Conditions: Neuroendocrine Tumors
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 40
Healthy volunteers: no

Brief summary:
The purpose of this clinical phase I/II study was to investigate the safety and tolerability of satoreotide tetraxetan (177Lu-IPN01072, formerly known as 177Lu-OPS201) used for the treatment of patients with neuroendocrine tumors (NETs). The secondary objectives of this study were the assessment of biodistribution, dosimetry and preliminary efficacy of satoreotide tetraxetan.

Detailed description:

Arms:
arm 1: 177Lu-IPN01072 administered in 3 cycles at intervals of 8 weeks (+ up to 2 additional optional cycles)

Interventions: intervention 1: Satoreotide tetraxetan intervention 2: Amino acid solution intervention 3: Antiemetic
Intervention descriptions: intervention 1: Satoreotide tetraxetan administered in 3 cycles at intervals of 8 weeks (+ up to 2 additional optional cycles) intervention 2: Given as an auxiliary product the day of the IMP infusion for safety reasons to protect the renal function.

Centres can use their established amino acid infusion or Ipsen amino acid solution (auxiliary medical product OPS301) intervention 3: To counteract the known side effects of the amino acid infusion, such as nausea, dexamethasone (antiemetic) and as-required ondansetron will be administered 15 to 30 minutes before the start of the amino acid infusion (unless there are contraindications for these drugs).

Protocol document:
Prot_000.pdf: 
IPSEN GROUP 
OPS-C-001 / D-FR-01072-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 1 
 
PROTOCOL TITLE: AN INTERNATIONAL MULTI-CENTER, OPEN-LABEL STUDY 
TO EVALUATE SAFETY, TOLERABILITY, BIODISTRIBUTION, DOSIMETRY AND 
PRELIMINARY EFFICACY OF 177Lu-OPS201 FOR THE THERAPY OF 
SOMATOSTATIN RECEPTOR POSITIVE NEUROENDOCRINE TUMOURS (NETs) 
 
STUDY PROTOCOL 
STUDY number: OPS-C-001 / D-FR-01072-001 
 
177Lu-OPS201 
EudraCT number: 2015-002867-41 
ClinicalTrials.gov number: NCT02592707 
 
Version 10.0: 10 August 2020 
Study Sponsor: 
Ipsen Pharma 
65, quai Georges Gorse 
92100 Boulogne Billancourt 
France 
Tel: 
Fax:
Sponsor Signatory:  
 
Ipsen 
Taurusavenue 33b 
2132 LS Hoofddorp 
The Netherlands 
Tel: 
  
E-mail: 
 
Pharmacovigilance/Emergency Contact: 
 
ZI de Courtaboeuf - 5 avenue du Canada - 91940 Les Ulis - France 
Phone:  
 
 
Mobile:
 
The person listed above is medically qualified and designated by the sponsor as the first point of contact 
for emergency situations. 
For serious adverse events (SAEs) reporting: 
Email address (preferably):  
 
Fax:  
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the sponsor’s prior written 
authorisation. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


IPSEN GROUP 
OPS-C-001 / D-FR-01072-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 2 
 
INVESTIGATOR’S AGREEMENT 
 
Investigator Agreement and Signature: 
I have read and agree to Protocol OPS-C-001/D-FR-01072-001 entitled “an international 
multi-center, open-label study to evaluate safety, tolerability, biodistribution, dosimetry and 
preliminary efficacy of 177Lu-OPS201 for the therapy of somatostatin receptor positive 
neuroendocrine tumours (NETs)” with Amendment 10.0. I am aware of my responsibilities as 
an investigator under the guidelines of Good Clinical Practice (GCP), local regulations (as 
applicable) and the study protocol. I agree to conduct the study according to these guidelines 
and to appropriately direct and assist the staff under my control, who will be involved in the 
study. 
 
NAME:  
 
TITLE: 
PRINCIPAL 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
OFFICE: 
 
 
Sponsor's Representative Signature:  
NAME: 
 
 
TITLE: 
 
 IpsenSIGNATURE: 
 
DATE: 
OFFICE: 
Ipsen 
 
Taurusavenue 33b 
 
2132 LS Hoofddorp 
 
The Netherlands 
 
 
Tel: 
 
 
E-mail:
 
PPD
PPD
PPD
PPD


IPSEN GROUP 
OPS-C-001 / D-FR-01072-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 3 
 
COORDINATING INVESTIGATOR’S AGREEMENT 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol OPS-C-001/D-FR-01072-001 entitled “an international 
multi-center, open-label study to evaluate safety, tolerability, biodistribution, dosimetry and 
preliminary efficacy of 177Lu-OPS201 for the therapy of somatostatin receptor positive 
neuroendocrine tumours (NETs)” with Amendment 10.0. I am aware of my responsibilities as 
a coordinating investigator under the guidelines of Good Clinical Practice (GCP), local 
regulations (as applicable) and the study protocol. I agree to conduct the study according to 
these guidelines and to appropriately direct and assist the staff under my control, who will be 
involved in the study. 
 
NAME: 
 
TITLE: 
COORDINATING 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
OFFICE: 
 
 
Petersgraben 4 
 
CH-4031 Basel 
 
Switzerland 
 
Phone:
 
 
E-mail:
 
PPD
PPD
PPD
PPD


IPSEN GROUP 
OPS-C-001 / D-FR-01072-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 4 
 
SUMMARY OF CHANGES 
The current version of the protocol was released on 10 August 2020 and includes 
Amendment 10.0. For all protocol amendments, amendment forms were prepared and are 
provided in the appendices listed in Table 1. All modifications (except minor changes) are 
presented in the appendices. 
Table 1 
List of Protocol Amendments 
Version number 
Release date 
Amendment form 
3 
29 April 2016 
Appendix 6 
4 
04 October 2016 
Appendix 7 
5 
03 November 2017 
Appendix 8 
6 
27 February 2018 
Appendix 9 
7 
24 July 2018 
Appendix 10 
8 
07 May 2019 
Appendix 11 
9 
13 August 2019 
Appendix 12 
10 
10 August 2020 
Appendix 13 
 


IPSEN GROUP 
OPS-C-001 / D-FR-01072-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 5 
 
SYNOPSIS 
Name of sponsor/company: IPSEN PHARMA 
Name of finished product: 177Lu-OPS201 - 177Lu-satoreotide tetraxetan  
Name of active ingredient(s): 177Lu-OPS201 - INN for OPS201 is satoreotide tetraxetan 
Title of study: An International Multi-Center, Open-Label Study to Evaluate Safety, 
Tolerability, Biodistribution, Dosimetry and Preliminary Efficacy of 177Lu-OPS201 for the 
Therapy of Somatostatin Receptor Positive Neuroendocrine Tumours (NETs) 
Study number: OPS-C-001 / D-FR-01072-001 
Number of planned centres: 20 
Planned study period: 
January 2016 to November 2022 
Phase of development: 
Phase I/II 
Study type: Interventional, open-label, safety, tolerability, biodistribution, dosimetry and
preliminary efficacy study 
Objectives: 
Primary study objective: 
To assess the safety and tolerability of peptide receptor radionuclide therapy (PRRT) with 
177Lu-OPS201 administered in three cycles in subjects with somatostatin receptor (sstr)2 
positive NETs (including phaechromocytomas and paragangliomas). 
Secondary study objectives 
• 
To evaluate the optimal radioactivity and peptide mass dose to be used in future studies 
• 
To characterise 177Lu-OPS201 whole body biodistribution and pharmacokinetics (PK) 
of the radiopharmaceutical after each administration of 177Lu-OPS201. 
• 
To determine the radiation dosimetry of 177Lu-OPS201 (organ exposure to administered 
radioactivity) after each administration of 177Lu-OPS201 with three different peptide 
mass doses. 
• 
To undertake a preliminary assessment of the therapeutic efficacy of 177Lu-OPS201 
PRRT by determination of RECIST (Response Evaluation Criteria in Solid Tumours) 
(version) v1.1 status.  
• 
To evaluate the influence of 177Lu-OPS201 PRRT on the subject’s quality of life. 
Exploratory study objectives 
 
• 
To determine the PK of OPS201 in plasma and urine. 
 
 
CCI
CCI


IPSEN GROUP 
OPS-C-001 / D-FR-01072-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 6 
 
 
Study hypotheses: 177Lu-OPS201 will be sufficiently safe to permit further clinical 
investigation when administered in previously treated subjects with unresectable 
gastroenteropancreatic 
(GEP) 
NETs, 
lung 
NETs 
and 
malignant, 
unresectable
pheochromocytoma or paraganglioma. 
Increase of peptide mass doses leads to improved tumour to background ratio for 177Lu-OPS201 
with a possible positive impact on the safety profile  
Methodology:  
NOTE: the study medication (OPS201), and all the biosamples (including blood, urine and 
biopsy material taken on study) are all radioactive and all due precautions are to be taken to 
protect subjects, study staff, persons preparing, transporting or analysing materials and 
members of the public. 
This is a multi-centre, open-label study to evaluate the safety and tolerability of 177Lu-OPS201 
for the treatment of NETs. 
In total, up to 55 subjects with histologically confirmed NETs and a positive somatostatin 
receptor scan (SRS) will receive three administrations of 177Lu-OPS201 at 8-week intervals 
(+2 weeks, or up to +4 weeks in case of adverse events (AEs) which have not adequately 
recovered). The study will be performed in two parts (Part A and Part B) and has a safety review 
committee (SRC, Part A) and a data review board (DRB, Part B). In Part B, up to two additional 
cycles of 177Lu-OPS201 can be administered if the subject continues to meet the  criteria 
outlined in Section 6.4.2 and the subject has clinical benefit (defined as complete response 
(CR), partial response (PR) or stable disease (SD)). The additional cycles are optional and must 
be discussed with the sponsor before administration. 
Subjects will be recruited at the participating study centres specialised in the diagnosis and 
treatment of NETs. For each cycle, subjects will attend the following visits (Figure 1): 
• 
Screening Visit: Up to 4 weeks before the first administration of 177Lu-OPS201, subjects 
who provided signed informed consent will undergo a Screening Visit to check eligibility 
criteria. A contrast enhanced computed tomography (CT)/magnetic resonance imaging 
(MRI) scan will be performed as well as a screening SRS (unless the latter has already 
been performed within 6 months of Visit 1 Day 1). Eligibility read for SRS and CT/MRI 
scan will be performed locally at screening. However, all images, including SRS, will be 
sent to the imaging core laboratory for later evaluation. 
Part A 
• 
Visit 1: On Visit 1 Day 1, subjects will receive the first administration of 177Lu-OPS201 
followed by safety and extended dosimetry evaluations over 8 days, with additional 
laboratory safety tests repeated at Day 15 (±2 days). At 4 weeks (±5 days) after Visit 1 
Day 1 (i.e. Follow-up Visit 1), the safety of the subjects will be assessed.  
• 
Visit 2: 8 weeks after Visit 1 Day 1 (+2 weeks or plus up to 4 weeks in case of AEs 
which have not adequately recovered) subjects will receive the second administration of 
177Lu-OPS201 followed by safety and dosimetry evaluations over 8 days, with additional 
laboratory safety tests repeated at Day 15 (±2 days). At 4 weeks (±5 days) after Visit 2 
Day 1 (Follow-up Visit 2), the safety of the subjects will be assessed. Additionally, 
subjects will receive a CT/MRI scan to monitor the RECIST v1.1 status and tumour 
volume changes.  
• 
Visit 3: 8 weeks after Visit 2 Day 1 (+2 weeks or plus up to 4 weeks in case of AEs 
which have not adequately recovered) subjects will receive the third administration of 
CCI


IPSEN GROUP 
OPS-C-001 / D-FR-01072-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 7 
 
177Lu-OPS201 followed by safety and dosimetry evaluations over 8 days, with additional 
laboratory safety tests repeated at Day 15 (±2 days). At 4 weeks (±5 days) after Visit 3 
Day 1 (Follow-up Visit 3), the safety of the subjects will be assessed.  
• 
EOCT Visit: 8 weeks (±5 days) after Visit 3 Day 1, the safety and efficacy of the 
treatment will be evaluated. Subjects enrolled in Part A after the protocol version 6.0 
comes into effect will receive a CT/MRI scan to monitor the RECIST v1.1 status and 
tumour volume. CT/MRI scan images will be sent to the imaging core laboratory for 
later evaluation. 
Part B 
• 
Visit 1: On Visit 1 Day 1, subjects will receive the first administration of 177Lu-OPS201 
followed by safety and extended dosimetry evaluations over 8 days, with additional 
laboratory safety tests repeated at Day 15 (±2 days). At Week 4 (Day 29±5 days), Week 6
(Day 42±5 days) (i.e. Follow-up Visit 1) and at intermediate timepoints, the safety of the
subjects will be assessed.  
• 
Visit 2: 8 weeks after Visit 1 Day 1 (+2 weeks or up to +4 weeks in case of AEs which 
have not adequately recovered) subjects will receive a CT/MRI scan to monitor the 
RECIST v1.1 status and tumour volume. Subjects will then receive the second 
administration of 177Lu-OPS201 followed by safety and dosimetry evaluations over 
8 days, with additional laboratory safety tests repeated at Day 15 (±2 days). At Week 4 
(Day 29±5 days), Week 6 (Day 42±5 days) (Follow-up Visit 2) and at intermediate 
timepoints, the safety of the subjects will be assessed.  
• 
Visit 3: 8 weeks after Visit 2 Day 1 (+2 weeks or up to +4 weeks in case of AEs which 
have not adequately recovered) subjects will receive a CT/MRI scan to monitor the 
RECIST v1.1 status and tumour volume. Subjects will then receive the third 
administration of 177Lu-OPS201 followed by safety and dosimetry evaluations over 
8 days, with additional laboratory safety tests repeated at Day 15 (±2 days). At Week 4 
(Day 29±5 days), Week 6 (Day 42±5 days) (Follow-up Visit 3) and at intermediate 
timepoints, the safety of the subjects will be assessed. 
• 
End of Core Trial (EOCT) Visit: 8 weeks (±5 days) after Visit 3 Day 1, the safety and 
efficacy of the treatment will be evaluated. Subjects will receive a CT/MRI scan to 
monitor the RECIST v1.1 status and tumour volume. 
In case of additional cycles administration, subjects will have the same safety and dosimetry 
follow-up as during the core treatment cycles and up to the end of additional cycles (EOAC) or 
early withdrawal (EW). Subjects who are to receive additional cycles of therapy will undergo 
the EOCT assessment after Cycle 3. Where possible, the EOCT Visit and Visit 4, Day 1 
(additional cycle) can be combined. An additional EOAC assessment will be done 8 weeks 
after the last dose of therapy. 
The long-term follow-up period will start after the EOCT/EOAC/EW Visit. Long-term efficacy 
follow-up will be assessed every 3 months (±2 weeks) until whichever occurs first: documented 
disease progression (radiological or  clinical as per the investigator's judgment), 2 years after 
the EOCT/EOAC/EW Visit, withdrawal of consent, lost to follow-up or death. Long-term 
safety follow-up will continue every 3 months (±2 weeks) until whichever occurs first: 2 years 
after the EOCT/EOAC/EW Visit, withdrawal of consent, lost to follow-up or death.  
After the long-term follow-up period is completed, all subjects will be invited to participate in 
a safety surveillance study. 


IPSEN GROUP
OPS-C-001 / D-FR-01072-001
CONFIDENTIAL
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020
PAGE 8
Figure 1
Overview of Study Design for Part A and Part B and Post Study Follow-up
EOCT=end of core trial; W=weeks; *only for Part B
Part A and Part B of the Phase I study
The study will be performed in two parts: 
•
In Part A, it is planned to treat up to 15 subjects with three cycles of 4.5 GBq 
177Lu-OPS201. An SRC will decide, based on the dosimetry and safety data of the initial 
three and then six subjects, if the remaining nine subjects will continue at the same 
radioactivity level or if the radioactivity has to be adapted. Alternatively, Part A can be 
closed and Part B initiated. 
•
As a radioactivity and peptide mass dose escalation are planned in Part B, up to 
40 subjects are planned to be treated. The Part A SRC will decide, based on safety and 
dosimetry data from Part A, if a radioactivity and/or peptide dose escalation in Part B is
applicable or if the radioactivity has to be adapted (this can be higher/lower than 4.5 GBq 
or maintained at the same dose, but not exceeding 7.4 GBq per dose). In Part B, the 
objective of the DRB is to review the safety and radiation exposure data and decide 
whether to proceed with the enrolment of the next cohort dose level and the cumulative 
radioactivity within a cohort (see Appendix 3). Each dose escalation (both peptide and 
radioactivity) will be evaluated by the DRB as detailed in Appendix 3. As new safety 
and dosimetry information becomes available in other cohorts, this data will be used to 
evaluate the on-going cohorts and the subject dosing within the cohorts.
The estimated core trial duration of Part A is 18 to 21 months (for all subjects) including 6 to
10 months of treatment for a single subject, whereas the long-term follow-up will last for up to 
2 years after the EOCT/EW Visit. The estimated core trial duration of Part B is 14 to 20 months 
(for all subjects) including 6 to 10 months of treatment for a single subject, whereas the
long-term follow-up will last for up to 2 years after the EOCT/EOAC/EW Visit. 
Cohorts, dose(s) and route of administration
Part A: 
Initially, six subjects will be treated in Part A. Each subject will receive three cycles of 4.5 GBq
(target radioactivity of 4.5 GBq±10%) 177Lu-OPS201 (target peptide mass dose of 300±50 g),
8 weeks apart (+2 weeks, or up to +4 weeks in case of AEs which have not adequately 
recovered).
An SRC meeting will be held before exposing the remaining nine subjects in Part A to the entire
number of planned administrations. Safety and dosimetry data from the first six subjects (data 


IPSEN GROUP 
OPS-C-001 / D-FR-01072-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 9 
 
obtained up to 8 weeks after the last administration for each subject) will be evaluated during 
this SRC. 
Dose limiting toxicity (DLT) definition in Part A: investigational radiopharmaceutical product
(IRPP) related AEs with a severity of Grade 3 or higher are considered DLTs, with the 
exception of hair loss, lymphopenia, nonfebrile neutropenia lasting <4 weeks and 
thrombocytopenia lasting <4 weeks.  
• 
If DLTs occur in 33% of subjects, the remaining nine subjects will continue at the same 
radioactivity level. 
• 
If DLTs occur in >33% of subjects, the administered radioactivity will be reduced to a 
cumulative radioactivity which did not lead to DLT occurrence with this frequency, e.g. 
the number of administrations will be reduced from three to two. 
After treatment completion of the sixth subject (Part A), the SRC will decide, based on the 
safety and dosimetry data from Part A, if a radioactivity escalation is applicable in Part B.  
Part B: 
Part B will encompass radioactivity and peptide mass dose escalation as well as intra-individual 
peptide mass dose evaluation. It consists of up to eight cohorts characterised as shown in 
Table 2. 
Table 2 
Radioactivity and Peptide Mass Dose in Each Cohort and Cycle 
Cohorts 
Planned dose escalation 
Nominal OPS201 dose 
per cycle (g) 
OPS201 range per 
cycle (g) [a] 
Nominal radioactivity 
and range 
(GBq) 
Cumulative 
radioactivity 
(3 cycles, GBq) 
1 
300 
[250 to 350] 
6.0±10% 
18.0 
2 [b] 
300 
[250 to 350] 
7.4±10% 
22.2 
3 
300 (Cycle 1) 
700 (Cycle 2) 
300 (Cycle 3) 
300 (Cycles 4 and 5)[c] 
[250 to 350]  
[550 to 850] 
[250 to 350] 
[250 to 350]  
4.5±10% 
13.5 
4 
700 
[550 to 850] 
6.0±10% 
18.0 
5 
700 
[550 to 850] 
7.4±10%  
22.2 
6 
300 (Cycle 1) 
1300 (Cycle 2) 
300 (Cycle 3) 
300 (Cycles 4 and 5)[c] 
[250 to 350]  
[1100 to 1500] 
[250 to 350] 
[250 to 350] 
4.5±10% 
13.5 
7 [b] 
1300 
[1100 to 1500] 
6.0±10% 
18.0 
8 [b] 
1300 
[1100 to 1500] 
7.4±10% 
22.2 
C=cycle; GBq=gigaBecquerel; IRPP=investigational radiopharmaceutical product. 
a 
IRPP will be provided either through local or centralised manufacturing. OPS201 ranges include the ranges validated 
for local IRPP manufacturing in radiopharmacy of selected centres and the general validated range for centralised IRPP 
manufacturing (i.e. nominal OPS201 dose±15%). 
b optional. 
c    For additional cycles, if any. 
The schema for the dosing and cohorts in Part B is shown in Figure 2.  
In each cohort, each subject will receive three cycles of the defined radioactivity and peptide 
mass dose of 177Lu-OPS201. Each cycle will be 8 (+2) weeks apart. In case of AEs which are 
not adequately recovered, a further 4 weeks can be added between dosing.  
After the three core-treatment cycles, up to two additional cycles of 177Lu-OPS201 can be 
administered if the subject continues to meet the  criteria outlined in Section 6.4.2 and the
subject has clinical benefit (defined as CR, PR or SD). The additional cycles are optional and 
must be discussed with the sponsor before administration. 


