. 
o Subjects missing more than two scheduled doses, or in whom dose were administered 
more than 30 days outside the date, specified per protocol. 
• 
Everolimus arm:  
o Subjects missing more than 14 doses, within a visit interval of 30 days (with exception of 
treatment interruptions due to toxicity (see Section 5.4.3.1). 
9.3.3.3 
Safety Analysis Set (SAF)  
All patients who received at least one dose of any study treatment will be included in the Safety 
Analysis Set (SAF). Patients will be analysed according to the treatment they actually received. 
Analyses of safety parameters will be based on the SAF. 
9.3.3.4 
Other Populations 
In case of specific assessments in specific groups of patients, analyses will only be conducted in the 
appropriate group of patients where relevant. As an example, the analysis of substudy variables will 
only be analysed based on the population of patients who actually participated in the corresponding 
substudy. 
9.3.4 
Statistical Analyses 
The detailed procedures for data analysis are described in the Statistical Analysis Plan (SAP), which 
will be defined before start of statistical evaluation. Any changes in the original statistical methodology 
will be documented in the SAP. 

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Statistical analyses will be performed after the data base has been appropriately locked (See Section 
9.3.2). 
All data from the CRF and other study documents will be reported in listings. Continuous parameters 
will be summarised using descriptive statistics (number, mean, standard deviation, minimum, median, 
maximum) and categorical parameters will be summarised using frequency tables. Corresponding 
95% confidence intervals will be presented additionally where meaningful. 
Statistical hypothesis testing of the primary variable and the key secondary variables will be performed 
maintaining an overall Type I Error (alpha) of 5% (two-sided). 
Multiplicity will be accounted for by adhering strictly to the described interim analysis and hierarchy 
testing plan with regard to the primary and the key secondary endpoints (see Section 9.3.2). 
Exploratory statistical hypothesis tests will be used at a significance level of 0.05 (two-sided), and 
considered at a purely descriptive level. 
Withdrawals and protocol deviations will be listed. Missing data that cannot be obtained will not be 
substituted, unless stated otherwise (see SAP for more details). A given data set entry is presumed 
to be an outlier if the value is evidently contrary to generally accepted data. Such occurrences will be 
recorded. Results from analyses excluding outliers may be explored by comparing to results based 
on the complete data set; differences will be discussed. 
All statistical evaluations, including graphical data summaries, will be performed using appropriate 
software. 
9.4 
Determination of Sample Size 
Considering that everolimus will be used as comparator in the planned study, a sample size estimation 
was conducted, based on a median PFS of 11.0 months reported for everolimus (Yao et al., 2011, 
2016). and a median PFS of 32 months in NET patients (34.5 in GEP-NET patients), as determined 
for 177Lu-edotreotide in subjects treated with ≥2 PRRT cycles in the retrospective study (van Echteld 
2015, Baum et al., 2016). 
 
 
 
 
 
 
 
 
 
 
  

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Figure 4: PFS for everolimus and 177Lu-edotreotide in NET 
Kaplan Meier estimates of PFS, reported for everolimus (blue), and 177Lu-edotreotide (≥ 2 cycles; green), in 
patients with NET (N=32) 
Figure 4 shows the Kaplan Meier estimates of PFS reported for everolimus (Yao et al., 2011) and 
177Lu-edotreotide (van Echteld et al., 2015; Baum et al., 2016) in NET patients. 
A prolongation of mPFS by ≥6 months, compared to comparator is already considered a relevant 
clinical benefit, constituting superiority over existing treatments in patients with advanced GEP-NET. 
To visualise, the dotted blue curve in Figure 4 is a simulated curve representing this mPFS benefit of 
6 months, which shows a difference of 25% in PFS at 11 months.  
For the sample size calculations, i.e. estimating the sample size, the power and/or the effect size, the 
following considerations were taken into account:  
 
 
 
 
. Study 
duration per patient will be 30 months. The accrual across time is uniform. Of note, the trial sample 
size was not revised (i.e. decreased) after the protocol amendment that extended the patient follow-
up from 24 months to 30 months. 
Based on this HR a total sample size of 300 will compensate for a dropout rate (censored data) of 
15% for primary endpoint analysis. Switching from the one group to the other is not allowed in this 
study and therefore not considered in the sample size calculation. 