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OPS-C-001 / D-FR-01072-001 
 
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PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 10 
 
The population of Cohorts 3 and 6 will enrol eight to 10 subjects to ensure a minimum of eight
completed subjects. All remaining Cohorts (1, 2, 4, 5, 7 and 8) will enrol three to five subjects 
to ensure a minimum of three completed subjects per cohort. A completed subject is defined as 
one who has received at least 3 cycles of study treatment or fewer than 3 cycles if one of the 
following has occurred: exceedance of organ dose limits, treatment-related safety issues or 
disease progression.  
Figure 2 Study Design - Part B 
 
DRB=data review board; GBq=gigaBecquerel; SRC=safety review committee. 
Priority for the conduct of the cohorts is as follows: Cohorts 1 and 3, Cohort 6, Cohort 4, Cohort 5. Each cohort consists of 
three cycles of treatment. Cohort 2 will not be conducted if 700 ȝg or 1300 ȝg peptide mass is shown to be optimal. Cohorts 7 
and 8 will not be conducted if 1300 g peptide mass is seen to be too high. Cohorts 3 and 6 require 10 subjects for eight to be 
completed. All other cohorts are three to five subjects (minimum of three subjects to be completed). 
Radioactivity evaluation (Part A) 
In Part A, a cumulative radioactivity of 13.5 GBq (4.5 GBq/cycle × three cycles) with a peptide 
mass dose of 300 g will be evaluated (Table 2).  
In Part B, the radioactivity and peptide mass dosing for each cycle in each cohort is illustrated
in Table 2.  
Radioactivity escalation (Cohorts 1 and 2 – Part B) 
Cohort 1 will investigate a radioactivity of 6 GBq/cycle (cumulative radioactivity 18 GBq) with 
the same peptide mass dose as in Part A (300 g) for three cycles (Table 2).  
Once the third subject of Cohort 1 has completed at least two cycles, if no safety signal is 
observed and if the subjects did not reach the cumulative absorbed dose in each of the target 


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CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 11 
 
organs, Cohort 2 (300 g; 7.4 GBq/cycle; cumulative 22.2 GBq; Table 2) will be initiated (see 
priority classification in Figure 2). However, if improved safety regarding DLTs is seen with 
increased peptide mass, Cohort 2 (300 g; 7.4 GBq/cycle; cumulative 22.2 GBq) may be 
delayed until experience is gained with the 7.4 GBq dose at the higher peptide mass (700 g).
If optimal peptide mass is evaluated to be >300 g then this cohort will not be opened. 
Intra-individual peptide mass dose evaluation (Cohorts 3 and 6 – Part B) 
Cohorts 3 and 6 will allow the intra-individual evaluation of peptide mass. In both Cohorts 3 
and 6, subjects will receive the same cumulative radioactivity as in Part A (4.5 GBq/cycle; 
cumulative, 13.5 GBq; Table 2). The associated peptide mass dose will also be the same 
(300 g) in Cycles 1 and 3, and will be increased to 700 g in Cohort 3 and 1300 g in Cohort 6 
during Cycle 2.  
Peptide mass dose escalation (Cohorts 4 and 5 and optional Cohorts 7 and 8 – Part B) 
In Cohort 4, subjects will receive 6 GBq/cycle (cumulative 18 GBq) with a peptide mass dose 
of 700 g, for three cycles (Table 2). After one cycle, if no safety signal is observed in Cohort 4,
Cohort 5 will be initiated. In Cohort 5, subjects will receive 7.4 GBq/cycle (cumulative, 22.2 
GBq) with a peptide masse dose of 700 g, for three cycles (Table 2). 
Cohorts 7 and 8 will be cancelled if ssr2 saturation is seen with peptide mass dose of 700g 
and 1300 g in Cohort 3 or 6 and/or if there are other safety signals (Table 2). There will be no 
further dose escalation of OPS201 peptide after 1300 g. 
The dose escalation rules 
The DRB will consist of a team of “permanent” decision makers (the core team), including 
selected principal investigators and Ipsen personnel. All final decisions will be made by the 
core team. The number of DRB meetings may change as needed and the DRB can be called 
upon rapidly if there is a safety issue of concern in a cohort. The aim is to have all meetings via
conference call, but if the timing does not allow for this, then the meeting can be conducted via 
email exchange or two conference calls with split attendees. A DRB charter will be developed 
with further details. Ad-hoc DRBs can be convened at any time during the trial. 
Dose escalation (peptide mass dose and radioactivity, see Figure 2) will primarily be decided 
based on the clinical and safety data of the subjects.  
DLT definition in Part B: IRPP related AEs with a severity of Grade 3 or higher are considered 
DLTs, with the exception of hair loss, lymphopenia, nonfebrile neutropenia lasting <4 weeks 
and thrombocytopenia lasting <4 weeks.  
Proceeding to the next cohort will be determined by the following DLT rules based on three 
evaluable subjects: 
• 
if DLTs occur in >33% of subjects in the cohort, the next cohort will not be initiated. 
• 
if DLTs occur in 33% and 2 of the three subjects have a cumulative absorbed dose in 
each target organ exceeding the acceptability limits (1.5 Gy in bone marrow (BM) and 
23 Gy in kidney), subjects in the next cohort will receive the same cumulative 
radioactivity or less than in the preceding cohort.  
• 
if DLTs occur in 33%, and <2 of the three subjects did not reach the cumulative 
absorbed dose in each target organ (1.5 Gy in BM and 23 Gy in kidney), the next cohort 
will be initiated as planned. 
Each dose escalation (both peptide and radioactivity) will be carefully evaluated by the DRB. 
As safety and dosimetry information becomes available in other cohorts, this data will be used 
to evaluate the on-going cohorts and the subjects’ dosing within the cohorts.  


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OPS-C-001 / D-FR-01072-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 12 
 
The DRB can make a recommendation as to the radioactivity dosing for the next cohort. This 
could include continuing the current cohort to complete five subjects for review. Based on the 
overall safety results, the DRB can also decide to start earlier or delay cohorts depending on 
the information available. Notification will be given to the principal investigators if this is to 
occur, with the rationale, as well as to the institutional review board (IRB)/ethics committee 
(EC). 
Number of subjects planned:  
Up to 55 subjects with histologically confirmed diagnosis of GEP NETs, lung NETs or 
pheochromocytoma or paraganglioma will be recruited in the trial: 
• 
Part A: a minimum of six subjects and up to 15 subjects. 
• 
Part B: a minimum of 25 subjects and up to 40 subjects.  
For Part B dose escalation, it is anticipated that approximately 40 subjects will be included, in 
up to eight escalation steps (cohorts). Three to five subjects will be treated per cohort in order 
to yield a minimum of three completed subjects for three cycles of treatment. For Cohorts 3 
and 6, eight to 10 subjects will be treated per cohort to yield a minimum of eight completed 
subjects. Any cohort can be closed for safety issues before all the subjects are completed. 
Diagnosis and criteria for inclusion:  
Inclusion criteria: 
(1) 
Written informed consent. 
(2) 
Subjects of either gender, aged 18 years. 
(3) 
Women of childbearing potential (not surgically sterile or less than 2 years 
postmenopausal) must use a medically accepted method of contraception and must agree 
to continue use of this method for the duration of the study and for 6 months after the 
last dose. Acceptable methods of contraception include abstinence, or double 
contraception: steroidal contraceptive (oral, transdermal, implanted, and injected) in 
conjunction with a barrier method (intrauterine device, condom, etc.). 
(4) 
Male subjects must use a medically accepted method of contraception and must agree to 
continue the use of this method for the duration of the study and for 6 months after the 
last radioactivity administration. 
(5) 
Karnofsky performance score 60. 
(6) 
Life expectancy of at least 6 months. 
(7) 
Histologically confirmed diagnosis of: 
• 
unresectable GEP NET (Grade I and Grade II according to World Health 
Organization (WHO) classification (2010, see Annex 01), functioning and 
nonfunctioning). 
• 
unresectable “typical lung carcinoid” or “atypical lung carcinoid” are acceptable 
(with the exception of Large Cell Bronchial Neuroendocrine Neoplasms and 
Small Cell Lung Cancers) (Caplin 2015). 
• 
malignant, unresectable pheochromocytoma or paraganglioma. 
- 
subjects, who have histologically confirmed NET, but no clear localisation 
of their primary tumour, can be included. 
(8) 
Documentation of progressive disease (PD) based on RECIST v1.1 under prior 
antitumour therapy within 6 months of Visit 1 Day 1 (although the progression might 
have occurred more than 6 months before Visit 1 Day1). Subjects should not have 


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received further antitumour therapy once disease progression is documented. All images 
should be sent to the imaging core laboratory. 
(9) 
In countries where sunitinib or everolimus are marketed, subjects with GEP NET and 
lung NET will be progressive under this prior antitumour treatment for the respective 
indication. Subjects not suitable for everolimus/sunitinib therapy according to a tumour 
board decision (or comparable local practice) may also be enrolled into the study. 
Subjects having everolimus/sunitinib therapy should have a wash-out phase of 4 weeks 
before the first treatment. 
(10) Measurable disease based on RECIST v1.1.: 
(11) For Part A: Confirmed presence of sstr on technically evaluable tumour lesions 
documented by a positive SRS*. If this has not been performed within 6 months of 
Visit 1 Day 1, then it must be repeated during screening 
* presence of at least one lesion that is 20 mm in the longest dimension (as measured 
on correlative CT or MRI scan) and with a maximum standardised uptake value 
(SUVmax) of 2 × the SUVmean of the liver background on 68Ga-positron-emission 
tomography (PET) imaging or a score of “3” or “4” according to the Krenning scale on
single photon emission computed tomography (SPECT) imaging.  
For Part B: Confirmed presence of sstr on technically evaluable tumour lesions 
documented by a positive SRS*. If this has not been performed within 6 months of 
Visit 1 Day 1, then it must be repeated during screening. 
*presence of at least two lesions that are 20 mm in the longest dimension (as measured 
on correlative CT or MRI scan) with an SUVmax of 2× the SUVmean of the liver
background on 68Ga-PET imaging or a score of “3” or “4” according to the Krenning 
scale on SPECT imaging. 
(12) Calculated glomerular filtration rate (GFR) 55 mL/min. 
(13) Blood test results as follows: 
• 
Leukocytes: 4*109/L. 
• 
Erythrocytes: 3.5*1012/L  
• 
Platelets: 100*109/L  
• 
Albumin: >30 g/L. 
• 
Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase: 
5 times upper limit of normal (ULN). 
• 
Bilirubin: 2 times ULN (2×1.1 mg/dL). 
Exclusion criteria: 
Eligible subjects must not have any of the following conditions: 
(1) 
Known hypersensitivity to 177Lu, DOTA, JR11 or to any of the excipients of 
177Lu-OPS201.  
(2) 
Any previous PRRT. 
(3) 
Diagnosis of thymic NET. 
(4) 
Presence of active infection at screening, or history of serious infection within the 
previous 6 weeks. 
(5) 
Administration of any other investigational medicinal product (IMP) within 60 days 
prior to entry (Visit 1 Day 1). 


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(6) 
Prior or planned administration of a therapeutic radiopharmaceutical within 8 half-lives
of the radionuclide including any time during the current study. 
(7) 
Any extensive radiotherapy 3 months before first IRPP administration. 
(8) 
Chemotherapy 3 months before first IRPP administration. 
(9) 
For Part B: Nephrectomy, renal transplant or concomitant nephrotoxic therapy putting 
the subject at high risk of renal toxicity during the study as assessed by the investigator.
(10a) Pregnant or breast-feeding women. A serum pregnancy test will be performed at the start
of the study for all female subjects of childbearing potential (i.e. not surgically sterile or
up to 2 years postmenopausal). 
(11) Any uncontrolled significant medical, psychiatric or surgical condition (active infection 
(including subject with known hepatitis B or hepatitis C and subjects with known human 
immunodeficiency virus (HIV) positive), unstable angina pectoris, cardiac arrhythmia, 
poorly controlled hypertension, poorly controlled diabetes mellitus (glycated 
haemoglobin (HbA1c) 9%), uncontrolled congestive heart disease, etc.) or laboratory 
findings that, in the opinion of the investigator, might jeopardise the subject's safety or 
that would limit compliance with the objectives and assessments of the study. Note: the 
subject should be able to tolerate high volume load. 
(12) Current history of any malignancy other than NET within 5 years of enrolment except 
for fully-resected non-melanoma skin cancer or cervical cancer in situ. 
(13) Any mental condition rendering the subject unable to understand the nature, scope and 
possible consequences of the study, and/or evidence of an uncooperative attitude. 
Test product, dose, mode of administration: 
Investigational radiopharmaceutical product (IRPP), 177Lu-OPS201:  
177Lu-OPS201 is a therapeutic radiopharmaceutical product with three main components, 
namely (a) 177Lutetium (177Lu), a ȕ- and Ȗ- emitting radionuclide with a half-life of 6.65 days; 
(b) DOTA, (international nonproprietary name: tetraxetan) a chemical chelator group; and (c) 
JR11, an antagonistic somatostatin analogue which binds to sstr2 on NET cells 
(OPS201=DOTA-JR11). All doses are presented as a sterile aqueous solution, equivalent to the 
respective dose of radioactivity, for intravenous (i.v.) infusion.  
Therapeutic administrations: 
At each PRRT cycle (Visits 1 to 3 and additional cycles, if any) the study medication will be 
administered after the conduct of a safety examination of the subject. The IRPP (20 mL of 
177Lu-OPS201) will be administered by an i.v. infusion at a rate of 10 mL/h over 120 minutes. 
Infusion rate modification (up or down) would be under the investigator’s judgement and may 
be temporarily halted or even further slowed down if the subject does not tolerate the IRPP 
infusion. The overall infusion duration should not exceed 4 hours.  
Note: Prior to adoption of the protocol version 8.0, infusion was to be administered over 30 to 
60 minutes.  
Prophylaxis may be considered if the subject is thought to be at increased risk of 
infusion-related reactions as per the site’s standard of care. Appropriate treatment should be 
administered should an infusion-related reaction occur including somatostatin analogues. At 
any time, if infusion-related reactions are encountered, the infusion should be slowed or 
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Duration of treatment: 
The estimated core trial duration of Part A is 18 to 21 months (for all subjects) including 6 to
10 months of treatment for a single subject, while the long-term follow-up will last for up to 
2 years after the EOCT/EW Visit. The estimated core trial duration of Part B is 14 to 20 months 
(for all subjects) including 6 to 10 months of treatment for a single subject, while the long-term
follow-up will last for up to 2 years after the EOCT/EOAC/EW Visit. After the long-term
follow-up period is completed, all subjects will be invited to participate in a safety surveillance 
study. 
Reference therapy, dose and mode of administration:  
Not applicable 
Criteria for evaluation (endpoints): 
Safety endpoints 
• 
Frequency and/or descriptive summaries of standard safety and tolerability parameters: 
AEs (including SAEs) according to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 and vital signs, laboratory tests 
(haematology, biochemistry and urinalysis, and pituitary markers), 12-lead and Holter 
electrocardiogram (ECG), DLTs, physical examination results and use of concomitant 
medication throughout the study 
Biodistribution and radioactive PK of the radiopharmaceutical endpoints 
• 
Maximal uptake (%) at the target lesions 
• 
Maximal uptake (%) in discernible organs and blood 
• 
Area under the curve (AUC) of 177Lu-OPS201 in discernible thoracic and abdominal 
organs, target lesions and blood 
• 
Terminal half-life of radioactivity concentrations of the radiopharmaceutical in blood 
Radiation dosimetry endpoints  
• 
Organs receiving the highest absorbed dose  
• 
Specific absorbed dose to the target lesion (Gy/GBq) 
• 
Specific absorbed dose per organ (Gy/GBq) 
• 
Cumulative absorbed organ doses (Gy) 
OPS201 PK endpoints 
• 
If OPS201 levels are measurable in plasma and urine, PK parameters of OPS201 
(including, but not limited to, maximum observed concentration (Cmax), AUC, 
elimination half-life (t1/2), apparent total body clearance of the drug from plasma (CL), 
apparent volume of distribution (Vd), cumulative amount of unchanged drug excreted 
into the urine (Ae), renal clearance of the drug from plasma (CLR)) will be derived using
the noncompartmental approach on the individual plasma concentration-time profiles of 
OPS201 and on the individual urine concentrations. 
 
 
Secondary efficacy endpoints 
The following secondary efficacy variables will be assessed:  
• 
Objective tumour response based on RECIST v1.1 (CT/MRI scan) by calculating best 
overall response (BOR), overall response rate (ORR) and disease control rate (DCR) 
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• 
Progression free survival (PFS) based on RECIST v1.1  
Influence of 177Lu-OPS201 PRRT on the Quality of Life of the Subjects 
• 
Quality of Life Questionnaire ((QLQ)-C30; GI.NET21) change from baseline to EOCT 
 
 
 
 
 
 
 
 
 
 
Statistical methods: 
All data will be analysed by descriptive statistical methods, as follows: 
Primary variable (safety and tolerability)  
Frequency and/or descriptive summaries of abnormal findings in physical examination, vital 
signs, ECG (12-lead and Holter), and clinical laboratory parameters; reports of SAEs and AEs 
will be summarised by severity and relationship; frequency and type of DLTs; use of 
concomitant medications. 
Secondary variables 
(a) 
Biodistribution and PK of the radiopharmaceutical:  
• 
Maximal uptake (%) at the target lesion 
• 
Maximal uptake (%) in discernible organs and blood 
• 
AUC of 177Lu-OPS201 in discernible thoracic and abdominal organs, target lesion 
and blood 
• 
Terminal half-life of radioactivity concentrations of the radiopharmaceutical in 
blood 
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(b) 
Radiation dosimetry:  
• 
Organs receiving the highest absorbed dose 
• 
Specific absorbed dose to the target lesion (Gy/GBq) 
• 
Specific absorbed dose per organ (Gy/GBq) 
• 
Cumulative absorbed organ doses (Gy) 
(c) 
Pharmacokinetics: 
• 
If OPS201 levels are measurable in plasma and/or urine, PK parameters of 
OPS201 (including, but not limited to, Cmax, AUC, t1/2, CL, Vd, Ae and CLR) will 
be derived using a non-compartmental approach 
(d) 
Efficacy (tumour response): 
• 
Objective tumour response based on RECIST v1.1 (CT/MRI scan) by calculating
BOR, ORR and DCR 
• 
PFS based on RECIST v1.1  
(e) 
Influence of 177Lu-OPS201 PRRT on the quality of life: 
• 
Quality of Life Questionnaire (QLQ-C30; GI.NET21) 
 
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TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...................................................................................... 2 
COORDINATING INVESTIGATOR’S AGREEMENT..................................................... 3 
SUMMARY OF CHANGES ................................................................................................... 4 
SYNOPSIS ................................................................................................................................ 5 
LIST OF ABBREVIATIONS ................................................................................................ 26 
1 
BACKGROUND INFORMATION ............................................................................ 31 
1.1 
Introduction ................................................................................................................... 31 
1.1.1 
Gastroenteropancreatic Neuroendocrine Tumours (GEP NETs) ............ 31 
1.1.2 
Lung Neuroendocrine Tumours ................................................................. 31 
1.1.3 
Pheochromocytoma-Paraganglioma .......................................................... 32 
1.1.4 
Somatostatin Analogues ............................................................................. 33 
1.1.5 
Radiolabelled Somatostatin Analogues ...................................................... 33 
1.1.6 
Antagonistic Somatostatin Analogues ........................................................ 33 
1.2 
General Considerations for 177Lu-OPS201 ................................................................. 34 
1.2.1 
Chemical Name: .......................................................................................... 35 
1.2.2 
Chemical Structure: .................................................................................... 35 
1.3 
Previous Experience with Study Drug ........................................................................ 36 
1.3.1 
Preclinical Studies ....................................................................................... 36 
1.3.1.1 
Antagonistic Behaviour – Internalisation and Calcium Release ................. 36 
1.3.1.2 
Somatostatin Receptor 2 Binding ................................................................. 36 
1.3.2 
Preclinical In Vivo Results ......................................................................... 37 
1.3.2.1 
Biodistribution ............................................................................................. 37 
1.3.2.2 
In Vivo Pharmacology, Activity on Tumour Growth in an SCLC Model .... 39 
1.3.3 
Nonclinical Safety (Toxicity Test) of OPS201 ........................................... 39 
1.3.4 
Dosimetry in Pigs ........................................................................................ 40 
1.3.5 
Previous Human Exposure: Academic Pilot Study ................................... 42 
1.3.6 
Adverse Effects ............................................................................................ 42 
1.3.6.1 
Acute Reaction ............................................................................................. 43 
1.3.6.2 
Delayed Reactions ....................................................................................... 43 
1.4 
Phase I Investigator Study ........................................................................................... 43 
1.5 
Rationale for the Study ................................................................................................. 44 
1.6 
Justification of Dose ...................................................................................................... 44 
1.7 
Risk-benefit Assessment ............................................................................................... 45 
1.8 
Compliance Statement .................................................................................................. 47 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 48 
2.1 
Purpose of the Study ..................................................................................................... 48 
2.2 
Study Objectives ........................................................................................................... 48 
2.3 
Study Hypotheses .......................................................................................................... 49 


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3 
STUDY DESIGN ........................................................................................................... 49 
3.1 
General Design and Study Schema ............................................................................. 49 
3.1.1 
Part A Design .............................................................................................. 51 
3.1.2 
Part B Design .............................................................................................. 51 
3.1.3 
Justification for Part B Design ................................................................... 52 
3.1.4 
Long-Term Follow-Up ................................................................................ 54 
3.1.5 
Additional Optional Cycles, Part B ............................................................ 54 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 55 
3.2.1 
Primary Safety Endpoints and Evaluations ............................................... 55 
3.2.2 
Secondary Endpoints and Evaluations ...................................................... 55 
3.2.2.1 
Biodistribution 
and 
Radioactive 
Pharmacokinetics 
of 
the 
Radiopharmaceutical Endpoints .................................................................. 55 
3.2.2.2 
Radiation Dosimetry Endpoints ................................................................... 55 
3.2.2.3 
OPS201 Pharmacokinetics Endpoints ......................................................... 55 
3.2.2.4 
Secondary Efficacy Endpoints ..................................................................... 55 
3.2.2.5 
Influence of 177Lu-OPS201 PRRT on the Quality of Life of the Subjects ..... 55 
3.3 
Exploratory Endpoints ................................................................................................. 56 
3.3.1 
Exploratory Efficacy Endpoints ................................................................. 56 
3.3.2 
Exploratory Biomarkers ............................................................................. 56 
3.3.3 
Biobanking .................................................................................................. 56 
3.4 
Randomisation and Blinding ....................................................................................... 56 
3.5 
Maintenance of Randomisation and Blinding ............................................................ 56 
3.6 
Study Treatments and Dosage ..................................................................................... 56 
3.7 
Study Duration .............................................................................................................. 57 
3.8 
Safety Review Committee (Part A) and Data Review Board (Part B) ..................... 57 
3.9 
Source Data Recorded on the Case Report Form ...................................................... 59 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 59 
4.1 
Inclusion Criteria .......................................................................................................... 59 
4.2 
Exclusion Criteria ......................................................................................................... 61 
4.3 
Rationale for Inclusion/Exclusion Criteria ................................................................. 61 
4.4 
Recruitment ................................................................................................................... 62 
4.5 
Subject Participation Card .......................................................................................... 62 
4.6 
Stopping Rules, Discontinuation and Withdrawal Criteria and Procedures .......... 62 
4.6.1 
Withdrawal Criteria .................................................................................... 62 
4.6.2 
Withdrawal Criteria for Optional Biobanking ........................................... 63 
4.6.3 
Study or Site Termination ........................................................................... 63 
5 
STUDY PROCEDURES .............................................................................................. 64 
5.1 
Study Schedule .............................................................................................................. 64 
5.2 
Study Visits .................................................................................................................... 71 
5.2.1 
Screening Visit ............................................................................................ 71 
5.2.2 
Visit 1 ........................................................................................................... 71 


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5.2.2.1 
Visit 1, Day 1 (Week 0) ................................................................................ 72 
5.2.2.2 
Visit 1, Day 2 ................................................................................................ 73 
5.2.2.3 
Visit 1, Day 3 ................................................................................................ 73 
5.2.2.4 
Visit 1, Day 4 (-Day 5) ................................................................................. 74 
5.2.2.5 
Visit 1, Day 7 (-Day 8) ................................................................................. 74 
5.2.2.6 
Visit 1, Day 15 (±2 Days) ............................................................................ 74 
5.2.3 
Follow-up Visit 1 ......................................................................................... 74 
5.2.3.1 
Week 4 (Day 29±5) ...................................................................................... 75 
5.2.3.2 
Week 6 (Day 42±5) - Part B only ................................................................. 75 
5.2.4 
Visit 2 ........................................................................................................... 75 
5.2.4.1 
Visit 2, Day 1 (Week 8 (+2 Weeks or Up to +4 Weeks in Case of AEs which 
have Not Adequately Recovered)) ................................................................ 75 
5.2.4.2 
Visit 2, Day 2 ................................................................................................ 76 
5.2.4.3 
Visit 2, Day 3 ................................................................................................ 76 
5.2.4.4 
Visit 2, Day 4 (-Day 5) ................................................................................. 76 
5.2.4.5 
Visit 2, Day 7 (-Day 8) ................................................................................. 77 
5.2.4.6 
Visit 2, Day 15 (±2 Days) ............................................................................ 77 
5.2.5 
Follow-up Visit 2 ......................................................................................... 77 
5.2.5.1 
Week 12 (Day 29±5) .................................................................................... 77 
5.2.5.2 
Week 14 (Day 42±5) - Part B only ............................................................... 77 
5.2.6 
Visit 3 ........................................................................................................... 78 
5.2.6.1 
Visit 3, Day 1 (Week 8 (+2 Weeks or Up to +4 Weeks in Case of AEs which 
have Not Adequately Recovered)) ................................................................ 78 
5.2.6.2 
Visit 3, Day 2 ................................................................................................ 79 
5.2.6.3 
Visit 3, Day 3 ................................................................................................ 79 
5.2.6.4 
Visit 3, Day 4 (-Day 5) ................................................................................. 79 
5.2.6.5 
Visit 3, Day 7 (-Day 8) ................................................................................. 79 
5.2.6.6 
Visit 3, Day 15 (±2 Days) ............................................................................ 80 
5.2.7 
Follow-up Visit 3 ......................................................................................... 80 
5.2.7.1 
Week 20 (Day 29±5) .................................................................................... 80 
5.2.7.2 
Week 22 (Day 42±5) - Part B only ............................................................... 80 
5.2.8 
End of Core-trial Visit ................................................................................. 80 
5.2.9 
Long-term Follow-up Visits (1 to 8) ........................................................... 81 
5.2.10 
Early Withdrawal Visit ................................................................................ 81 
5.3 
Laboratory Assessments ............................................................................................... 82 
5.4 
Functional Imaging: Somatostatin Receptor Scan .................................................... 82 
6 
TREATMENT OF SUBJECTS ................................................................................... 83 
6.1 
Investigational Medicinal Product Preparation Storage and Accountability ......... 83 
6.1.1 
Investigational Medicinal Product Storage and Security .......................... 83 
6.1.2 
Investigational Medicinal Product Preparation ........................................ 84 
6.1.3 
Investigational Medicinal Product Accountability .................................... 84 


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6.2 
Study Drugs Administered ........................................................................................... 85 
6.2.1 
Dosage and Administration of Study Medication ...................................... 86 
6.3 
Concomitant Medication/Therapy .............................................................................. 86 
6.3.1 
Interruption of Somatostatin Analogue Therapy ...................................... 86 
6.3.2 
Amino Acid Infusion: Renal Protection .................................................... 87 
6.3.3 
Antiemetic .................................................................................................... 87 
6.3.4 
Optional: Loop Diuretic .............................................................................. 88 
6.3.5 
Administration Scheme ............................................................................... 88 
6.3.6 
Prior and Further Concomitant Treatments .............................................. 88 
6.4 
Delay of Administration and Withdrawal from Treatment ..................................... 89 
6.4.1 
Part A ........................................................................................................... 89 
6.4.2 
Part B ........................................................................................................... 89 
6.5 
Treatment of Overdose ................................................................................................. 90 
6.6 
Post Study Treatments ................................................................................................. 90 
6.7 
Procedures for Monitoring Subject Compliance ....................................................... 90 
7 
ASSESSMENT OF EFFICACY .................................................................................. 91 
7.1 
Efficacy Endpoints and Evaluations ........................................................................... 91 
7.2 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data ......... 91 
7.2.1 
Contrast Enhanced CT Imaging/MRI ....................................................... 91 
7.2.2 
Quality of Life Questionnaire ..................................................................... 92 
8 
ASSESSMENT OF SAFETY ....................................................................................... 92 
8.1 
Adverse Events .............................................................................................................. 92 
8.1.1 
Definition of an Adverse Event .................................................................. 92 
8.1.2 
Categorisation of Adverse Events ............................................................... 93 
8.1.2.1 
Intensity Classification ................................................................................. 93 
8.1.2.2 
Causality Classification ............................................................................... 93 
8.1.2.3 
Assessment of Expectedness ......................................................................... 94 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 94 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 94 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 95 
8.1.3 
Adverse Events of Special Interest ............................................................. 95 
8.1.4 
Recording and Follow-up of Adverse Events ............................................. 95 
8.1.4.1 
Reporting of Adverse Events ........................................................................ 96 
8.1.5 
Reporting of Serious Adverse Events ......................................................... 96 
8.1.6 
Suspected Unexpected Serious Adverse Reactions .................................... 98 
8.1.7 
Pregnancy .................................................................................................... 98 
8.1.8 
Deaths .......................................................................................................... 98 
8.1.9 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 98 
8.1.10 
Investigational Product Complaints ........................................................... 99 
8.1.11 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ....... 99 


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8.1.12 
Risk-benefit Management ........................................................................... 99 
8.2 
Clinical Laboratory Tests ............................................................................................ 99 
8.2.1 
Haematology ................................................................................................ 99 
8.2.2 
Blood Biochemistry ..................................................................................... 99 
8.2.3 
Urinalysis ................................................................................................... 100 
8.2.4 
Pregnancy Test .......................................................................................... 100 
8.2.5 
Pituitary Marker (Marker of Pituitary Function) ................................... 100 
8.3 
Physical Examination ................................................................................................. 100 
8.4 
Height and Weight ...................................................................................................... 100 
8.5 
Vital Signs .................................................................................................................... 100 
8.6 
Electrocardiography ................................................................................................... 101 
8.7 
Performance Status ..................................................................................................... 101 
8.8 
Subject Demographics ................................................................................................ 101 
8.9 
Medical History ........................................................................................................... 101 
8.10 Prior and Concomitant Medication .......................................................................... 101 
9 
ASSESSMENTS OF PHARMACOKINETICS ....................................................... 102 
9.1 
Pharmacokinetics of the Radiopharmaceutical ....................................................... 102 
9.1.1 
Blood Sample Collection ........................................................................... 102 
9.1.2 
Urine Sample Collection ........................................................................... 102 
9.1.3 
Analytical Procedures ............................................................................... 102 
9.2 
Nuclear Medicine Imaging for Dosimetry ................................................................ 103 
9.2.1 
Whole Body Scan ...................................................................................... 103 
9.2.2 
SPECT/CT Scan ........................................................................................ 103 
9.3 
Pharmacokinetics of the OPS201 .............................................................................. 103 
9.3.1 
Blood Sample Collection ........................................................................... 103 
9.3.2 
Urine Sample Collection ........................................................................... 103 
9.3.3 
Analytical Procedures ............................................................................... 104 
9.4 
 ......................................................................... 104 
10 
EXPLORATORY BIOMARKERS AND BIOBANKING ..................................... 104 
10.1 Exploratory Biomarkers ............................................................................................ 104 
10.1.1 
Circulating Tumour Markers ................................................................... 104 
10.1.2 
Systemic Immune Response (Part B Only) .............................................. 104 
10.1.3 
Circulating cfDNA Tumour Markers (Part B Only) ............................... 104 
10.1.4 
Exploratory Evaluation of Tumour Biomarker from Biopsy .................. 105 
10.1.5 
Specific Renal Safety Biomarker .............................................................. 105 
10.2 Biobanking ................................................................................................................... 105 
10.2.1 
Serum ......................................................................................................... 106 
10.2.2 
Blood for RNA for Biobank ...................................................................... 106 
11 
STATISTICS ............................................................................................................... 106 
11.1 Analyses Populations .................................................................................................. 106 
11.1.1 
Populations Analysed ................................................................................ 107 
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11.1.2 
Reasons for Exclusion from the Analyses ............................................... 107 
11.2 Sample Size Determination ........................................................................................ 107 
11.3 Significance Testing and Estimations ....................................................................... 107 
11.4 Statistical/Analytical Methods ................................................................................... 107 
11.4.1 
Demographic and Other Baseline Characteristics .................................. 108 
11.4.2 
Subject Disposition and Withdrawals ....................................................... 108 
11.4.3 
Efficacy Data ............................................................................................. 108 
11.4.4 
Biodistribution 
and 
Radioactive 
Pharmacokinetics 
of 
the 
Radiopharmaceutical ................................................................................ 108 
11.4.5 
Pharmacokinetic Data .............................................................................. 108 
11.4.6 
Evaluation of Radiation Dosimetry .......................................................... 109 
11.4.7 
Documentation of Biodistribution Results ............................................... 109 
11.4.8 
Evaluation of Tumour Response .............................................................. 110 
11.4.9 
Adjustment for Country/Centre Effect ..................................................... 110 
11.4.10 
Safety Evaluation ...................................................................................... 110 
11.5 Subgroup Analyses ..................................................................................................... 111 
11.6 Interim Analyses/Safety Review Committees/Data Review Boards ....................... 112 
12 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................. 112 
13 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 112 
13.1 Protocol Amendments and Protocol Deviations ...................................................... 112 
13.1.1 
Protocol Amendments ............................................................................... 112 
13.1.2 
Protocol Deviations and Exceptions......................................................... 113 
13.2 Information to Study Personnel ................................................................................ 113 
13.3 Study Monitoring ........................................................................................................ 114 
13.4 Investigator’s Regulatory Obligations ...................................................................... 115 
13.5 Audit and Inspection .................................................................................................. 115 
13.6 Data Quality Assurance .............................................................................................. 115 
14 
ETHICS ....................................................................................................................... 116 
14.1 Compliance with Good Clinical Practice and Ethical Considerations .................. 116 
14.2 Informed Consent for Participation in the Study .................................................... 116 
14.2.1 
Optional Informed Consent for Biobanking ............................................ 117 
14.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards .......................................................................................................................... 117 
14.4 Confidentiality Regarding Study Subjects ............................................................... 117 
15 
DATA HANDLING AND RECORD KEEPING ..................................................... 118 
15.1 Data Recording of Study Data ................................................................................... 118 
15.2 Data Management ....................................................................................................... 118 
15.3 Record Archiving and Retention ............................................................................... 118 
16 
FINANCING AND INSURANCE ............................................................................. 119 
16.1 Contractual and Financial Details ............................................................................. 119 
16.2 Insurance, Indemnity and Compensation ................................................................ 119 


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17 
REPORTING AND PUBLICATIONS OF RESULTS ........................................... 119 
17.1 Publication Policy ....................................................................................................... 120 
17.2 Clinical Study Report ................................................................................................. 121 
18 
REFERENCES ............................................................................................................ 122 
19 
LIST OF APPENDICES ............................................................................................ 127 
 