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With regard to overall response rates, group sample sizes of 200 in the 177Lu-edotreotide group and 
100 in the everolimus group achieve 
% power to detect an odds ratio between the group ORRs of 
 (that corresponds to rates of % and 
%). The proportion in the 177Lu-edotreotide group is 
assumed to be 
% under the null hypothesis and 18% under the alternative hypothesis. The 
proportion in the everolimus group is assumed to be 5% according to results of the RADIANT-3 study 
(Yao et al., 2011). The test statistic used is the two-sided Fisher's Exact Test. The significance level 
of the test is 5%. A dropout rate of 15% is included in this calculation using PASS software. 
With regard to overall survival, a two-sided logrank test with an overall sample size of N=300 subjects 
(
 events; 
, N1=100 subjects 
] in the everolimus group and N2=200 
subjects [
 events] in the 177Lu-edotreotide group) achieves 
 power at a 
 significance level 
to detect a hazard ratio (HR) of 
 when the everolimus group median overall survival time is 
44 months as in the RADIANT-3 study (Yao et al., 2016) (i.e., a difference of an additional 23 months 
in the 177Lu-edotreotide group). The observation time for overall survival will be 5 years (60 months) 
after EOS for all patients.  
The sample size of 300 patients was chosen as the primary endpoint and the 2 key secondary 
endpoints are to be tested in a confirmatory manner. This sample size allows to address historically 
assumed PFS treatment effect (which would require 
 events) and minimal clinically relevant PFS 
difference (which would need 
 events). 
 
 
  
• 
 
 
• 
 
• 
 
 
In conclusion, the trial sample size of 300 randomized patients associated with the interim analysis 
plan will allow to cover all the possible treatment effect assumptions (minimal, expected and historical) 
at an overall two-sided level of significance of 0.05 and with acceptable power (i.e. 
). 
 
The sample size estimation was performed using SAS, PASS Power Analysis and Sample Size 
Software (version 13). 

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10 
Data Handling and Quality Assurance 
10.1 
Data Recording 
10.1.1 
Case Report Form (CRF) 
For this study patient data will be entered into a sponsor defined eCRF, transmitted electronically to 
the sponsor or designee and combined with data provided from other sources in a validated data 
system. The case report form will be supplied for recording all study data from each patient. It is the 
responsibility of the investigator to ensure that the CRFs are completed in full. All data therein must 
be supported by source documentation at the study centre. The completion of study page of the CRF 
must be signed by the principal investigator at the end of the study confirming that he/she is satisfied 
with its completion and accuracy. A CRF must be completed for every patient who signed an informed 
consent. The eCRFs must be kept up-to-date so that they always reflect the latest observations on 
the patient. 
Study monitors must never write in the CRF (except to write queries). 
In all cases, subject initials or personal data will not be collected by or transmitted to the sponsor or 
the coordinating CRO. 
10.1.2 
Missing Data 
If any information is not available, and it is considered by the investigator that it will never be available 
(e.g. the weight on a particular visit was not recorded), the investigator will explain in the eCRF, why 
the investigation was missed out (e.g. the patient was not well enough to undergo the procedure). 
10.1.3 
Storage 
It will be the responsibility of the investigator to guarantee adequate storage for all study records, 
including the hospital notes during the study (and for a minimum of 25 years following the end of the 
study). If he/she leaves the employ of the hospital he/she will inform the sponsor and nominate a 
contact person who will have access to the study documents. 
The investigator should take measures to prevent accidental or premature destruction of these 
documents. Essential documents shall be stored in such a way that ensures that they are readily 
available upon authorities’ request. 
Archiving is described in Section 10.6. 

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10.2 
Monitoring 
This study will be monitored at all stages of its development by the clinical research personnel 
designated by the sponsor. Monitoring will include personal visits and telephone communication to 
ensure that the investigation is conducted according to the protocol and in order to comply with 
guidelines of GCP and applicable regulatory requirements. On-site and remote (according to local 
regulations) review of CRFs will include a review of forms for completeness and clarity, and 
consistency with source documents available for each patient. 
During monitoring visits, the data recorded in the CRFs, source documents, and other study-related 
records will be compared against each other in order to ensure accurate, authentic and complete data 
that reflects the actual experience of the patient in the study, i.e. source data verification. In addition, 
monitoring must ensure that the safety and rights of subjects are being protected. The investigator 
must ensure that the hospital notes will be available for direct verification of source data. The sponsor 
will not keep any records of patient’s full identity. 
To this end, the investigator agrees to allow regular visits by the study monitors and ensures direct 
access to study documents. He/she also agrees to allocate their time and the time of their staff to 
discuss findings and any issues with the monitor. 
Medical monitors and CRAs or assistants may request to witness patient evaluations occurring as 
part of this protocol. The investigator and appropriate personnel will be periodically requested to 
attend meetings or trainings organised by the sponsor to ensure acceptable protocol execution. 
The study may be audited or inspected by the sponsor (or a designated CRO), regulatory or health 
authorities or IEC/IRB. If such an audit or inspection occurs, the investigator must agree to allow 
access to the study site, required patient records and study documents. If notified of audits/inspections 
by bodies other than the sponsor, the investigator is to notify the sponsor of any such inspection 
immediately. By signing this protocol, the investigator grants permission to personnel from the 
sponsor, its representatives, and appropriate regulatory authorities for on-site monitoring of all 
appropriate study documentation, as well as on-site review of the procedures employed in the CRF 
generation, where clinically appropriate. The investigator agrees to allocate his/her time and the time 
of the study team to accompany the audit and to discuss the findings with the auditor. The investigator 
will be informed about the outcome of the audit. 
The following activities will be undertaken to ensure the quality of trial-related activities: 
• 
Adherence to the trial site SOPs to maintain accurate and consistent practices and procedures 
• 
Conduct of a site initiation visit to ensure the investigator and all personnel involved in the trial 
understand the protocol, including the study procedures and their responsibilities 
• 
Completion of a standard CRF in accordance with GCP requirements to ensure accurate and 
reliable data 
• 
Periodic monitoring to ensure the trial data are accurate, complete and verifiable from source 
documents, and that the protocol is being followed 

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Quality control procedures regarding data entry and statistical analysis will be documented in the 
SAP. 
10.3 
Data Processing 
The CRO will be responsible for the processing and quality control of data. Data management will be 
carried out as described in the CRO’s SOPs for clinical studies to ensure the integrity of the data, e.g. 
removing errors and inconsistencies of the data. Data entry and correction will be tracked by a 
validated audit trail. All systems are validated and compliant to FDA’s ordinance 21 CFR part 11. 
The FDA-validated medical dictionary MedDRA (current version) will be used for data coding (e.g. 
AEs, baseline findings, medication, medical/surgical history). The processes used for coding will be 
specified in the SAP. 
10.4 
Data Confidentiality 
10.4.1 
Documentation of Patients’ Participation 
For all patients who give informed consent, regardless of whether they receive any study medication, 
the investigator must record patient identification data in the "Patient Identification List" (full name, 
initials, date of birth, patient identification code). The patient identification list must allow for the definite 
identification of any patient that takes part in the study. In addition, study participation must be 
documented in the patient’s regular medical records. For details about patient identification, see 
Section 4.5. 
10.4.2 
Data Protection 
To protect the patient's identity, a unique patient identification code will be assigned by the investigator 
to each trial patient and used in lieu of the patient's name when the investigator reports adverse 
events and/or other trial related data (see Section 4.5). Thus, this number, rather than the patient's 
name, will appear on all documents and will be cross-referenced by the patient's date of birth. 
Personal information will be treated as confidential, but may need to be reviewed by the PIs, the ethics 
committee and regulatory authorities. 
In order to be compliant with any country-specific laws, all relevant submissions to the respective 
authorities will be done and the corresponding approvals will be obtained before collection of any data 
considered to be sensitive, such as: ethnic origin, race, full date of birth etc. 
10.5 
Auditing 
A member of the sponsor’s (or a designated clinical research organisation, e.g. a CRO) quality 
assurance unit may arrange to visit the investigator in order to audit the performance of the study at 