LIST OF FIGURES 
Figure 1 
Overview of Study Design for Part A and Part B and Post Study Follow-up
 ................................................................................................................................. 8 
Figure 2 
Study Design - Part B .......................................................................................... 10 
Figure 3 
Superior Binding Behaviour of Antagonistic Somatostatin Analogues ......... 34 
Figure 4 
Chemical Structure of 177Lu-OPS201 ................................................................ 35 
Figure 5 
Internalisation of sstr2 After Receptor Stimulation with Somatostatin 
Analogues ............................................................................................................. 36 
Figure 6 
In Vivo Biodistribution ....................................................................................... 37 
Figure 7 
AUC Tumour Uptake .......................................................................................... 38 
Figure 8 
AUC Tumour-to-Kidney ..................................................................................... 38 
Figure 9 
Peptide Dose Escalation ...................................................................................... 39 
Figure 10 68Ga-Dota-Tate PET Images of Patient 2 Before (A) and 3 Months After (B) 
Treatment with 15.2 GBq of 177Lu-OPS201 and 68Ga-Dota-Tate PET 
Images of Patient 3 Before (C) and 12 Months after (D) Treatment with 5.9 
GBq of 177Lu-OPS201 .......................................................................................... 42 
Figure 11 Overview of Study Design for Part A and Part B and Post Study Follow-up
 ............................................................................................................................... 51 
Figure 12 Study Design - Part A .......................................................................................... 51 
Figure 13 Study Design - Part B .......................................................................................... 52 
Figure 14 Administration Schedule for Study Treatment and Concomitant 
Medication ............................................................................................................ 88 
Figure 15 Part B Cohort Schema with DRB Designations ............................................. 133 
Figure 16 Overview of study design for Part A and Part B and post study follow-up . 203 
 
LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 4 
Table 2 
Radioactivity and Peptide Mass Dose in Each Cohort and Cycle .................... 9 
Table 3 
Radiophysical Characteristics of 177Lutetium .................................................. 35 
Table 4 
Sstr2 Receptor Binding Affinities [38] ............................................................... 36 
Table 5 
Residence Times (=Time Integrated Activity Coefficient) in the Organs ...... 40 
Table 6 
Absorbed Dose Coefficients For Each Organ and Pig ..................................... 41 
Table 7 
Study Procedures and Assessments Part A ....................................................... 65 


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Table 8 
Study Procedures and Assessments Part B ....................................................... 67 
Table 9 
Volume of Blood During the Core Trial ............................................................ 82 
Table 10 
Krenning Scale ..................................................................................................... 83 
Table 11 
Radioactivity and Peptide Mass Dose in Each Cohort and Cycle – Part B ... 85 
Table 12 
Details of each DRB, the Timing, Question and Decision Matrix ................. 134 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
Wording Definition  
3D 
Three-dimensional 
68Ga 
Positron-emitting isotope of Gallium 
68Ga-OPS202 
68Ga-labeled somatostatin antagonist for diagnostic imaging 
90Y 
90Yttrium 
177Lu 
177Lutetium 
177Lu-OPS201 
Study medication, 177Lu-labeled somatostatin antagonist for PRRT 
AC 
Atypical carcinoid 
ADL 
Activity of daily living 
ADR  
Adverse drug reaction 
Ae 
Cumulative amount of unchanged drug excreted into the urine 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate transaminase 
AUC 
Area under the whole blood or plasma/serum concentration time 
curve  
BM 
Bone marrow 
BOR 
Best overall response 
CA 
Competent authority 
cfDNA 
Cell-free deoxyribonucleic acid 
CFR 
Code of Federal Regulations (United States of America) 
Cg A 
Chromogranin A 
CL 
Apparent total body clearance of the drug from plasma 
CLR 
Renal clearance of the drug from plasma 
Cmax 
Maximum observed concentration 
CR 
Complete response 
CRA 
Clinical Research Associate 
CRO 
Contract research organisation 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DCR 
Disease control rate 


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ABBREVIATION 
Wording Definition  
DLT 
Dose limiting toxicity 
DOTA 
Tetraxetan, a chemical chelator group 
DOM 
Dosimetry operational manual 
DoR 
Duration of response 
DRB 
Data review board 
DTPA 
Diethylene triamine penta-acetic acid 
EANM 
European Association of Nuclear Medicine 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOAC 
End of additional cycles 
EOCT 
End of Core Trial 
EU 
European Union 
EW 
Early withdrawal 
FDA 
Food and Drug Administration 
fT4 
Free thyroxine 
GBq 
Gigabecquerel, SI unit of radioactivity 
GCP 
Good Clinical Practice 
GEP 
Gastroenteropancreatic 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
GMP 
Good Manufacturing Practice 
GST 
Glutathione S-transferase 
Gy 
Gray, SI unit of absorbed radiation dose 
HbA1c 
Glycated haemoglobin 
HCG 
Human chorionic gonadotropin 
HEK 
Human embryonic kidney 
HPLC 
High-performance liquid chromatography 
HIV 
Human immunodeficiency virus 
IAEA 
International Atomic Energy Agency 
IA/ROI 
Injected activity/region of interest 


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ABBREVIATION 
Wording Definition  
IB 
Investigator’s brochure 
IC50 
Half maximal inhibitory concentration 
ICH 
International Council for Harmonisation 
IDMS 
Isotope dilution mass spectrometry 
IEC 
Independent ethics committee 
IGF 
Insulin-like growth factor 
IIT 
Investigator-initiated trial 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
IRPP 
Investigational radiopharmaceutical product 
IRR 
Infusion related reaction 
ISF 
Investigator’s site file 
ITT 
Intent-to-treat 
ITT-DAS 
Intent-to-treat dosimetry analysis set 
i.v. 
Intravenous 
JR11 
Somatostatin analogue peptide JR11 
Kd 
dissociation constant 
KIM-1 
Kidney injury molecule-1 
LCNEC 
Large cell neuroendocrine carcinoma 
MBq 
Megabecquerel, SI unit of radioactivity 
MDRD 
Modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN-1 
Multiple endocrine neoplasia 1 
mRECIST 
Modified RECIST 
MRI 
Magnetic resonance imaging 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MS/MS 
Tandem mass spectrometry 
NCI 
National Cancer Institute 
NET 
Neuroendocrine tumour 
NODAGA 
A chemical chelator group 
NOS 
Not otherwise specified 
NSE 
Neuron-specific enolase 
OPS201 
Somatostatin analogue peptide JR11 coupled to DOTA 


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ABBREVIATION 
Wording Definition  
OPS202 
Somatostatin analogue peptide JR11 coupled to NODEGA 
ORR 
Objective response rate 
PD 
Progressive disease 
PET 
Positron-emission tomography 
PFS 
Progression free survival 
PK 
Pharmacokinetic(s) 
PP 
Per protocol 
PP-DAS 
Per protocol-dosimetry analysis set 
PR 
Partial response 
PRRT 
Peptide receptor radionuclide therapy 
PT 
Preferred term 
QLQ 
Quality of Life Questionnaire 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SDV 
Source document verification 
SNMMI 
Society of Nuclear Medicine and Molecular Imaging 
SOC 
System organ class 
SOP 
Standard operating procedure 
SPECT 
Single photon emission computed tomography 
SRC 
Safety review committee 
SRS 
Somatostatin receptor scintigraphy 
SSA 
Somatostatin analogue 
sstr 
Somatostatin receptor  
SUSAR 
Suspected unexpected serious adverse reaction 
SUV 
Standardised uptake value 
SUVmax 
Maximum standardised uptake value 
SUVmean 
Mean standardised uptake value 
t½ 
Elimination half-life 
TAC 
Time activity curve 


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ABBREVIATION 
Wording Definition  
TC 
Typical carcinoid 
TEAE 
Treatment emergent adverse event 
TGR 
Tumour growth rate 
TMF 
Trial master file 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US(A) 
United States (of America) 
Vd 
Apparent volume of distribution 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 


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1 
BACKGROUND INFORMATION 
1.1 
Introduction 
Neuroendocrine tumours (NETs) are as heterogeneous in their clinical appearance as they are 
rare in occurrence.[1] Improvements in diagnosis by advanced endoscopic and radiological 
imaging have led to an increase in reported incidence rates in the United States of America 
(USA) from 1.09 in 100,000 in 1973 to 5.25 in 100,000 in 2004.[2] They primarily appear as 
carcinoid tumours of bronchopulmonary or gastrointestinal origin representing 0.46% of 
malignant diseases in general.[3] 
1.1.1 
Gastroenteropancreatic Neuroendocrine Tumours (GEP NETs) 
Gastroenteropancreatic (GEP) NETs arise from local totipotent stem cells of the diffuse 
neuroendocrine system in the gastrointestinal tract and pancreas rather than from the neural 
crest, as it was previously thought.[4] There are at least 13 gastrointestinal neuroendocrine cell 
types, producing different sets of bioactive peptides or amines as serotonin, somatostatin, 
histamine or gastrin, stored in secretory vesicles. Therefore, vesicular proteins such as 
chromogranin A (Cg A) and synaptophysin are markers of neuroendocrine cells.  
In most cases GEP NETs are slow-growing tumours, which remain unnoticed until the 
occurrence of mass effects or predominantly hepatic metastases. Functioning tumours can 
secrete a variety of bioactive peptides and neuro-amines which produce distinct syndromes such 
as carcinoid syndrome, hypoglycaemic syndrome or Zollinger-Ellison syndrome.[5] Although 
the clinical symptoms of functioning tumours (e.g. flushing, diarrhoea and asthma in carcinoid 
syndrome) are a burden for the quality of life of the patient, they have the beneficial effect of 
allowing an early diagnosis and better prognosis. However, the majority (90%) of GEP NETs 
develop in a nonfunctioning form, leading to delayed diagnosis and metastatic disease.[6] 
The diagnosis of GEP NETs is driven by a high index of suspicion. In general, diagnosis is 
based on clinical presentation, hormone assays, markers such as Cg A, and pathology. These 
are enhanced by a variety of imaging techniques such as endoscopic ultrasonography, computed 
tomography (CT), magnetic resonance imaging (MRI), selective angiography (with hormonal 
sampling), nuclear imaging as somatostatin receptor (sstr) single photon emission computed 
tomography (SPECT), bone scanning and various intraoperative methods. However, due to 
their heterogeneity, no imaging method covers the whole variety of GEP NETs. The prognosis 
of GEP NET patients depends on the characteristic of the tumour. In well-differentiated 
neuroendocrine carcinoma the 5-year survival can be 60% to 100%, whereas in regional disease 
and with distant metastases it decreases to 40% and 29%, respectively.[1] 
The treatment of GEP NETs is highly individualised, based on tumour burden and symptoms. 
In slow growing tumours, surgery can be a method of cure, for instance in insulinomas. In more 
severe cases, surgery or embolisation can be applied as a method of cytoreduction. For 
functioning tumours, apart from the removal or reduction of tumour mass, the management of 
the symptoms is a major goal of treatment, leading to an increase in quality of life for the 
patients. 
1.1.2 
Lung Neuroendocrine Tumours 
Lung NETs have a low incidence which has been increasing in the past three decades mostly 
due to better detection methods and increased use of imaging techniques.[7, 8, 9] 
The 2004 World Health Organization (WHO) classification includes four types of lung NET: 
small cell lung cancer (SCLC), large cell neuroendocrine carcinoma (LCNEC), typical 
carcinoid (TC) and atypical carcinoid (AC).[10] Neuroendocrine tumours represent 25% of 
primary lung cancers and the most common lung NET is SCLC (20%), followed by LCNEC 
(3%) and carcinoids. Lung carcinoid tumours account for 5% of most common multiple 


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endocrine neoplasia 1 (MEN-1) neoplasm. SCLC and LCNEC are both associated with 
smoking while carcinoids have no predilection for smoking history.[11] 
Most bronchial NETs are located in major bronchi (70%); therefore, most of these are detected 
due to symptoms such as haemoptysis, cough, infections, fever and unilateral wheezing while 
peripheral NETs are usually discovered incidentally.[12, 13] Differently from GEP NET, lung 
carcinoids are rarely functioning and hypersecreting (2% versus 10% in GEP NET).[11, 14] In 
a small percentage of patients with Cushing’s syndrome the cause is production of 
adrenocorticotrophic hormone from a bronchial or thymic NET.[7, 8, 13] 
As for GEP NET, diagnosis is based on specific markers (e.g. p-Cg A, p-neuron-specific 
enolase (NSE)), imaging techniques including somatostatin receptor scintigraphy (SRS) and 
positron-emission tomography (PET) scanning (fluorodeoxyglucose PET for SCLC and 
LCNEC), bronchoscopy and MEN-1 genetic screening when indicated.[7, 8]. Prognosis of lung 
NET varies depending on the histological type: 5-year survival for SCLC is less than 5%, for 
LCNEC is 15% to 57% and for carcinoids varies from a high 5-year survival rate for TC (>87%) 
to a poorer prognosis for AC since these are more aggressive (5-year survival rate of 44% to 
78%).[7, 8, 11, 13]  
The treatment of lung NET varies depending on the tumour type: SCLC, since considered a 
nonsurgical disease, is mainly treated with chemotherapy regimens and radiotherapy; for 
LCNEC there is still no consensus on the clinical management since it is quite rare; carcinoid 
tumours are primarily a surgical disease not very sensitive to radiotherapy and chemotherapy. 
Peptide receptor radionuclide therapy (PRRT) showed some promising results in tumour 
growth but remains investigational.[7, 8, 11, 15] 
1.1.3 
Pheochromocytoma-Paraganglioma 
According to the 2004 WHO classification of endocrine tumours, pheochromocytoma is a 
malignancy arising from the adrenal medulla catecholamine-producing chromaffin cells, while 
paraganglioma arises from the same cells in the extra-adrenal paraganglia.[16] 
Pheochromocytoma and paragangliomas occur in 0.1% of hypertensive patients and in 4% of 
patients is fortuitously discovered as adrenal mass.[17] These tumours may cause symptoms 
such as hypertension, arrhythmia and/or hyperglycaemia by releasing catecholamines. Only a 
small portion of pheochromocytomas are malignant (10% to 17%) with lymph nodes, visceral, 
or bone metastases.[18, 19] 
Pheochromocytomas may be associated with genetically inherited diseases such as familial 
pheochromocytoma-paraganglioma syndromes, multiple endocrine neoplasia type 2, 
neurofibromatosis 1 and von Hippel-Lindau disease, or may be sporadic[18] 
Besides imaging studies, diagnosis currently is mostly based on plasma or urinary metanephrine 
levels which are diagnostic if results are at least four times the upper limit of normal (ULN).[20] 
No staging system is available for pheochromocytoma and the overall 5-year survival rate is 
between 34% and 60% depending on tumour size, location and succinate dehydrogenase 
subunit B mutation status.[16, 18] 
At present, no cure for malignant pheochromocytoma or paraganglioma is available and no 
reliable tumour markers have been identified to diagnose malignancy or assess prognosis. The 
main therapeutic strategies are wait and see, therapeutic embolisation, radiofrequency ablation, 
systemic 
chemotherapy 
and 
radionuclide 
therapies. 
Currently, 
131I-labeled 
metaiodobenzylguanidine therapy is the single most used adjuvant therapy after surgical 
treatment of malignant pheochromocytomas.[16, 18] 


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1.1.4 
Somatostatin Analogues 
One approach to ease the symptoms of functioning NETs is the application of somatostatin 
analogues (SSAs). Physiologically, somatostatin inhibits the secretion of endocrine hormones 
or bioactive amines including insulin, glucagon and gastrin[21] depending on receptor and cell 
type. Somatostatin binds to the five different G-protein coupled receptors, sstr 1 to 5. Around 
80% of GEP NETs express sstr subtypes (1 to 5) in well-differentiated forms.[6, 22, 23] 
Somatostatin binds all its natural receptors with high affinity but has a short half-life in vivo. 
Synthetic SSAs are less prone to degradation by peptidases and have an increased half-life but 
differing receptor affinities, with high affinities mainly to sstr2 and partially sstr5. Their 
biological activities are prolonged to 1.5 to 2 hours versus 1 to 2 minutes with the natural 
peptide.[24] Somatostatin analogues are widely used in clinical practice and are known to 
ameliorate the symptoms of carcinoid syndrome. Apart from this symptomatic treatment, SSAs 
are reported to have a beneficial effect on tumour growth. This antiproliferative effect has been 
attributed to cell cycle arrest, induction of apoptosis, antiangiogenic inhibition of vascular 
endothelial growth factor, immunomodulation and further secondary effects connected to the 
physiological somatostatin function. For the two approved SSAs octreotide (PROMID study, 
Novartis) and lanreotide (CLARINET study, Ipsen), large scale, controlled phase III studies 
proved disease stabilisation and prolonged progression free survival (PFS) in patients with 
metastasised NETs, including functioning and nonfunctioning tumours.[25] 
1.1.5 
Radiolabelled Somatostatin Analogues 
The clinical impact of SSAs is not limited to their pharmacological activity as the peptides can 
also be used for in vivo receptor targeting. Radiolabelled octreotide is applied for the imaging 
of NETs expressing sstr2, sstr3 and sstr5. The localisation of the primary tumour and its 
metastases is crucial for the management of the malignant disease. As a diagnostic SSA of the 
first generation, octreotide is fused to the chelator diethylene triamine penta-acetic acid (DTPA) 
and can be labelled with 111Indium (OctreoScanTM) for the imaging of its gamma radiation in 
SRS using a gamma camera or SPECT. 
Second generation SSA peptides, like DOTA-TOC and DOTA-TATE, show higher affinities 
to distinct sstrs and by utilising DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic 
acid) as a chelator can be labelled with the ȕ emitter 68Gallium as PET/CT tracers. The PET/CT 
scan with second generation peptides showed good diagnostic performance. In a meta-analysis 
of published studies, PET/CT was shown to provide higher sensitivity and detect more lesions 
than SRS. 
Depending on the nuclide, radiolabelled SSAs can be used as tracers for imaging or for PRRT. 
Labelled with a ȕ-emitting radionuclide such as 90Yttrium (90Y) or 177Lutetium (177Lu), 
DOTA-TOC and DOTA-TATE have entered clinical practice in many leading centres in the 
field of NETs. In contrast to the very nonspecific toxic effects of conventional chemotherapy, 
PRRT specifically targets malignant NET cells and has been proven to be safe and effective.[26, 
27] 
1.1.6 
Antagonistic Somatostatin Analogues 
Agonists, like octreotide or DOTA-TOC and DOTA-TATE, were preferred for in vivo receptor 
targeting since they trigger receptor internalisation and thereby transport the radionuclide into 
the cell, while antagonists do not.[28] However, recent studies suggest that antagonists could 
be even more effective. Although internalisation is not induced by high affinity antagonists, an 
increased tumour uptake may be observed for the antagonist 111In-DOTA-BASS (half maximal 
inhibitory concentration (IC50) (sstr2)=9.4 nM) compared to the agonist 111In-DTPA-TATE 
(IC50 (sstr2)=1.3 nM).[29] Scatchard plots demonstrated many more sites labelled by the 


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antagonist compared to the agonist. It is hypothesised that the antagonist binds to a variety of 
receptor conformations independent of the activation state, whereas the agonist depends on the 
bound guanine nucleotide of the G-protein coupled receptor (Figure 1).[30] This increase in
binding sites correlates with a higher tumour-to-tissue ratio of the SRS utilising the 
antagonist.[29]
Figure 3
Superior Binding Behaviour of Antagonistic Somatostatin Analogues
The new class of antagonistic peptides (left) is independent of the sstr activation state (G-protein 
phosphorylation). Therefore, they utilise many more binding sites on the tumour cell surface, 
while agonistic peptides (right) only target activated receptors. [30]
These preclinical findings were confirmed in a first clinical application of an sstr antagonist 
used for SRS imaging in 5 NET patients. A comparison of the antagonist 111In-DOTA-BASS 
to the approved 111In DTPA-octreotide (OctreoScanTM/Mallinckrodt) in SRS showed an up to 
4.1 times higher uptake in the tumour and an up to 5.2 times higher tumour-to-kidney uptake 
ratio. Moreover, out of 28 lesions identified in CT scans, only 17 could be detected by SRS 
with the agonist while 25 were verified in the antagonistic scan.[31]
Following the hypothesis of favourable antagonistic SSAs the third generation peptide 
DOTA-JR11 (OPS201) was developed, demonstrating higher affinity than DOTA-BASS and 
selectivity for sstr2 (0.7±0.12 nM).[32]
Somatostatin analogue peptide JR11 is currently developed for a theranostic approach based on 
the same peptide somatostatin antagonist. In the diagnostic compound OPS202, it is coupled to 
the chelator NODAGA and can be labelled with the radionuclide 68Gallium. The therapeutic 
peptide OPS201 contains the chelating agent DOTA and can be labelled with isotopes like 90Y 
or 177Lu. In this phase I/II study, the clinical safety and tolerability, as well as the efficacy of a 
PRRT treatment with three cycles of the study medication, the 177Lu-labelled somatostatin 
antagonist for PRRT (177Lu-OPS201) will be evaluated.
1.2
General Considerations for 177Lu-OPS201
The chemical name and structure of the study medication 177Lu-OPS201 are given below.