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the study site and the study documents originating there. The auditor(s) will usually be accompanied 
by a CRA or the study team lead. The investigator will be informed about the outcome of the audit. 
In addition, inspections by health authority representatives – including foreign authorities – and IEC(s) 
/ IRB(s) are possible at any time. The investigator is to notify the sponsor of any such inspection 
immediately. 
10.6 
Archiving 
The sponsor and the investigator / medical institution shall, in every case, retain the essential 
documents relating to this study for at least 25 years after its completion. They shall retain the 
documents for a longer period if required by other applicable regulatory requirements or by a separate 
agreement between the sponsor and the investigator. Essential documents shall be archived in such 
a way that ensures that they are readily available upon authorities’ request. 
Electronic CRFs (including queries and audit trails) will be retained by the sponsor, and copies will be 
sent to the investigator to maintain as the investigator copy. 
Patient (hospital) files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the hospital, institution or private practice. The ISF is not to be 
destroyed without the sponsor’s approval. The investigator’s contract will contain all regulations 
relevant for the study centre. 
Storage is described in Section 10.1.3. 
11 
Premature Termination of the Study 
At the discretion of the PI, the patients’ treatment may be interrupted for medical reasons. In addition, 
the sponsor retains the right to end the study for medical-scientific or GCP-relevant reasons. In case 
of premature termination, the investigators, IRB / IECs and regulatory authorities will be informed by 
the study manager. As required by local law, current safety-relevant information will be provided to 
the IEC / IRB and the regulatory authorities by the sponsor. The sponsor will also inform all 
investigators about relevant safety events according to the applicable regulations. Stopping criteria 
are described in Section 11.1. 
If the trial is prematurely terminated or suspended for any reason, the investigator should promptly 
inform the trial subjects and should assure appropriate therapy and follow-up. Should the study be 
terminated and/or the site closed for whatever reason, all documentation will be stored at the 
institution for the legally required period. Access will be granted to the coordinating CRO during this 
period. All study medication pertaining to the study must be returned to the sponsor or its 
representative in compliance with the applicable local regulations. 

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11.1 
Stopping Criteria 
11.1.1 
Stopping Criteria for the Entire Trial 
The entire study must be stopped if there is evidence of serious safety issues. An independent data 
safety monitoring board (IDSMB, see Section 11.2) will review safety data at regular intervals and 
may suggest terminating the trial.  
To identify any possible safety issues in due time, all SAEs, deaths, instances of DMT (see Section 
5.4.3.2), any instances of premature treatment discontinuation, as well as other AEs of interest (e.g. 
creatinine values) will be reviewed by the IDSMB on an ongoing basis during treatment of the first 36 
PRRT patients who have actually received a 177Lu-edotreotide dose. Written safety assessments with 
conclusions and recommendations will be initially issued by the IDSMB for every 12 PRRT patients 
(i.e. after patient 1 - 12, 13 - 24, and 25 - 36), thereafter in 6-monthly intervals (see Section 11.2). The 
IDSMB will take into consideration the observed safety data, the safety profile of comparable PRRT 
agents, the safety profile of other licensed treatments for neuroendocrine tumours, and the natural 
history of the disease when making a recommendation to stop the trial. 
The IDSMB may recommend to stop the trial for any serious safety issue of concern.  
Only patients who have actually received at least one PRRT cycle will be considered for these 
stopping criteria. 
Statistical stopping criteria are not planned.  
The study may also be stopped by the sponsor for medical-scientific or GCP-relevant reasons. 
11.1.2 
Stopping Criteria for Individual Patients 
Study participation for an individual patient must be stopped 
• 
In case of tumour progression (see Section 8.2.4) 
• 
In case of excessive toxicity defined as an AE considered by the Investigator to necessitate 
permanent discontinuation of 177Lu-edotreotide, e.g., serious, treatment-related adverse 
events (see Section 8.3.2.5) 
• 
If the patient decides to withdraw from the trial (see Section 13.2) 
Study participation for an individual patient may be discontinued (see Section 4.4.1): 
• 
For medical reasons at the discretion of the Investigator 
• 
Due to non-compliance 
• 
Following a protocol deviation 
• 
Due to pregnancy 
• 
If the patient is lost to follow-up. 

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Study treatment for an individual patient must be discontinued in the case of pregnancy (see 
Section 4.4.1). See Section 8.3.1.1 for follow-up procedures in the case of pregnancy. 
177Lu-edotreotide treatment for an individual patient must be discontinued in the case of 
hypersensitivity or anaphylactic reaction, or TLS or CRS development (see Section 8.3.2.4). 
11.2 
Independent Data Safety Monitoring Board 
An independent data safety monitoring board (IDSMB) will review safety data at regular intervals 
throughout the study. If there are any signs of safety issues, the IDSMB may suggest terminating the 
trial.  
Corresponding to the previously described toxicity pattern for PRRT agents (IAEA PRRNT monograph 
2013), the IDSMB will put special emphasis on identifying possible acute and delayed radiotoxic 
effects which are predominantly expected for bone marrow and kidneys. 
To identify relevant safety issues in a timely fashion, the IDSMB will perform an ongoing review of 
SAE notifications, deaths, instances of DMT (see Section 5.4.3.2), instances of patients not meeting 
the pre-defined eligibility criteria for continued administration of 177Lu-edotreotide after cycle 1 (see 
Section 5.4.1.2), or other toxicities requiring discontinuation of 177Lu-edotreotide treatment in the 
opinion of the investigator, as well as other AEs of interest (e.g. creatinine values). The IDSMB will 
prepare summary reports with safety assessments and recommendations. For the first 36 PRRT 
patients, the IDSMB will review 3 consecutive cohorts of 12 PRRT patients who have reached the 
day 90 (±14) day evaluation (i.e. baseline for cycle 2), allowing to characterise a representative safety 
profile at the end of this treatment cycle, but will also consider any available additional data from 
patients who have already advanced beyond cycle 1 at the time of review. After the first 36 PRRT 
patients, the IDSMB will convene in 6-monthly intervals. Details will be described in the IDSMB 
charter. 
Results of previous trials have shown that 177Lu-edotreotide has the potential to perform considerably 
better than current standard therapy (Baum et al., 2016). Therefore, termination for futility was not 
considered. Patients who experience progression under everolimus may switch to treatment with 
177Lu-edotreotide off-study at the discretion of the Investigator (see Section 7.4.2). 
12 
Investigator’s Obligations and Regulatory Aspects 
12.1 
Investigator’s Commitment 
By signing this protocol, the investigator accepts to carry out all procedures related to this study 
according to the laws and guidelines of their respective countries related to the conduct of clinical 
research. All investigators must allow access to all documents pertinent to the study. In particular, the 
investigator must comply with ICH harmonised tripartite guidelines for Good Clinical Practice 

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(finalised, July 1996). The investigator’s responsibilities as detailed in these guidelines are available 
upon request. 
The study may be subject to inspection or audit by regulatory authorities and will be monitored by 
authorised company personnel to ensure adherence to these guidelines. 
The protocol must be read thoroughly and the instructions herein must be followed exactly. Any 
deviations should be agreed between the sponsor and the investigator, with appropriate written 
protocol amendments made to reflect the changes agreed upon. Substantial amendments to the 
protocol will not be implemented until after approval by the appropriate EC / IRB / regulatory authority 
according to national legislation (see Section 3.5). Where the deviation occurs for the well-being of 
the patient, the monitor must be informed and a course of action agreed. Subsequently all such 
deviations, including the reasons thereof, will be submitted to the sponsor and the IEC(s) / IRB(s) as 
well as the relevant Competent Regulatory Agencies/Authorities if applicable and according to 
national regulations.  
If an investigator moves, withdraws from the study or retires, the responsibility for conducting the 
study and maintaining the records may be transferred to another investigator at the same centre who 
will accept responsibility for taking over the study. Notice of transfer must be made to, and agreed by 
the sponsor. 
12.2 
Documentation 
12.2.1 
Approvals and Agreements 
The following documents must be made available to the sponsor prior to enrolling patients into the 
study: 
• 
Signed final protocol investigator’s agreement page. 
• 
Completed and signed investigator agreement, where applicable. 
• 
Curriculum Vitae and Financial disclosure of the principal investigator together with 
investigators at his/her centre, where appropriate. Each should be up-to-date, signed and 
dated, confirming their accuracy. 
• 
Copy of the ethics committee/investigational review board’s approval. 
• 
List of members of the ethics committee/investigational review board and their affiliations. 
• 
Sample of the consent form and patient information leaflet to be used (if different from the 
ones provided by the sponsor). 
12.2.2 
Hospital Case Notes 
The investigator should maintain individual patient records, usually hospital notes. The records should 
include patient visit dates, records of vital signs, medical history, examinations, any adverse event, 
and other notes as appropriate. Source documents containing key data relevant to the patient’s 