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1.2.1
Chemical Name: 
Lutetium-177(3+),S2,S7-cyclo[N-{4,7,10-tricarboxymethyl-1,4,7,10-tetraaza-cyclododecan-1-
yl-acetyl}-4-chloro-L-phenylalanyl-D-cysteinyl-4-[(4S)-2,6-dioxo-1,3-diazinane-4-
carboxamido]-L-phenylalanyl-4-(carbamoylamino)-D-phenylalanyl-L-lysyl-L-threonyl-L-
cysteinyl-D-tyrosinamide]
1.2.2
Chemical Structure:
Figure 4
Chemical Structure of 177Lu-OPS201
177Lu-OPS201 has three main components, namely the SSA JR11, the chemical chelator group 
DOTA and the ȕ emitter 177Lutetium (177Lu). 
JR11 is an SAA with the chemical formula Cpa-D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys-
D-Tyr-NH2. Due to its antagonistic properties, binding to sstrs does not activate any 
physiological cell response (e.g. signal transduction via phosphorylation, receptor 
internalisation) as is observed with agonists. 
DOTA (international nonproprietary name: tetraxetan) is a chelating agent with the chemical 
formula 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid. DOTA is already in use in 
clinical studies for example in the monoclonal antibody, 90Y-clivatuzumab tetraxetan, for the 
radiotherapy of pancreatic cancer which is currently in phase III.[33]
177Lu is a ȕ- and Ȗ- emitting radionuclide. It has a half-life of 6.65 days and maximum and mean 
ȕ particle energies of 0.498 MeV and 0.134 MeV, respectively. This reflects in the maximum 
and mean soft-tissue penetration depths of 1.7 mm and 0.23 mm, respectively. [35] The two 
main gamma emission lines are 113 keV (6% relative abundance) and 208 keV (10.4% relative 
abundance), [34] which allows post treatment imaging and dosimetry assessments.[35]
Table 3
Radiophysical Characteristics of 177Lutetium
Physical half-life t½
6.65 days
Decay product
177Hf
Maximum ȕ- particle energy
0.498 MeV 
Mean ȕ-particle energy
0.133 MeV
Mean tissue penetration
0.23 mm
Maximum tissue penetration
1.7 mm
Main gamma emission lines
113 keV (6.2%)
208 keV (10.4%)
177Hf=hafnium-177; keV=kiloelectron volt.


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In preclinical and clinical assessments, OPS201 showed increased tumour uptake and improved 
tumour to-tissue uptake ratios compared to agonistic SSAs. The elongated residence time at the 
tumour suits well to the physical half-life of 177Lu, which makes it an ideal compound for the 
PRRT of GEP NET lesions. 
1.3 
Previous Experience with Study Drug 
1.3.1 
Preclinical Studies 
1.3.1.1 
Antagonistic Behaviour – Internalisation and Calcium Release 
In contrast to receptor antagonists, the binding of agonists to sstr leads to receptor 
internalisation and activation of intracellular signal transduction pathways. Ultimately, sstr 
activation produces a wide range of physiological effects throughout the body including the 
inhibition of the secretion of many hormones.[36] 
An 
internalisation 
assay 
based 
on 
sstr2 
immunofluorescence 
microscopy 
with 
sstr2-overexpressing human embryonic kidneys (HEK) cells was performed to determine 
whether OPS201 (compound 31 in citation) acts as an agonist or antagonist. In comparison to 
the control analogue TOC, OPS201 did not induce internalisation of sstr2 receptors (Figure 5). 
Furthermore, unlike the agonist it did not activate calcium signalling in a calcium release assay 
and therefore acts as a receptor antagonist.[32] 
Figure 5 Internalisation of sstr2 After Receptor Stimulation with Somatostatin Analogues 
 
Adapted from Cescato et al 2008 [32] 
1.3.1.2 
Somatostatin Receptor 2 Binding 
The sstr subtype sstr2 plays a major role in the tumour biology of GEP NETs.[37] Therefore, 
the receptor binding affinities of OPS201 and 
natLu-OPS201 were analysed in 
sstr2-overexpressing HEK cells by autoradiography. natLu-OPS201 coupling to DOTA retained 
a high sstr2 affinity comparable to the OPS201 compound without metal (see Table 4). 
natGa-DOTA-TATE was used as a reference compound.[38] 
Table 4 
Sstr2 Receptor Binding Affinities [38] 
Compound 
sstr2 (IC50, nmol/L)[a] 
OPS201 (DOTA-JR11) 
0.72±0.12 
natLu-OPS201 (natLu-DOTA-JR11) 
0.73±0.15 
Reference agonist natGa-DOTA-TATE 
0.2±0.04 
DOTA=tetraxetan; Ga=gallium; JR11=Somatostatin analogue peptide JR11; OPS201=Somatostatin analogue peptide JR11 
coupled to DOTA; sstr2=somatostatin receptor subtype-2; TATE=tyrosine-3-octreotate 
a 
IC50 values are shown as mean±standard error of the mean (SEM) (nmol/L) 
The antagonistic peptide natLu-OPS201 showed slightly weaker affinity to the sstr2 compared 
to the strongest agonistic peptide Ga-DOTA-TATE. Nevertheless, due to the higher number of 
available binding sites (activated and nonactivated receptors) on the tumour cells accessible to 
antagonistic peptides, a higher uptake of 177Lu-OPS201 in sstr2 tumours is possible [29,32] and 
could be shown in preclinical and clinical in vivo studies. 


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1.3.2 
 
Preclinical In Vivo Results 
1.3.2.1 
Biodistribution 
Figure 6 In Vivo Biodistribution 
 
Small-animal PET images (coronal sections) of mice bearing HEK-HSST2 tumour injected with 68Ga DOTATATE, 68Ga-
OPS201, and 68Ga-OPS202 (NODAGA-JR11)[38] 
In 
vivo 
biodistribution 
studies 
comparing 
the 
68Ga-DOTATATE 
agonist 
with 
68Ga-DOTA-JR11 and 68Ga NODAGA-JR11 showed not only that the JR11 antagonist 
radio-ligands were superior to the agonist ligands, but also that 68Ga-labeled somatostatin 
antagonist for diagnostic imaging (68Ga-OPS202, NODAGA-JR11) was the tracer of choice for 
PET imaging and preferable to 68Ga-OPS201 (DOTA-JR11) in transplanted HEK293-hSST2 
tumours in mice (Figure 6).[38] For this reason, 68Ga-OPS202 (NODAGA-JR11) was chosen 
for the clinical development as a PET/CT imaging compound. 
 
 
 
In another preclinical study on HEK-hSST2 xenografts in nude mice, OPS201 was 
radiolabelled with 68Ga for PET imaging and with 177Lu for therapy. 68Ga-OPS201 and 
177Lu-OPS201 were compared head-to-head with 68Ga-DOTA-TATE and 177Lu-DOTA-TATE 
in terms of receptor affinity, tumour uptake, image contrast and pharmacokinetics (PK). 
Pharmacokinetics, mass-dependence as well as PET and SPECT/CT imaging studies were 
performed.[39]. 
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Figure 7 AUC Tumour Uptake 
 
AUC=area under the curve; h=hour 
Red: 177Lu-OPS201, Blue: 177Lu-DOTA-TATE [39] 
Figure 8 AUC Tumour-to-Kidney 
 
AUC=area under the curve; h=hour 
Red: 177Lu-OPS201, Blue: 177Lu-DOTA-TATE [39] 
With 68Ga-OPS201 a 1.3-fold higher tumour uptake and with 177Lu-OPS201 an approximately 
35% higher tumour uptake (Figure 7) could be observed in comparison to the DOTA-TATE 
equivalent. For 177Lu-OPS201 the highest uptake was monitored at 4 hours after the injection. 
For 177Lu-OPS201 the mean tumour residence time was 19.1 hours, compared to 7.5 hours for 
177Lu-DOTA-TATE, resulting in a 2.5 times higher tumour dose for the antagonist than for the 
agonist. Despite a 1.8-fold increased kidney dose, the therapeutic index defined as 
tumour-to-kidney dose ratio showed a 34% increase in favour of 177Lu-OPS201 (Figure 8). 
With an escalation of the used peptide dose from 10 pmol to, 200 pmol to 2000 pmol of 
177Lu-OPS201, no relevant saturation effect in the tumour could be achieved while the 
background saturation significantly decreased (Figure 9). 
0
25
50
75
100
125
150
175
0
5
10
15
20
25
Time (h)
% IA/g
AUC tumour uptake
0
25
50
75
100
125
150
175
0
2
4
6
Time (h)
Ratio
AUC Tumour-to-Kidney


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Figure 9 Peptide Dose Escalation 
 
A) tumour uptake of red: 177Lu-OPS201 and blue 177Lu-DOTA-TATE in % injected radioactivity with increasing peptide mass 
doses. for 177Lu-OPS201 no saturation effect is shown, while for 177Lu-DOTA-TATE the tumour uptake decreases with 
increasing peptide concentrations. B) SPECT/CT images of HEK-HSST2 xenografts in nude mice with 177Lu-OPS201 in two 
different peptide mass doses.[39] 
Tissue distribution of 177Lu-OPS201 was also evaluated in sstr2-expressing tumour bearing 
mice (human SCLC H69) at peptide doses of 0.5 ȝg (300 pmol), 1 ȝg (600 pmol) and 2 ȝg 
(1200 pmol).[40] Injection of 0.5 ȝg and 1 ȝg of 177Lu-OPS201 resulted in the highest tumour 
uptake. High uptake was also seen in the kidneys, as a consequence of urinary excretion, and 
in the sstr2-expressing pancreas and stomach. Kidney, stomach and pancreas radioactivity 
decreased relatively quickly, whereas tumour uptake remained twice as long. Dosimetry 
calculations resulted in a tumour radiation dose of 1.8±0.7 Gy/MBq after injection of 0.5 ȝg of 
OPS201. The tumour, pancreas, and stomach doses were considerably reduced with higher 
peptide amount (1.9, 2.9 and 3.2-fold reduction, from 0.5 to 2.0 ȝg of peptide, respectively), 
whereas the kidney dose remained constant. In this study, the optimal peptide dose appeared to 
be 1 ȝg in H69 tumour-bearing mice with the highest absorbed dose to the tumour compared 
to the other tissues. 
1.3.2.2 
In Vivo Pharmacology, Activity on Tumour Growth in an SCLC Model 
177Lu-OPS201 demonstrated its potency to reduce tumour growth in one animal model, 
NCI-H69 xenograft in mice SCLC model. In the therapy experiment, mice with subcutaneous 
H69 xenografts were intravenously injected with 0.5 mg/30 MBq (megabecquerels) of 
177Lu-OPS201, 0.5 mg/30 MBq of 177Lu-DOTA-TATE, or 200 mL of injection fluid. Animals 
treated with 177Lu-OPS201 showed a decrease in tumour size up to 45±7 days after cell 
implantation after which tumour regrowth occurred. For 177Lu-DOTA-TATE, tumour regrowth 
was already observed 41±2 days after injection of the radiotracer. Furthermore, median survival 
rates were 43.5, 61, and 71 days for the control group, the 177Lu-DOTA-TATE group, and the 
177Lu-OPS201 treated group, respectively.[40] 
1.3.3 
Nonclinical Safety (Toxicity Test) of OPS201 
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1.3.4 
Dosimetry in Pigs 
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1.3.6
Adverse Effects 
 
First insights into potential side effects of a PRRT with 177Lu-OPS201 in humans could be 
gained in a preliminary therapeutic study under compassionate use at the University Hospital 
in Freiburg. Four patients with histologically proven, progressively metastasised inoperable 
NETs, and limited treatment options due to chronic Grade 2 or 3 kidney disease, were treated 
with two to three cycles of 177Lu-OPS201 (1.87 GBq to 5.89 GBq) at an interval of 8 weeks.[31] 
These first cases of PRRT with 177Lu-OPS201 showed promising results. Regarding adverse 
events (AEs), one patient experienced a short episode of flush just after injection of 
177Lu-OPS201. Another patient developed Grade 3 thrombocytopenia (41,000/mm3), which 
completely recovered within 8 weeks after injection of 177Lu-OPS201. There was no relevant 
decrease of tubular kidney function within 12 months of follow-up. Also, creatinine levels did 
not significantly change before and approximately 12 months after treatment. In summary, the 
first treated patients showed promising clinical results without any adverse reactions of concern.
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Since the expected side effects of 177Lu-OPS201 are caused by the administered radioactivity 
rather than by toxic effects of the peptide itself, known adverse reactions comparable to PRRTs 
with the established agonistic SSAs 177Lu-DOTA-TATE and 177Lu-DOTA-TOC are 
anticipated.[35] 
1.3.6.1 
Acute Reaction 
Adverse events such as nausea, headache and rarely vomiting due to metabolic acidosis induced 
by the amino acid coadministration do occur in the majority of subjects.  
The PRRT may exacerbate the syndromes related to the respective functional tumours, due to 
the sudden massive release of the hormones and receptor stimulation. The clinical manifestation 
is dependent on the specific hormone involved.  
1.3.6.2 
Delayed Reactions 
Delayed adverse reactions of PRRTs have been reported mainly for kidney function and blood 
building cells in the bone marrow.[35] 
1.3.6.2.1 Renal Toxicity 
To safeguard the kidneys as the dose-limiting organs from the activities normally reached with 
PRRT, kidney protection measures such as infusion of cationic amino acids must be performed. 
However, in some cases, despite kidney protection, loss of kidney function can occur after 
PRRT, with a creatinine clearance loss of about 3.8% per year for 177Lu-DOTA-TATE. Delayed 
renal toxicity was observed more frequently in subjects with predisposing risk factors including 
longstanding and poorly controlled hypertension and diabetes mellitus. 
1.3.6.2.2 Bone Marrow Toxicity 
Severe (Grade 3 and 4), mostly reversible, acute bone marrow toxicity is observed in only 2% 
to 3% of cycles with 177Lu-DOTA-TATE. Nevertheless, sporadic cases of myelodysplastic 
syndrome or overt acute myelogenous leukaemia have been reported. 
1.4 
Phase I Investigator Study 
An investigator sponsored study by Memorial Sloan Kettering Cancer Center (MSKCC), New 
York, USA was also initiated (NCT02609737). A total of 19 subjects (52% female) with heavily 
treated NETs and an average age of 55 years (range: 22 to 73) were included in this study. 
Subjects received an administration of approximately 1 to 2 GBq of 177Lu-OPS201 for 
dosimetry purposes. The cumulative radioactivity for the consecutive therapeutic 
administrations was calculated based on the dosimetry results, ensuring that organ dose limits 
are not exceeded. The cumulative radioactivity was fractionated into two single administrations 
with a highest single radioactivity of 7.86 GBq and a highest cumulative radioactivity of 
16.65 GBq. The administered compound contains up to 100 g peptide (based on information 
from July 2016). 
Seven subjects received two therapeutic cycles of 177Lu-OPS201 with cumulative activities 
ranging from 13.28 to 16.65 GBq and the other subjects received only one therapeutic cycle 
with cumulative activities ranging from 6.94 to 9.43 GBq. After the first cycle the subacute 
haematological toxicity was mild to moderate in 17 subjects (79%) and two subjects exhibited 
Grade 3 leukopenia that reversed to Grade 1 or Grade 0 before the second cycle. By contrast, 
four of seven subjects were noted to have Grade 4 haematological toxicities (four 
thrombocytopenia and one leukopenia) starting 4 to 6 weeks after the second cycle. These 
Grade 4 toxicities were long lasting and resolved to Grade 2 or lower in 16 to 26 weeks after 
the last treatment cycle; none of these subjects demonstrated fever, infection, bleeding, or renal 
toxicity. The mean relative bone marrow absorbed dose (image-based method) was 
0.077 Gy/GBq (range: 0.049 to 0.11) and the individual bone marrow absorbed doses ranged 