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condition, procedures and outcome must be kept by the investigator and will be reviewed by the study 
monitor. All entries in the eCRF must be backed up by source data. 
13 
Ethical and Legal Aspects 
13.1 
Ethical and Legal Conduct of the Study 
The planning and conduct of this clinical study are subject to national laws. Only when all of the 
requirements of the appropriate regulatory authority have been fulfilled will the study begin. The 
guidelines of the World Medical Association Declaration of Helsinki, the Guidelines of GCP 
(CPMP/ICH/135/95) as well as the demands of national drug and data protection laws and other 
applicable regulatory requirements will be strictly followed. 
The investigator is responsible for ensuring that no patient is subject to any study-related examination 
or activity before that patient has given informed consent. The patient must give written consent prior 
to any study-related activity and after the receipt of detailed information. The verbal explanation will 
cover all the elements specified in the written information provided for the patient. 
The investigator will inform the patient of the aims, methods, anticipated benefits and potential 
hazards of the study including any discomfort it may entail. The investigator will inform patients that 
in providing informed consent, they are giving permission for representatives of the study centre PIs, 
ethics committees, or regulatory authorities to inspect their medical records to verify the collected 
information. Patients will be informed that all personal information made available for inspection will 
be handled in strictest confidence and in accordance with local data protection laws. The patient must 
be given every opportunity to clarify any points he/she does not understand and if necessary, ask for 
more information. At the end of the interview the patient may be given time to reflect if this is required, 
or if the patient requests more time. Patients will be required to sign and date the informed consent 
form. After completion, the consent forms will be kept and archived by the investigator in the 
investigator’s study file. 
It should be emphasised that the patient has the liberty to withdraw his/her consent to participate at 
any time, without penalty or loss of benefits to which the patient is otherwise entitled. Patients who 
refuse to give or withdraw written informed consent may not be included or continued in the study. 
13.2 
Patient Information and Consent 
All relevant information on the study will be summarised in an integrated patient information and 
consent sheet provided by the sponsor. A sample patient information and informed consent form is 
provided as a document separate to this protocol. 
Based on this patient information sheet, the investigator will explain all relevant aspects of the study 
to each patient before his/her entry into the study (i.e., before examinations and procedures 
associated with selection for the study are performed). 

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The investigator will also mention that written approval of the IRB / IEC has been obtained. 
Each patient will have ample time and opportunity to ask questions and will be informed about the 
right to withdraw from the study at any time without any disadvantage and without having to provide 
reasons for this decision. 
Following this informative discussion, the patient will be asked if he/she is willing to sign and 
personally date a statement of informed consent, which includes consenting to the processing of 
his/her data as explained in the patient information sheet. Only if the patient voluntarily agrees to sign 
the informed consent form and has done so, may he/she enter the study. Additionally, the investigator 
will personally sign and date the form, too. The patient will receive a duplicate of the signed and dated 
form. 
The signed informed consent statement is to remain in the ISF or, if locally required, in the patient’s 
note / file of the medical institution. In addition, the consent process will be documented in the source 
documents with an independent entry. 
The investigator will document on the CRF the time and date of obtaining informed consent. In the 
event that informed consent is obtained on the date that baseline study procedures are performed, 
the study record or patient's clinical record must clearly show that informed consent was obtained 
prior to these procedures. 
If the patient is not capable of providing a signature, a verbal statement of consent can also be given 
in the presence of an impartial witness (independent of the sponsor and the investigator). This is to 
be documented by a signature from the informing physician as well as by a signature from the witness. 
The informed consent form and any other written information provided to patients will be revised 
whenever important new information becomes available that may be relevant to the subject’s consent, 
or there is an amendment to the protocol which necessitates a change to the content of the patient 
information and/or the written informed consent form. The investigator will inform the patient of 
changes in a timely manner and will ask the subject to confirm his/her participation in the study by 
signing the revised informed consent form. Any revised written informed consent form and written 
information must receive the IRB / IEC's approval / favourable opinion in advance of use. 
13.3 
Financial Disclosure 
Each investigator (including principal and/or any other investigators; who is directly involved in the 
treatment or evaluation of research subjects) has to provide a financial disclosure (also on behalf of 
spouses and dependent children) according to all applicable legal requirements. All relevant 
documentation will be filed in the TMF and/or ISF, as appropriate. 