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from 1.3 Gy to 1.5 Gy in subjects who showed severe thrombocytopenia whereas it was below 
1 Gy in the other subjects. 
Following these safety events, the study was put on clinical hold and restarted following a 
protocol amendment that included lower radioactivity of 177Lu-OPS201 in each cycle and a 
lower limit of permitted exposure to the bone marrow (1 Gy). 
The median tumour absorbed dose in this study was about 7.2 Gy/GBq. Preliminary efficacy 
results indicate that one subject had a CR (5%), six had a partial response (PR) (32%), nine had 
SD (47%) and three had disease progression (16%). Among the seven subjects who received 
the two therapeutic cycles (13.28 GBq to 16.65 GBq), one subject had a CR (14%), three had a 
PR (43%), two had SD (29%) and one had disease progression (14%). 
1.5 
Rationale for the Study 
In preclinical studies the high potential of 177Lu-OPS201 as therapeutic agent for PRRT against 
GEP NETs has been demonstrated. In a preliminary study under compassionate use it was 
shown that these results are reflected in clinical examples.[43] 
Other NETs beside GEP NET also express sstr2 (the target of 177Lu-OPS201) thus providing 
scientific rationale for the inclusion of patients with NET tumours. Indeed, in the academic pilot 
study, which is described in Section 1.3.5, a patient with lung NET had been included who 
presented with a PR after treatment with 177Lu-OPS201. Furthermore, since NET is a rare 
disease, enlargement of the population to more subtypes of this disease will facilitate 
recruitment for this study. 
To make this treatment available to NET patients, systematic assessments are required for 
marketing approval. The first milestone is the demonstration of the safety and tolerability of the 
treatment, which is the classical endpoint of a phase I trial. In radiopharmaceutical studies this 
safety assessment also includes dosimetry studies to evaluate the radioactive exposure of 
organs. For PRRT the dose-limiting organ is usually the kidney with a safety limit of 23 Gy. 
Since a single administration of 177Lu-OPS201 would only carry a burden for the patient without 
the benefit of a complete PRRT treatment, it was decided to expand the study to a phase I/II 
trial with three cycles of 177Lu-OPS201 treatment with an implemented radioactivity escalation 
step (in case the bone marrow and kidney dose do not exceed 1.5 Gy and 23 Gy, respectively). 
This provides not only the possibility to evaluate the safety and tolerability of a whole PRRT 
treatment with 177Lu-OPS201, but also first information about the efficacy of the treatment. To 
create sufficient data for the set-up of a phase II/III trial, based on the phase I/II results, a study 
population of up to 55 subjects with histologically confirmed diagnosis of GEP and lung NETs 
and pheochromocytoma and paraganglioma is planned. 
1.6 
Justification of Dose 
In a joint practical guidance, the International Atomic Energy Agency (IAEA), the European 
Association of Nuclear Medicine (EANM), and the Society of Nuclear Medicine and Molecular 
Imaging (SNMMI) describe the performance of PRRT in NETs as a very practical 
orientation.[35] 
For the agonistic SSAs 177Lu-DOTA-TATE and 177Lu-DOTA-TOC they suggest an applied 
radioactivity of 5.55 GBq to 7.4 GBq per cycle and a total of three to five cycles with a time 
interval between the cycles of 6 to 12 weeks.[35] 
For this phase I/II study the planned radioactivity escalation ranges are in these limits. The 
original starting radioactivity chosen for this study was three cycles of 5.5 GBq of 
177Lu-OPS201. However, after preliminary results from an investigator-initiated trial (IIT) 
(refer to Appendix 5: Safety Information Letter), this radioactivity is now reduced to 4.5 GBq 
(target radioactivity 4.5 GBq±10%), resulting in a maximal targeted cumulative administered 


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radioactivity of 13.5 GBq fractionated into three administrations. This is in line with the pilot 
trial from Wild et al, [31] where the mean bone marrow dose was 0.1 Gy/GBq, and a cumulative 
radioactivity of 13.7 GBq with a bone marrow dose of 1.3 Gy did not lead to high grade 
haematotoxicity. A lower dose was not chosen to prevent under-treatment of patients. The 
international limit of the maximum bone marrow dose for nonmyeloablative therapeutic 
administrations is 2 Gy. In the referenced IIT, Grade 3 and higher haematotoxicity has been 
seen above bone marrow doses of 1.3 Gy and 0.9 Gy depending on the method of bone marrow 
dosimetry, which were based on blood and image analysis or blood analysis only. In the Wild 
et al [31] trial, Grade 3 thrombocytopenia was seen in one patient with a bone marrow dose of 
1.5 Gy, calculated by a dosimetry method based on blood analysis only. Results of bone marrow 
dosimetry are variable and depend on the methodology used. Compared to methods taking into 
account blood and image analysis, methods based on blood analysis seem to underestimate the 
bone marrow dose.[44] In this study a method based on blood and image analysis will be used 
and the maximum bone marrow dose will be reduced to 1.5 Gy. The cumulative organ doses of 
kidney (maximum cumulative kidney dose is 23 Gy) and bone marrow are monitored in an 
ongoing manner. If a previous cumulative dose indicates that the organ limits will be exceeded 
with the next cycle, the radioactivity of the next cycle can be reduced or the cycle can be 
delayed.  
In Part B of this study both the radioactivity and the peptide mass dose will be escalated. The 
planned radioactivity escalation can be reduced or increased to three cycles of up to 7.4 GBq 
(target injected radioactivity of 7.4 GBq±10%) 177Lu-OPS201, depending on the safety data 
from Part A and ongoing evaluation of Part B.  
Based on clinical experience, the practical guidance proposes peptide mass doses of 100 g to 
200 g and an upper limit of 250 g for 177Lu-labelled agonists. However, this limit was not 
explained. 
In the preliminary therapeutic study under compassionate use performed at the University 
Hospital in Freiburg, a peptide dose of 105±35 g was applied.[43]  
 
 
 
 
 
 
Peptide 
mass doses of 300 g, 700 g and 1300 g (target mass dose±15%) will thus be evaluated in 
this study. The lowest peptide mass dose (300 g) is higher than the dose of 100 g used in 
the Wild 2014 study. [43] 
Subject safety will be monitored by a safety review committee (SRC) in Part A and a data 
review board (DRB) in Part B (see Section 3.8).  
1.7 
Risk-benefit Assessment 
As many radiopharmaceuticals are excreted rapidly in the urine, the absorbed dose to the wall 
of the urinary bladder is often large compared with the absorbed dose to other organs and tissues 
exposed to the same study dose [45]. In the urinary bladder wall and liver, the estimated 
absorbed doses (8.2 and 10.9 Gy, respectively) at the anticipated highest cumulative 
administered activity (3x7.4=22.2 GBq) are far lower than the radiation dose limit thresholds 
in the published literature (35 Gy for liver and 60 Gy for urinary bladder wall) [46]. 
Another factor that may potentially affect the development of haematological toxicity is 
radiation exposure to the spleen. As the spleen is part of the immune system, it can produce 
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blood cells and act as a major reservoir for red, white blood cells and platelets [47, 48, 49]. It 
is reported to be the organ that receives the highest mean absorbed dose of all organs during 
PRRT [50, 51], partly because of the presence of somatostatin receptors on lymphocytes [52, 
53]. A dose dependent relationship may exist between the total absorbed dose to the spleen and 
the blood cell count [54]. In the spleen, the estimated absorbed dose is 66.6 Gy at the anticipated 
highest administered activity (3x7.4=22.2 GBq).  However, there are no known radiation dose 
limits described in the literature. 
Another potential risk is toxicity to other organs expressing somatostatin receptors (sstr2), such 
as the pituitary gland and pancreas as these organs are also potentially targeted by PRRT [55, 
56, 57]. Therefore, it is not unlikely that patients treated with PRRT maybe are at risk of 
developing hormone disturbances or deficiencies during their follow-up period. To monitor any 
adverse effect on organs expressing sstr2, specific markers will be measured at each cycle 
during the study. For example, specific markers of the function of the hypothalamic-pituitary-
adrenal axis, thyroid stimulating hormone (TSH), cortisol and IGF-1 will be measured at 
baseline, on Day 1 of each cycle and Day 2 of the first cycle and at the end of the core trial. 
Blood glucose will also be monitored. 
All the other organs show less uptake with specific absorbed doses around 0.1 Gy/GBq and 
thus do not present any risk of overexposure compared to the radiation dose limit thresholds in 
the published literature [43]. The exception is the ovaries, where the radiation dose limit is 2 to 
3 Gy (over this limit, there is a risk of permanent sterilisation). With a specific absorbed dose 
of 0.1 Gy/GBq, absorbed doses of about 2.2 Gy could be reached at the highest administered 
activity (22.2 GBq). 
For Part A, every subject enrolled in this study must meet the inclusion criteria of having 
histologically confirmed diagnosis of unresectable NET and progressive disease (PD) 
according to the Response Evaluation Criteria In Solid Tumours (RECIST; v1.1 – see Appendix 
2). PRRT is an effective therapy for patients with inoperable or metastasised NETs; conditions 
that are very common for this type of cancer due to the typically late diagnosis.[7, 8] Even in 
heavily pretreated patients with GEP NET, PRRT with 177Lu-labelled sstr2 agonists have 
achieved remarkable response rates, and combined with kidney protective agents, the side 
effects of this therapy are few and mild.[58, 59] 
For Part B, since the data became available that increasing peptide mass might be beneficial by 
improving the lesion to background radioactivity level, the study design was changed. Eight 
cohorts have been developed in a dose escalation methodology to assess both increasing peptide 
mass dose and increasing radioactivity. The design in two cohorts is a test-retest of increasing 
peptide at the second cycle to evaluate if receptor saturation is occurring. To ensure sstr2 lesions 
can be precisely evaluated with image dosimetry, a minimum of two sstr2 positive lesions are 
required for entry into the study. Hence the eligibility criteria are changed for Part B. This 
change is more stringent than the current eligibility criteria for Part A. 
Preliminary data from the MSKCC study have been taken into account in the design of 
Study OPS-C-001. The new study investigates the same compound (177Lu-OPS201), but with 
a higher peptide mass dose of 300 g for Part A (compared to <100 g in the MSKCC study). 
The planned cumulative radioactivity to be administered in Part A of the study is no more than 
13.5 GBq, which is generally lower than the therapeutic cumulative radioactivity used in the 
MSKCC study. Furthermore, this cumulative radioactivity is fractionated into multiple 
administrations at lower radioactivity compared to the MSKCC study (3×4.5 GBq versus 2×of 
up >7 GBq). This approach is used since fractionation has been shown to contribute to better 
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Additional precautionary measures will include sequential recruitment in the first phase. An 
SRC will be held after full exposure of the first six subjects and before exposing a further 
nine subjects to the full radioactivity in Part A of the study (i.e. the seventh to fifteenth subjects 
can have up to two administrations but not more until the SRC on the first six subjects has been 
completed). The SRC will evaluate the safety data obtained until 8 weeks after the last 
administration of the sixth subject.  
Prior to Part B, the SRC will review the safety and dosimetry data of all subjects included in 
Part A and a minimum of six completed subjects.  
Detailed criteria, based on the percentage of subjects experiencing dose limiting toxicities 
(DLTs), have been carefully defined in the protocol in order to guide the radioactive dose 
selection for further enrolment in Part A and throughout Part B.  
Haematology will be closely followed-up after each administration with daily monitoring 
during the first week and additional monitoring at 2 weeks after administration and every 
2 weeks thereafter. 
Participating subjects may be hospitalised until Day 2. The period of hospitalisation is left at 
the discretion of the investigator to allow the radioactivity levels to come back to safe levels for 
discharge and to protect medical personnel and relatives.  
Maximum cumulative bone marrow exposure will be reduced to 1.5 Gy, a dose level used in 
the pilot study with no reported high grade haematotoxicity.[43]  
Dosimetry will be measured up to 168 hours after each administration to describe the full bone 
marrow dose over the entire administration course. 
The decision regarding the administered radioactivity at Visits 2 and 3 will be made only after 
careful consideration of the dosimetry and safety data following the preceding administration. 
If the investigator is considering additional cycles for subjects, the benefit-risk need to be 
considered and discussed with the subjects with the approval of the sponsor. 
In conclusion, the reduced radioactivity of 4.5 GBq together with the increased peptide mass in 
the proposed study compared to the MSKCC and the pilot[43] studies, are considered safe for 
administration to subjects, especially with the additional safety measures defined in the protocol 
(e.g. sequential recruitment and possible radioactivity reduction at Cycles 2 and 3). 
Treatment benefit has been seen in the MSKCC and the pilot studies at even lower cumulative 
radioactivities than those planned, hence treatment benefit is also expected in this study. Taken 
together, an overall favourable benefit/risk ratio is expected for the subjects participating in 
Study OPS-C-001. 
1.8 
Compliance Statement 
The study will be conducted in compliance with independent ethics committees/institutional 
review boards (IECs/IRBs), informed consent regulations, the Declaration of Helsinki and 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. Any 
episode of noncompliance will be documented. In addition, the study will adhere to all 
appropriate local regulatory requirements and relevant company policies.  
Data will be collected by using an electronic case report form (eCRF) in compliance with Food 
and Drug Administration (FDA) 21 Code of Federal Regulations (CFR) Part 11. 
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided to 


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subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
Almost all NETs express sstr2, making these tumours a potential target for treatment with 
PRRT. Therefore, the scientific rationale is to use sstr2 specific overexpression as a mean to 
target the delivery of the radioactivity to the tumour cells. This characteristic of sstr2 targeting 
shows promise as a personalised treatment approach such as theranostic combining imaging 
and therapy. The SSA peptide component (OPS200) is the targeting moiety of the compound 
with selective high affinity for sstr2 (OPS201 IC50=0.70 nM and 177Lu-OPS201 dissociation 
constant (Kd=0.072 nM) and antagonistic behaviour, thus no signal transduction is expected by 
the binding of 177Lu-OPS201 to sstr2.  
177Lu is the active moiety of the compound; it is a ȕ minus emitting radionuclide, with a mean 
energy of 0.133 MeV and a mean penetration depth of 0.23 mm.[35] In addition to ȕ-emission, 
177Lu has gamma rays which allow performing SPECT images and consequently dosimetry. 
Hence, the compound 177Lu-OPS201 may offer a treatment option beyond standard of care for 
NETs where there are still unmet clinical and therapeutic needs (see Section 1.3.2.2). 
The purpose of the phase I of the study is to evaluate the safety and tolerability of the compound 
177Lu-OPS201 in previously treated subjects with unresectable GEP NETs, Lung NETs and 
malignant, unresectable pheochromocytoma or paraganglioma as well as to recommend a 
treatment schedule for the phase II; i.e. recommended cumulative radioactivity and 
fractionation, dosing interval and peptide mass dose.  
2.2 
Study Objectives 
The primary objective of the study is to assess the safety and tolerability of PRRT with 
177Lu-OPS201 administered in three cycles in subjects with sstr2 positive NETs (including 
phaechromocytomas and paragangliomas). 
The secondary objectives of the study are as follows: 
• 
to evaluate the optimal radioactivity and peptide mass dose to be used in future studies; 
• 
to characterise 
177Lu-OPS201 whole body biodistribution and PK of the 
radiopharmaceutical after each administration of 177Lu-OPS201; 
• 
to determine the radiation dosimetry of 177Lu-OPS201 (organ exposure to administered 
radioactivity) after each administration of 177Lu-OPS201 with three different peptide 
mass doses; 
• 
to undertake a preliminary assessment of the therapeutic efficacy of 177Lu-OPS201 PRRT 
by determination of RECIST v1.1 status; 
• 
to evaluate the influence of 177Lu-OPS201 PRRT on the subject’s quality of life. 
The exploratory objectives of the study are as follows: 
• 
to determine the PK of OPS201 in plasma and urine; 
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2.3 
Study Hypotheses 
(1) 
177Lu-OPS201 will be sufficiently safe to permit further clinical investigation when 
administered in previously treated subjects with unresectable GEP NETs, lung NETs and 
malignant, unresectable pheochromocytoma or paraganglioma. 
(2) 
Increase of peptide mass doses leads to improved tumour to background ratio for 
177Lu-OPS201 administration, with a possible positive impact on the safety profile with 
an increasing tumour to bone marrow ratio. 
3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is an open-label study to evaluate the safety and tolerability of 177Lu-OPS201 for the 
treatment of NETs. This international, multicentre study is planned to be conducted in 
approximately 20 sites with distinguished experience in PRRT or comparable nuclear medicinal 
applications in Europe, USA and Australia. 
The study will be performed in two parts, Part A and Part B. 
Up to 55 subjects with histologically confirmed diagnosis of GEP NETs, lung NETs or 
pheochromocytoma or paraganglioma will be recruited in the trial: 
• 
Part A: a minimum of six subjects and up to 15 subjects; 
• 
Part B: a minimum of 25 subjects and up to 40 subjects.  
Eligible subjects will receive three administrations (or up to 5 cycles in Part B; see 
Section 3.1.5) of 177Lu-OPS201 at 8-week intervals (+2 weeks, or up to +4 weeks in case of 
AEs which have not adequately recovered (see Section 4.6)).  
Subject safety and dose escalation (before initiating Part B) will be evaluated by an SRC in 
Part A and a DRB (Part B) (see Section 3.8 and Appendix 3). 
The overall study design is shown in Figure 11, Figure 12 (Part A) and Figure 13 (Part B). 
After signing informed consent, subjects will undergo screening (Screening Visit) 
up to 4 weeks before the first administration of 177Lu-OPS201 to check enrolment eligibility 
criteria. A contrast enhanced CT/MRI scan (baseline for RECIST v1.1 evaluation) will be 
performed and a screening SRS will also be performed (unless already performed within 
6 months prior to Visit 1 Day 1). Eligibility read for SRS and CT/MRI scans will be performed 
locally at screening. However, all images, including SRS, will be sent to the imaging core 
laboratory for later evaluation.  
Although the visits are similar in Part A and Part B, there is a change in the amendment 
version 6.0 in the CT/MRI imaging which only affects Part B, hence visits for Part A and B are 
described separately. In both Part A and Part B, the end of the core study is defined as the End 
of Core Trial (EOCT) Visit of the last subject. 
During the study, subjects will attend the following visits: 
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Part A 
Visit 1: On Visit 1 Day 1, subjects will receive the first administration of 177Lu-OPS201 
followed by safety and extended dosimetry evaluations over 8 days, with additional laboratory 
safety tests repeated at Day 15 (±2 days). At 4 weeks (±5 days) after Visit 1 Day 1 (i.e. 
Follow-up Visit 1), the safety of the subjects will be assessed. 
Visit 2: 8 weeks after Visit 1 Day 1 (+2 weeks or up to +4 weeks in case of AEs which have not 
adequately recovered) subjects will receive the second administration of 177Lu-OPS201 
followed by safety and dosimetry evaluations over 8 days, with additional laboratory safety 
tests repeated at Day 15 (±2 days). At 4 weeks (±5 days) after Visit 2 Day 1 (Follow-up 
Visit 2), the safety of the subjects will be assessed. Additionally, subjects will receive a CT/MRI 
scan to monitor the RECIST v1.1 status and tumour volume changes. 
Visit 3: 8 weeks after Visit 2 Day 1 (+2 weeks or up to +4 weeks in case of AEs which have not 
adequately recovered), subjects will receive the third administration of 177Lu-OPS201 followed 
by safety and dosimetry evaluations over 8 days, with additional laboratory safety tests repeated 
at Day 15 (±2 days). At 4 weeks (±5 days) after Visit 3 Day 1 (Follow-up Visit 3), the safety of 
the subjects will be monitored. 
EOCT Visit: 8 weeks (±5 days) after Visit 3 Day 1, the safety and efficacy of the treatment will 
be evaluated. Subjects enrolled in Part A after the protocol version (v6.0) comes into effect will 
receive a CT/MRI scan to monitor the RECIST v1.1 status and tumour volume.  
Part B 
Visit 1: On Visit 1 Day 1, subjects will receive the first administration of 177Lu-OPS201 
followed by safety and extended dosimetry evaluations over 8 days, with additional laboratory 
safety tests repeated at Day 15 (±2 days). At Week 4 (Day 29±5 days), Week 6 (Day 42±5 days) 
(i.e. Follow-up Visit 1) and at intermediate timepoints, the safety of the subjects will be 
assessed.  
Visit 2: 8 weeks after Visit 1 Day 1 (+2 weeks or up to +4 weeks in case of AEs which have not 
adequately recovered) subjects will receive a CT/MRI scan to monitor the RECIST v1.1 status 
and tumour volume. Subjects will then receive the second administration of 177Lu-OPS201 
followed by safety and dosimetry evaluations over 8 days, with additional laboratory safety 
tests repeated at Day 15 (±2 days). At Week 4 (Day 29±5 days), Week 6 (Day 42±5 days) 
(Follow-up Visit 2) and at intermediate timepoints, the safety of the subjects will be assessed.  
Visit 3: 8 weeks after Visit 2 Day 1 (+2 weeks or up to +4 weeks in case of AEs which have not 
adequately recovered), subjects will receive a CT/MRI scan to monitor the RECIST v1.1 status 
and tumour volume. Subjects will then receive the third administration of 177Lu-OPS201 
followed by safety and dosimetry evaluations over 8 days, with additional laboratory safety 
tests repeated at Day 15 (±2 days). At Week 4 (Day 29±5 days), Week 6 (Day 42±5 days) 
(Follow-up Visit 3) and at intermediate timepoints, the safety of the subjects will be monitored. 
EOCT Visit: 8 weeks (±5 days) after Visit 3 Day 1, the safety and efficacy of the treatment will 
be evaluated. Subjects will receive a CT/MRI scan to monitor the RECIST v1.1 status and 
tumour volume. Subjects who are to receive additional cycles of therapy (see Section 3.1.5) 
will undergo the EOCT assessment after Cycle 3. Where possible, the EOCT visit and Visit 4, 
Day 1 of the first additional cycle can be combined. 


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Figure 11 Overview of Study Design for Part A and Part B and Post Study Follow-up
EOCT=end of core trial; W=weeks. *only for Part B
3.1.1
Part A Design
In Part A, it is planned to treat up to 15 subjects with three cycles of 4.5 GBq 177Lu-OPS201. 
An SRC will decide, based on the dosimetry and safety data of the initial three and then 
six subjects, if the remaining nine subjects will continue at the same radioactivity level or if the 
radioactivity has to be adapted. Alternatively, Part A can be closed and Part B initiated.
Figure 12 shows the study design for Part A.
Figure 12 Study Design - Part A
3.1.2
Part B Design 
Part B is a dose escalation both of peptide mass and radioactivity. Up to eight cohorts will be 
enrolled as described below, see Figure 13. 
Part B will encompass radioactivity and peptide mass dose escalation as well as intra-individual 
peptide mass dose evaluation. It consists of up to eight cohorts. In each cohort, each subject 
will receive three cycles of the defined radioactivity and peptide mass dose of 177Lu-OPS201 


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(see Section 6.2, Table 11). Each cycle will be 8 (+2) weeks apart. In case of AEs which are 
not adequately recovered, a further 4 weeks can be added between dosing.  
After the three core-treatment cycles, up to two additional cycles of 177Lu-OPS201 can be 
administered if the subject continues to meet the  criteria outlined in Section 6.4.2 and the 
subject has clinical benefit (defined as CR, PR or SD). The additional cycles are optional and 
must be discussed with the sponsor before administration. 
The population of Cohorts 3 and 6 will enrol eight to 10 subjects to ensure a minimum of eight 
completed subjects. All remaining cohorts (1, 2, 4, 5, 7 and 8) will enrol three to five subjects 
to ensure a minimum of three completed subjects per cohort (see Section 3.3). A completed 
subject is defined as one who has received at least 3 cycles of study treatment or fewer than 
3 cycles if one of the following has occurred: exceedance of organ dose limits, treatment-related 
safety issues or disease progression. 
Figure 13 Study Design - Part B 
 
DRB=data review board; GBq=gigaBecquerel; SRC=safety review committee. 
Each cohort consists of three cycles of treatment. Cohort 2 will not be conducted if 700 ȝg or 1300 ȝg peptide mass is shown 
to be optimal. Cohorts 7 and 8 will not be conducted if 1300 g peptide mass is seen to be too high. Cohorts 3 and 6 require 
10 subjects for eight to be completed. All other cohorts are three to five subjects (minimum of three subjects to be completed). 
3.1.3 
Justification for Part B Design 
In animal experiments, no saturation of the sstr2 was observed when higher peptide mass doses 
were administered in a xenograft mouse model.[39] Nevertheless, the effect of the increasing 
peptide mass dose and the peptide mass at which lesion receptor saturation occurs in humans is 
unknown. The extrapolation from animal experiments may be limited by the fact that, in these 


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xenografts, receptor density was relatively high in comparison to normal distribution of 
receptors in the mouse. 
Receptor saturation by the peptide is predicated on:  
(a) 
the number of receptors in nontumoural tissue (physiological expression) and  
(b) 
tumour burden and related sstr2 density (total receptor burden).  
Regardless of tumour type, the higher the receptor burden the more peptide maybe required 
before saturation occurs. It is therefore important that the peptide masses being studied in this 
protocol are evaluated for sstr2 saturation. Hence Cohorts 3 and 6 will evaluate the peptide 
mass and specifically if receptor saturation has occurred, starting with 300 g for Cycle 1, then 
increasing to 700 g and 1300 g respectively for Cycle 2 before repeating the 300 g dosing 
for Cycle 3 (see Figure 13). Thus, the tumour-to-background dose ratio, and the tumour-to-
bone-marrow dose ratio, using imaging dosimetry, can be evaluated in the same subjects. In 
these cohorts, administering 4.5 GBq/cycle, which was shown to be tolerated in Part A of the 
study, will allow comparison of intra-subject variability of the uptake due only to the peptide 
mass. It also allows Cohort 3 to start in parallel to Cohort 1 which is the next logical increase 
in dosing at 300 g (6 GBq per cycle) following Part A.  
The other cohorts in Part B will be initiated in a staggered manner after gaining experience with 
previous cohorts, thereby allowing safer investigation at higher radioactivity and/or higher 
peptide mass dose. If tumour sstr2 saturation is observed, then the lower peptide dose will be 
confirmed. Therefore, Cohorts 7 and 8 will be cancelled if the peptide saturation is seen in 
Cohorts 3 and/or 6. Similarly, Cohort 2 may be cancelled if a peptide mass dose range of 700 g 
to 1300 g is found to be optimal. 
Subject numbers 
Cohorts 3 and 6 will require 8 subjects to ensure there is sufficient power to demonstrate any 
tumour sstr2 saturation. Therefore 10 subjects will be enrolled to obtain a minimum of 
8 completed subjects. All remaining cohorts (1, 2, 4, 5, 7 and 8) will enrol three to five subjects 
to obtain a minimum of three completed subjects per cohort.  
Hence, it is anticipated that 10 subjects will be enrolled in Cohorts 3 and 6, and five subjects 
will be enrolled in Cohort 1, so the end-point can be achieved in these initial three cohorts 
rapidly (total of 25). To maintain the subject numbers to a maximum of 40 in Part B, if all 
remaining cohorts are utilised (total of five), each will have three subjects enrolled (total of 15).  
Change in eligibility criteria for Part B 
To ensure sufficient precision for the imaging dosimetry (specifically in Cohorts 3 and 6, but 
also for the whole study), eligibility will require a minimum of two lesions 20 mm in diameter. 
Tumour dosimetry should be performed on tumour lesions identified by the imaging core 
laboratory and on no more than five lesions (maximum two per organ, size 20 mm diameter, 
accessible for dosimetry). Furthermore, this ensures the modelling is based on a minimal total 
receptor burden.  
Infusion rate 
The i.v. infusion of 177Lu-OPS201, should be at a rate of 10 mL/h over 120 minutes (see Section 
6.2.1). 
Investigators are advised that prophylaxis may be considered if the patient is thought to be at 
increased risk of infusion-related reactions as per the site’s standard of care (see also 6.3.3 and 
Section 6.3.4). Appropriate treatment should be administered should an infusion-related 
reaction occur including somatostatin analogues. The administered radioactivity and mass dose 
follows the escalation scheme (see Section 6.2).  


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3.1.4 
Long-Term Follow-Up 
The long-term follow-up period will start after the EOCT/end of additional cycles 
(EOAC)/early withdrawal (EW) Visit. 
Tumour assessments will be performed every 3 months (±2 weeks) until whichever occurs first: 
documented disease progression (radiological or clinical as per the investigator's judgment), 
2 years after the EOCT/EOAC/EW Visit, withdrawal of consent, lost to follow-up or death.  
Safety assessments, and the subject’s status, will be performed every 3 months (±2 weeks) until 
whichever occurs first: 2 years after the EOCT/EOAC/EW Visit, withdrawal of consent, lost to 
follow-up or death; please refer to Section 8.1.4.1. 
After the long-term follow-up period is completed i.e. 2 years after the EOCT/EOAC/EW Visit, 
all subjects will be invited to participate in a safety surveillance study, as part of a separate 
study protocol. All subjects will be asked to sign a new informed consent form to enter this 
study. The purpose of the safety surveillance study is to monitor any long-term effects of 
177Lu-OPS201 up to 5 years from the first dose of 177Lu-OPS201. 
The schedule of assessments is provided in a flow chart (see Section 5.1) and is listed in 
Section 5.2. Unless otherwise specified, all assessments will be performed by the investigator 
or accredited study personnel. 
Extra visits, examinations, tests and interventions can be performed at any time if clinically 
indicated, as judged by the investigator.  
3.1.5 
Additional Optional Cycles, Part B 
If a subject tolerates the treatment well and shows clinical benefit (e.g. CR, PR, or SD) up to 
two additional cycles at a radioactivity dose adjusted based on dosimetry results can be 
administered to this subject provided limiting organ absorbed dose levels have not been 
exceeded. Two cycles would consist of 177Lu-OPS201 administration every 8 weeks (+2 weeks, 
or plus up to 4 weeks in case of AEs which are not adequately recovered) with administration 
of the same peptide mass dose as Cycle 1. In this case, subjects will have the same assessments 
as during the core treatment cycles and up to EOAC or EW except for exploratory biomarkers 
. Dosimetry will thus be performed after each 
additional cycle to prevent exceeding limiting organ absorbed doses. For these subjects, an 
EOAC visit will be done 8 weeks (±5 days) after the last 177Lu-OPS201 dose administration. In 
this case, the 2-year long-term follow-up will start at the EOAC (instead of EOCT). 
The decision to administer additional cycles or any other antitumoural treatment is at the 
investigator’s and subject’s discretions and must be discussed with and confirmed by the 
sponsor. However, the investigator should follow the following rules before proceeding to any 
additional administration: 
• 
subjects with DLTs after first, second or third administration will be discontinued from 
177Lu-OPS201. 
• 
subject will be eligible for an additional administration of 177Lu-OPS201 only if: 
- 
renal function and blood cell counts are in the range defined in the study inclusion 
criteria (#12 and #13), within the treatment cycle. 
- 
organ absorbed doses did not exceed 1.5 Gy in bone marrow (BM) and 23 Gy in 
kidneys. 
- 
subject is likely to benefit from additional cycles of 177Lu-OPS201 therapy. 
The planned maintenance dose for any cycle may be adjusted such that the limiting organ 
absorbed doses are not exceeded. 
Subjects who are to receive additional cycles of therapy will undergo the EOCT assessment 
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after Cycle 3. Where possible, the EOCT visit and Visit 4, Day 1 of the first additional cycle 
can be combined. An additional EOAC assessment will be done 8 weeks after the last dose of 
therapy. 
3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Primary Safety Endpoints and Evaluations 
Frequencies and/or descriptive summaries of standard safety and tolerability parameters: AEs 
(including SAEs) according to National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) v5.0 and vital signs, laboratory tests (haematology, biochemistry 
and urinalysis, and pituitary markers), 12-lead and Holter electrocardiogram (ECG), DLTs, 
physical examination results and use of concomitant medication throughout the study. 
3.2.2 
Secondary Endpoints and Evaluations 
3.2.2.1 
Biodistribution and Radioactive Pharmacokinetics of the Radiopharmaceutical 
Endpoints 
• 
Maximal uptake (%) at the target lesions; 
• 
Maximal uptake (%) in discernible organs and blood; 
• 
AUC of 177Lu-OPS201 in discernible thoracic and abdominal organs, target lesions and 
blood; 
• 
Terminal half-life of radioactivity concentrations of the radiopharmaceutical in blood. 
3.2.2.2 
Radiation Dosimetry Endpoints  
• 
Organs receiving the highest absorbed dose; 
• 
Specific absorbed dose to the target lesion (Gy/GBq); 
• 
Specific absorbed dose per organ (Gy/GBq); 
• 
Cumulative absorbed organ doses (Gy). 
3.2.2.3 
OPS201 Pharmacokinetics Endpoints 
• 
If OPS201 levels are measurable in plasma and urine, PK parameters of OPS201 
(including, but not limited to, maximum observed concentration (Cmax), AUC, 
elimination half-life (t1/2), apparent total body clearance of the drug from plasma (CL), 
apparent volume of distribution (Vd), cumulative amount of unchanged drug excreted 
into the urine (Ae), renal clearance of the drug from plasma (CLR) will be derived using 
the noncompartmental approach on the individual plasma concentration-time profiles of 
OPS201 and on the individual urine concentrations. 
 
 
3.2.2.4 
Secondary Efficacy Endpoints 
• 
Objective tumour response based on RECIST v1.1 (CT/MRI scan) by calculating best 
overall response (BOR), overall response rate (ORR) and disease control rate (DCR); 
• 
PFS based on RECIST v1.1. 
3.2.2.5 
Influence of 177Lu-OPS201 PRRT on the Quality of Life of the Subjects 
• 
Quality of Life Questionnaire ((QLQ)-C30; GI.NET21) change from baseline to EOCT. 
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3.3 
Exploratory Endpoints 
3.4 
Randomisation and Blinding 
This is a nonrandomised, open label study. All eligible subjects will be assigned active study 
medication according to the radioactivity/peptide mass dose escalation plan. Independent 
readers will evaluate SPECT/CT Imaging and will be blinded to the radioactivity and peptide 
mass dose, investigator site and clinical status of the subject, including pathology, laboratory, 
medical history and physical examination findings.  
Independent readers are specialised radiologists and/or nuclear medicine physicians who are 
experienced in reading SPECT/CT scans. To minimise inter- and intra-reader variability in 
results, the readers will be specifically trained for this protocol. See the Imaging Review 
Charter. 
3.5 
Maintenance of Randomisation and Blinding 
This is a nonrandomised, open-label study. 
3.6 
Study Treatments and Dosage 
The study treatment is manufactured and supplied to the clinical site as follows: 
• 
clinical sites located in North America: from a central contract manufacturing 
organisation (Sofie Co., dba Sofie, 110 Clyde road, Somerset, NJ 08873, USA); 
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• 
clinical sites located in Europe: from a local radiopharmacy or from a central contract 
manufacturing organisation (Sofie Co., dba Sofie, 110 Clyde road, Somerset, NJ 08873, 
USA); 
• 
clinical sites located in Australia: from a local radiopharmacy or from a central 
radiopharmacy (Brett and Peter Pty Ltd, located at Australian Radiopharmacy Group, 19 
Prime Street, Thomastown, 3074, Victoria, Australia). 
The study treatment will be supplied in a type 1 borosilicate glass vial sealed with a chlorobutyl 
stopper and aluminium seal, within a secondary shielding container, and is shipped inside Type 
A package for transporting radioactive materials when relevant. The study treatment will be 
labelled according to good manufacturing practice (GMP) and any applicable local 
laws/regulations. 
The investigator’s representative will receive: 
• 
a Certificate of Analysis for each treatment which reflect the product release statement; 
• 
Material Data Safety Sheet; 
• 
packaging order. 
Each label will be designed in accordance with Appendix 13 of the European Union (EU)-GMP 
and in accordance with specific local requirements if any. 
For Part A the study treatment is a 20 mL solution for injection with OPS201 peptide mass dose 
of 300 ȝg with applied radioactivity of 4.5 GBq 177Lu-OPS201 at the intended time and date of 
administration. 
For Part B, the study treatment is a ready-to-inject 20 mL solution with OPS201 peptide mass 
dose nominally of either 300, 700 or 1300 ȝg and applied radioactivity dose of 4.5 GBq to 
7.4 GBq 177Lu-OPS201 at the intended time and date of administration. 
The investigator or designee will only dispense the study treatment to subjects included in this 
study. Each subject will be given the study treatment carrying his/her number. 
A more detailed description of administration procedures is given in Section 6.2. 
3.7 
Study Duration 
The estimated core trial duration of Part A is 18 to 21 months (for all subjects) including 6 to 
10 months of treatment for a single subject, while the long-term follow-up will last for up to 
2 years after the EOCT/EW Visit. The estimated core trial duration of Part B is 14 to 20 months 
(for all subjects) including 6 to 10 months of treatment for a single subject, while the long-term 
follow-up will last for up to 2 years after the EOCT/EOAC/EW Visit. After the long-term 
follow-up period is completed i.e. 2 years after the EOCT/EOAC/EW Visit, all subjects will be 
invited to participate in a safety surveillance study (see Section 3.1.4). 
3.8 
Safety Review Committee (Part A) and Data Review Board (Part B) 
The SRC will be composed of all investigators, who have treated at least one subject in the 
respective cohort with study medication, a dosimetry expert evaluating the dosimetry data of 
the study, an independent haematology expert and at least one sponsor representative. A 
specific charter will be developed to define roles and responsibilities, as well as the data set to 
be reviewed by the SRC. 
This study will be performed in two phases: 
Part A (15 subjects) 
Initially, six subjects will be treated in Part A. Each subject will receive three cycles of 4.5 GBq 
(target radioactivity of 4.5 GBq±10%) 177Lu-OPS201 (target dose of 300±50 g), 8 weeks apart 
(+2 weeks or up to +4 weeks in case of AEs which have not adequately recovered). 