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13.4 
Publication Policy 
The sponsor is interested in the publication of the results of every study it performs. As some of the 
information concerning the study drug and the sponsor’s development activities may be strictly 
confidential, any publication manuscript (including conference contributions, etc.) must first be 
reviewed by the sponsor before its submission or presentation. 
Publication of subgroup data and single centre data shall not be performed until the complete study 
has been published. 
All relevant aspects regarding publication will be part of the contract between the sponsor and the 
investigator / institution. 
The sponsor has committed to the global industry position on disclosure of information about clinical 
trials. The information regarding the study protocol is made publicly available on the internet at 
www.clinicaltrials.gov. This derives from the standards that international medical journal editors have 
established requiring protocol registration at the outset of the study as a prerequisite of consideration 
for publication. 
13.5 
Compensation for Health Damage of Patients / Insurance 
Where required by the laws and regulations of the country in which the study is performed, insurance 
of patients against health impairment occurring as a result of participation in the study will be set up 
in accordance with said laws and regulations. All relevant documentation regarding such insurance 
will be filed in the TMF and/or ISF, as appropriate. 

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14 
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Appendix 1: EORTC QLQ-C30 
 
 

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Appendix 2: EORTC QLQ-GI.NET21 
 
 

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Appendix 3: Karnofsky Performance Status (KPS) Scale 
The performance status is an attempt to quantify cancer patients' general well-being and activities of 
daily life. This study uses the performance status scale according to Karnofsky and Burchenal, 1949. 
Table 8 shows definition of scales in relation to ECOG score. 
Table 8: Karnofsky Performance Status (KPS) Scale 
KPS scale 
[%] 
ECOG 
score 
Definition 
100 
0 
Normal; no complaints; no evidence of disease. 
90 
0 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
1 
Normal activity with effort; some signs or symptoms of disease. 
70 
1 
Cares for self; unable to carry on normal activity or to do active work. 
60 
2 
Requires occasional assistance, but is able to care for most of his 
personal needs. 
50 
2 
Requires considerable assistance and frequent medical care. 
40 
3 
Disabled; requires special care and assistance. 
30 
3 
Severely disabled; hospital admission is indicated although death not 
imminent. 
20 
4 
Very sick; hospital admission necessary; active supportive treatment 
necessary. 
10 
4 
Moribund; fatal processes progressing rapidly. 
0 
5 
Dead 
 
 
 
 

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Appendix 4: Afinitor Dose Adjustment Recommendations 
(see Afinitor®, current version of local product information for the countries participating in this study) 
Table 9: Afinitor Dose Adjustment Recommendations 
Adverse reaction 
Severity1 
Afinitor dose adjustment 
Non-infectious pneumonitis  
Grade 2  
Consider interruption of therapy until symptoms improve to Grade ≤1.  
Re-initiate treatment at 5 mg daily.  
Discontinue treatment if failure to recover within 4 weeks.  
Grade 3  
Interrupt treatment until symptoms resolve to Grade ≤1.  
Consider re-initiating treatment at 5 mg daily. If toxicity recurs at Grade 3, consider discontinuation.  
Grade 4  
Discontinue treatment.  
Stomatitis  
Grade 2  
Temporary dose interruption until recovery to Grade ≤1.  
Re-initiate treatment at same dose.  
If stomatitis recurs at Grade 2, interrupt dose until recovery to Grade ≤1. Re-initiate treatment at 5 mg daily.  
Grade 3  
Temporary dose interruption until recovery to Grade ≤1.  
Re-initiate treatment at 5 mg daily.  
Grade 4  
Discontinue treatment.  
Other non-haematological toxicities 
(excluding metabolic events)  
Grade 2  
If toxicity is tolerable, no dose adjustment required.  
If toxicity becomes intolerable, temporary dose interruption until recovery to Grade ≤1. Re-initiate treatment at same 
dose.  
If toxicity recurs at Grade 2, interrupt treatment until recovery to Grade ≤1. Re-initiate treatment at 5 mg daily.  
Grade 3  
Temporary dose interruption until recovery to Grade ≤1.  
Consider re-initiating treatment at 5 mg daily. If toxicity recurs at Grade 3, consider discontinuation.  
Grade 4  
Discontinue treatment.  
Metabolic events (e.g. 
hyperglycaemia, dyslipidaemia)  
Grade 2  
No dose adjustment required.  
Grade 3  
Temporary dose interruption.  
Re-initiate treatment at 5 mg daily.  
Grade 4  
Discontinue treatment.  
Thrombocytopenia  
Grade 2 
(<75, ≥50x109/l)  
Temporary dose interruption until recovery to Grade ≤1 (≥75x109/l). Re-initiate treatment at same dose.  
Grade 3 & 4 
(<50x109/l)  
Temporary dose interruption until recovery to Grade ≤1 (≥75x109/l). Re-initiate treatment at 5 mg daily.  
Neutropenia  
Grade 2 
(≥1x109/l)  
No dose adjustment required.  
Grade 3 
(<1, ≥0.5x109/l)  
Temporary dose interruption until recovery to Grade ≤2 (≥1x109/l). Re-initiate treatment at same dose.  
Grade 4 
(<0.5x109/l)  
Temporary dose interruption until recovery to Grade ≤2 (≥1x109/l). Re-initiate treatment at 5 mg daily.  
Febrile neutropenia  
Grade 3  
Temporary dose interruption until recovery to Grade ≤2 (≥1.25x109/l) and no fever.  
Re-initiate treatment at 5 mg daily.  
Grade 4  
Discontinue treatment.  
1 Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03  
 

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Special populations:    
Elderly patients (≥65 years)    
- 
- No dose adjustment is required (see Section 5.2 of the original document), 
 Renal impairment      
- 
No dose adjustment is required (See Section 5.2 of the original document) 
Hepatic impairment  
- 
Mild hepatic impairment (Child-Pugh A) – the recommended dose is 7.5 mg daily.  
- 
Moderate hepatic impairment (Child-Pugh B) – the recommended dose is 5 mg daily.   
- 
Severe hepatic impairment (Child-Pugh C) – Afinitor is only recommended if the desired benefit outweighs the risk. In this case, a dose of 2.5 mg daily must 
not be exceeded.   
Dose adjustments should be made if a patient's hepatic (Child-Pugh) status changes during treatment (see also Sections 4.4 and 5.2 of the original document). 
 
 

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Appendix 5: Tumour Scoring 
 
SSTR positive is defined as: “lesions need to show adequate tracer uptake, defined as being clearly 
differentiable from background” (SSTR positive)” 
Examples for 111In-pentetreotide (OctreoScan®) for clearly differentiable from background are given 
in Figure 5. All lesions show increased uptake compared to surrounding tissue and will be considered 
SSTR positive. In Figure 6, liver lesions identified with III and IV are considered SSTR positive. Lesion 
defined with II would be SSTR negative. 
 
 
 
Figure 5: 111In-pentetreotide-positive lesions 
 
Figure 6: 111In-pentetreotide example of Liver Lesions 
The same approach applies for 68Ga-Dotatate, and other 68Ga-labelled PET imaging agents as well 
as 64Cu-Dotatate: the lesions are identified by increased uptake compared to surrounding tissue. This 
evaluation should first be performed on 68Ga-Dotatate MIP image data (Figure 7), and axial views can 
be looked at for further details. 

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Figure 7: 68Ga-Dotatate MIP 
Examples can be found in Figure 7 (arrows indicate SSTR positive lesions) and Figure 8 (A: no lesion 
uptake; to be classified as SSTR negative, B and C: increased uptake; to be classified as SSTR 
positive). 
 
 
Figure 8: 68Ga-Dotatate examples. A) negative, B) and C) positive 
For 64Cu-Dotatate, an example can be found in Figure 9 showing multiple small liver metastases 
(>10), peritoneal solitary tumour mass, and 3 lymph node metastases shown on 64Cu-DOTATATE 
PET/CT in patient with pancreatic NET. All findings on PET were confirmed to be true-positive (Pfeiffer 
et al., 2015). Figure 10 shows an example of patient with intestinal NET and multiple metastases 
(Johnbeck et al., 2017). 

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Figure 9: 64Cu-Dotatate examples (B) 64Cu-DOTATATE maximum-intensity-projection image with arrows 
pointing at liver and lymph node metastases. Insert is fused PET/CT of peritoneal solitary tumour 
mass. (D) Axial CT and PET of liver revealing several small liver metastases. 
 
 
Figure 10: 64Cu-Dotatate example PET/CT (left) and PET (right) scans of patient with intestinal NET and 
multiple metastases. 
 
Detailed descriptions of the evaluation will be included in the Subject Imaging Manual. 

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Figure 5 and Figure 6 reference: IAEA 2013 - Includes bibliographical references. 1. Nuclear 
medicine. 2. Neuroendocrine tumors. 3. Radioisotopes -Therapeutic use. I. International Atomic 
Energy Agency. II. Series. 
Figure 7 reference: Bodei et al., 2017 
Figure 8 reference: Velikyan et al., 2014 
Figure 9 reference: Pfeiffer et al., 2015 
Figure 10 reference: Johnbeck et al., 2017