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An SRC meeting will be held before exposing the remaining nine subjects in Part A to the entire 
number of planned administrations. Safety and dosimetry data from the first six subjects (data 
obtained up to 8 weeks after the last administration for each subject) will be evaluated during 
this SRC. 
Dose limiting toxicity definition: IRPP related AEs with a severity of Grade 3 or higher are 
considered DLT, with the exception of hair loss, lymphopenia, nonfebrile neutropenia lasting 
<4 weeks and thrombocytopenia lasting <4 weeks. 
• 
If DLTs occur in 33% of subjects, the remaining nine subjects will continue at the same 
radioactivity level. 
• 
If DLTs occur in >33% of subjects, the administered radioactivity will be reduced to a 
cumulative radioactivity which did not lead to DLT occurrence with this frequency, 
e.g. the number of administrations will be reduced from three to two. 
After treatment completion of the sixth subject (Part A), the SRC will decide, based on the 
safety and dosimetry data from Part A, if a radioactivity escalation is applicable in Part B.  
The decision must be unanimous among the SRC members. The IRB/ECs will be notified of 
the radioactivity dose decision by the SRC.  
Part B (up to 40 subjects) 
The DRB will consist of a team of “permanent” decision makers (the core team), including 
selected principal investigators and Ipsen personnel. All final decisions will be made by the 
core team. The number of DRB meetings may change as needed and the DRB can be called 
upon rapidly if there is a safety issue of concern in a cohort. The aim is to have all meetings via 
conference call, but if the timing does not allow for this, then the meeting can be conducted via 
email exchange or two conference calls with split attendees. A DRB charter will be developed 
with further details. Ad hoc DRBs can be convened at any time during the trial. See Appendix 
3 for the details of the review required by the DRB.  
Dose escalation (peptide mass dose and radioactivity, see Figure 13) will primarily be decided 
based on the clinical and safety data of the subjects.  
Dose limiting toxicity (DLT) definition in Part B: IRPP related AEs with a severity of Grade 3 
or higher are considered DLTs, with the exception of hair loss, lymphopenia, nonfebrile 
neutropenia lasting <4 weeks and thrombocytopenia lasting <4 weeks.  
Proceeding to the next cohort will be determined by the following DLT rules based on three 
evaluable subjects: 
If DLTs occur in >33% of subjects in the cohort, the next cohort will not be initiated. 
• 
If DLTs occur in 33% and 2 of the three subjects have a cumulative absorbed dose in 
each target organ exceeding the acceptability limits (1.5 Gy in BM and 23 Gy in kidney), 
subjects in the next cohort will receive the same cumulative radioactivity or less than in 
the preceding cohort.  
• 
If DLTs occur in 33%, and <2 of the three subjects did not reach the cumulative 
absorbed dose in each target organ (1.5 Gy in BM and 23 Gy in kidney), the next cohort 
will be initiated as planned. 
Each dose escalation (both peptide mass and radioactivity) will be carefully evaluated by the 
DRB. As safety and dosimetry information becomes available in other cohorts, this data will be 
used to evaluate the on-going cohorts and the subjects’ dosing within the cohorts.  
The DRB can make a recommendation as to the radioactivity dosing for the next cohort. This 
could include continuing the current cohort to complete five subjects for review. Alternatively, 
if any cohort dose (peptide or radioactivity) is closed down, with agreement from the DRB, the 


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next lowest dose may have three more subjects entered to confirm this is the maximum tolerated 
dose. 
Based on the overall safety results, the DRB can also decide to start earlier or delay cohorts 
depending on the information available. Notification will be given to the principal investigators 
if this is to occur, with the rationale, as well as to the IRB/EC. 
3.9 
Source Data Recorded on the Case Report Form 
Data will be collected in the eCRF in compliance with FDA 21 CFR Part 11. As required by 
GCP, the sponsor assigned monitor will verify, by direct reference to the source documents, 
that the data required by the protocol are accurately reported on the eCRF.  
The source documents must, as a minimum, contain a statement that the subject is included in 
a clinical study, the date that informed consent was obtained prior to participation in the study, 
the identity of the study, diagnosis and eligibility criteria, visit dates, IRPP administration, and 
any AEs and associated concomitant medication. 
As required by ICH GCP Section 6.4.9, if some items are recorded directly on the eCRF and 
are considered as source data, the identification of these data must be documented and agreed 
between the investigator and the sponsor. 
Definition for source data and source documents are given below: 
• 
Source data: All original records and certified copies of original records of clinical 
findings, observations, or other activities necessary for the reconstruction and evaluation 
of the study. Source data are contained in source documents (original records or certified 
copies). 
• 
Source documents: Original documents, data and records (e.g. hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories and at medicotechnical departments involved in 
the clinical study). 
Imaging data for all subjects will be recorded electronically on digital media. These data and 
print-outs will be considered as source. 
The subject must have consented to their medical records being viewed by the sponsor’s 
authorised personnel, and by local, and possibly foreign, Competent Authorities (CAs). This 
information is included in the informed consent. 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
All subjects must fulfil all the following criteria to be included in the study: 
(1) 
written informed consent; 
(2) 
subjects of either gender, aged 18 years; 
(3) 
women of childbearing potential (not surgically sterile or less than 2 years 
postmenopausal) must use a medically accepted method of contraception and must agree 
to continue use of this method for the duration of the study and for 6 months after the last 
dose. Acceptable methods of contraception include abstinence, or double contraception: 
steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a 
barrier method (intrauterine device, condom, etc.); 


IPSEN GROUP 
OPS-C-001 / D-FR-01072-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 60 
 
(4) 
male subjects must use a medically accepted method of contraception and must agree to 
continue the use of this method for the duration of the study and for 6 months after the 
last radioactivity administration; 
(5) 
Karnofsky performance score 60; 
(6) 
life expectancy of at least 6 months; 
(7) 
histologically confirmed diagnosis of: 
• 
unresectable GEP NET (Grade I and Grade II according to WHO classification 
(2010, see Appendix 1), functioning and nonfunctioning); 
• 
unresectable “typical lung carcinoid” or “atypical lung carcinoid” are acceptable 
(with the exception of Large Cell Bronchial Neuroendocrine Neoplasms and Small 
Cell Lung Cancers) [60]; 
• 
malignant, unresectable pheochromocytoma or paraganglioma; 
- 
subjects, who have histologically confirmed NET, but no clear localisation 
of their primary tumour, can be included; 
(8) 
documentation of PD based on RECIST v1.1 under prior antitumour therapy within 
6 months of Visit 1 Day 1 (although the progression might have occurred more than 
6 months before Visit 1 Day1). Subjects should not have received further antitumour 
therapy once disease progression is documented. All images should be sent to the 
imaging core laboratory; 
(9) 
in countries where sunitinib or everolimus are marketed, subjects with GEP NET and 
lung NET will be progressive under this prior antitumour treatment for the respective 
indication. Subjects not suitable for everolimus/sunitinib therapy according to a tumour 
board decision (or comparable local practice) may also be enrolled into the study. 
Subjects having everolimus/sunitinib therapy should have a wash-out phase of 4 weeks 
before the first treatment; 
(10) measurable disease based on RECIST v1.1; 
(11) For Part A: Confirmed presence of sstr on technically evaluable tumour lesions 
documented by a positive SRS*. If this has not been performed within 6 months of Visit 
1 Day 1, then it must be repeated during screening. 
* presence of at least one lesion that is 20 mm in the longest dimension (as measured 
on correlative CT or MRI scan) and with a maximum standardised uptake value (SUVmax) 
of 2 × the SUVmean of the liver background on 68Ga-PET imaging or a score of “3” or 
“4” according to the Krenning scale on SPECT imaging.  
For Part B: Confirmed presence of sstr on technically evaluable tumour lesions 
documented by a positive SRS*. If this has not been performed within 6 months of Visit 1 
Day 1, then it must be repeated during screening. 
* presence of at least two lesions that are 20 mm in the longest dimension (as measured 
on correlative CT or MRI scan) and with an SUVmax of 2× the SUVmean of the liver 
background on 68Ga-PET imaging or a score of “3” or “4” according to the Krenning 
scale on SPECT imaging. 
(12) calculated glomerular filtration rate (GFR) 55 mL/min; 
(13) blood test results as follows: 
• 
leukocytes: 4*109/L; 
• 
erythrocytes: 3.5*1012/L;  
• 
platelets: 100*109/L; 


IPSEN GROUP 
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• 
albumin: >30 g/L; 
• 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase: 5 times ULN; 
• 
bilirubin: 2 times ULN (2×1.1 mg/dL). 
4.2 
Exclusion Criteria 
Subjects will not be included in the study if the subject: 
(1) 
known hypersensitivity to 177Lu, DOTA, JR11 or to any of the excipients of 
177Lu-OPS201; 
(2) 
Any previous PRRT; 
(3) 
diagnosis of thymic NET; 
(4) 
presence of active infection at screening, or history of serious infection within the 
previous 6 weeks; 
(5) 
administration of any other investigational medicinal product (IMP) within 60 days prior 
to entry (Visit 1 Day 1); 
(6) 
prior or planned administration of a therapeutic radiopharmaceutical within 8 half-lives 
of the radionuclide including any time during the current study; 
(7) 
any extensive radiotherapy 3 months before first IRPP administration; 
(8) 
chemotherapy 3 months before first IRPP administration; 
(9) 
for Part B: Nephrectomy, renal transplant or concomitant nephrotoxic therapy putting 
the subject at high risk of renal toxicity during the study as assessed by the investigator; 
(10a) pregnant or breast-feeding women. A pregnancy serum test will be performed at the start 
of the study for all female subjects of childbearing potential (i.e. not surgically sterile or 
up to 2 years postmenopausal); 
(11) any uncontrolled significant medical, psychiatric or surgical condition (active infection 
(including subject with known hepatitis B or hepatitis C and subjects with known human 
immunodeficiency virus (HIV) positive), unstable angina pectoris, cardiac arrhythmia, 
poorly controlled hypertension, poorly controlled diabetes mellitus (glycated 
haemoglobin (HbA1c) 9%), uncontrolled congestive heart disease, etc.) or laboratory 
findings that, in the opinion of the investigator, might jeopardise the subject's safety or 
that would limit compliance with the objectives and assessments of the study. Note: the 
subject should be able to tolerate high volume load. 
(12) current history of any malignancy other than NET within 5 years of enrolment except for 
fully-resected non-melanoma skin cancer or cervical cancer in situ; 
(13) any mental condition rendering the subject unable to understand the nature, scope and 
possible consequences of the study, and/or evidence of an uncooperative attitude. 
4.3 
Rationale for Inclusion/Exclusion Criteria 
Eligibility criteria define subjects who fulfil the conditions for 177Lu-OPS201 therapy. Subjects 
with neuroendocrine tumours (Grade I and Grade II), including phaeochromocytomas and 
paragangliomas will constitute the population in this study. A documented presence of sstr2 is 
a prerequisite to ensure that the subject may benefit from the sstr2 targeted treatment with 
177Lu-OPS201. Only PD is considered at this early stage of the IRPP development, as it is 
common practice in oncology drug development. 
Importantly, some criteria are added to mitigate: 


IPSEN GROUP 
OPS-C-001 / D-FR-01072-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 62 
 
• 
risks known with PRRT treatment, especially haematological and renal side effects; of 
note, an exclusion criterion was added for Part B to avoid conditions that may put 
subjects at high risk of renal toxicity; 
• 
risk of exposing pregnant women to radiations; 
• 
other risks related to the subject’s current clinical status including co-morbidities and 
concomitant treatments that are not compatible with the study treatment or study 
procedures, or which could significantly interfere with data analysis and interpretation; 
• 
for Part B, more stringent requirements on the lesion burden to ensure sufficient receptor 
burden on target lesions. 
4.4 
Recruitment 
It is intended that potential subjects for this study will be identified from patients currently 
attending or being referred to the study centres for the diagnosis and treatment of NETs, 
including phaeochromocytomas and paragangliomas. Potentially suitable subjects will be 
approached by the investigating team to ascertain whether they would be interested in 
participating in the study. Interested subjects will be provided with an information sheet and 
undergo consenting procedures prior to any other study procedures. If a subject initially fails 
the Screening process due to a reversible condition, the Screening can potentially be repeated 
once at a later time point (re-enrolment). 
4.5 
Subject Participation Card 
A study participation card will be provided to each subject on the study. The card will indicate 
that they are participating in a clinical trial, and give the name and contact details of the sponsor 
and the investigator/study site. The subject will be asked to retain this card while they are 
participating in the trial and show it to any other medical practitioners they consult during this 
time. They will be advised to contact the investigator/study site if there are any questions. 
4.6 
 Stopping Rules, Discontinuation and Withdrawal Criteria and Procedures 
4.6.1 
Withdrawal Criteria 
Since this is a therapeutic study, subjects will be considered to have completed the core-study 
when the final visit of the study treatment period (EOCT Visit) is completed.  
Subjects may decide to withdraw from the study at any time and for any reason without 
prejudice to their further medical care. The investigator may withdraw a subject from the 
treatment or the study for any of the following reasons: 
• 
Safety Reason/AE: Clinical or laboratory events occurred that in the medical judgment 
of the investigator, for the best interest of the subject are reasons for discontinuation. 
This includes serious and nonserious AEs regardless of relation to study medication. 
• 
Disease Progression: The investigator documents disease progression (based on RECIST 
v1.1 or clinical symptoms) and does not expect any beneficial effect of the continuation 
of the study treatment.  
• 
Protocol Deviation: The subject’s findings or conduct failed to meet the protocol entry 
criteria or failed to adhere to the protocol requirements (e.g. drug noncompliance, 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 subject wished to withdraw from further participation in the 
study in the absence of an investigator-determined medical need to withdraw. If the 
subject gave a reason for withdrawing, it should be recorded in the eCRF. 


IPSEN GROUP 
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PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
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• 
Lost to Follow-up: The subject stopped coming for visits, and study personnel were 
unable to contact the subject. 
In the event of pregnancy, the subject is not allowed to receive further PRRT cycles and must 
be withdrawn from the study. 
The sponsor reserves the right to request the withdrawal of a subject due to protocol deviation 
or other significant reason. 
Although a subject is not obliged to give reason(s) for withdrawing, if a subject is discontinued 
at any time after entering the study, the investigator should make a reasonable effort to ascertain 
the reason(s) while fully respecting the subject’s rights. The investigator will make every effort 
to contact the subject and complete the termination status page on the eCRF and, if possible, 
conduct an EW Visit that will take place 8 weeks after the last administration study medication. 
In case of discontinuation of treatment/withdrawal from treatment as described in Section 6.4, 
the EW Visit and the Long-term Follow-up Visits will be performed as planned. 
The reasons for treatment and/or study discontinuation should be collected and reported in the 
eCRF. 
Appropriate follow-up of withdrawn subjects will be performed, as required. Attempts to 
contact subjects who withdraw from a study must be documented.  
Withdrawn subjects will be replaced if they do not complete treatment (the first three cycles) 
due to any reason other than exceedance of organ dose limits, treatment-related safety issues or 
disease progression. 
4.6.2 
Withdrawal Criteria for Optional Biobanking 
Subjects participating to the optional research biobanking program have the right to withdraw 
their consent at any time and for any reason during the study or during the period of sample 
storage (i.e. the entire 15 years during which the sample is kept). If a subject wishes to withdraw 
his consent for biobanking and the samples are still at the investigator site or at Central 
Laboratory at this time, the investigator must inform the study monitor in writing of the 
subject’s decision and destroy the samples. The study monitor will forward confirmation of the 
destruction to Biomarker/Biobanking study monitor. 
If the samples are at the sponsor’s repository (biobanking vendor), the investigator must inform 
directly Ipsen using the e-mail address, 
, mentioning only the 
subject study ID in this e-mail. Ipsen will ensure destruction of the samples and all 
corresponding aliquots and issue confirmation of the withdrawal, which will be forwarded to 
the investigator. Analyses conducted before the withdrawal will not be affected. 
4.6.3 
Study or Site Termination 
Study or site termination will occur if the sponsor or their representatives, investigator, or CA 
officials discover conditions during the study that indicate that the study or site involvement 
should be terminated. Conditions that may warrant termination of the study or involvement of 
a study site include, but are not limited to: 
• 
The discovery of an unexpected, serious, or unacceptable risk to subjects enrolled in the 
study; 
• 
The decision on the part of the sponsor to suspend or discontinue testing, evaluation, or 
development of the study drug; 
• 
Failure of the investigator(s) to comply with pertinent clinical trial regulations; 
• 
Submission of knowingly false information from the research facility to the sponsor, 
Clinical Monitor, or CA; 
• 
Insufficient adherence to protocol requirements. 
CCI


IPSEN GROUP 
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CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
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Study termination and follow-up will be performed in accordance with applicable local 
regulations. 
5 
STUDY PROCEDURES 
NOTE: the study medication (OPS201), and all the biosamples (including blood, urine and 
biopsy material taken on study) are all radioactive and all due precautions are to be taken to 
protect subjects, study staff, persons preparing, transporting or analysing materials and 
members of the public. 
If the COVID-19 pandemic prevents subjects from coming to the site, subjects can have their 
study visit assessments performed remotely as judged appropriate by the investigator. This must 
be discussed with the sponsor before being implemented. In such a case, the investigator will 
perform a telemedicine visit and will make every effort, where applicable, to contact the 
subject’s general practitioner or specialist physician to ensure all important medical information 
and safety event(s) occurring since the last visit are collected. Guidance on how to collect 
protocol-planned assessments will be provided to the investigator in a separate document. This 
document will be filed in the electronic trial master file. IECs/IRBs will be notified of the 
changes as applicable locally. Of note, as the adapted visit deviates from the regular protocol 
plan, the changes will be recorded as protocol deviations related to COVID-19. 
5.1 
Study Schedule 
The schedule of procedures and assessments during the study is summarised in Table 7 for 
Part A and in Table 8 for Part B. 
 


IPSEN GROUP 
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CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 65 OF 340 
 
Table 7 
Study Procedures and Assessments Part A 
Screening 
Visit 
Visit 1 
FU Visit 
1 
Visits 2/3 
FU 
Visits  
2 + 3[a] 
End of 
Core Trial 
Visit/ 
EW Visit[b] 
LTFU 
Visits 
(up to 2 
years)  
Week -4 
to -1 
Day 1 Day 2 Day 3 
Day4 
to 5 
Day 
7 to 8 
Day 
15 (±2 
days) 
Day 29 
(±5 
days) 
Day 1 Day 2 Day 3 
Day 4 
to 5 
Day 7 
to 8 
Day 15 
(±2 
days) 
Day 29 
(±5 
days) 
Study informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria check 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x[c] 
Pregnancy test [d] 
x 
x[e] 
 
 
 
 
 
 
x[e] 
 
 
 
 
 
 
 
 
Physical examination 
x 
x[e] 
 
 
 
 
 
x 
x[e] 
 
 
 
 
 
x 
x 
x 
Height* and weight** 
x* 
x**[e] 
 
 
 
 
 
 
x**[e] 
 
 
 
 
 
 
x** 
 
ECG (12-lead) 
x 
x[e] 
 
 
 
 
 
x 
x[e] 
 
 
 
 
 
x 
x 
x 
24 hour ECG (Holter) 
 
x[f] 
 
 
 
 
 
 
x[f]  
 
 
 
 
 
 
 
 
Vital signs 
x 
x[g] 
x 
x 
x 
x 
x 
x 
x[e] 
x 
x 
x 
x 
x 
x 
x 
x 
Performance status 
x 
x[e]  
 
 
 
 
 
 
x[e] 
 
 
 
 
 
 
x 
 
Quality of Life Questionnaire 
 
x[e]  
 
 
 
 
 
 
x[e] 
 
 
 
 
 
 
x 
 
Haematology/Biochemistry 
x 
x[e]  
x 
x 
x 
x 
x 
x 
x[e] 
x 
x 
x 
x 
x 
x 
x 
x 
Tumour markers 
x 
x[e]  
 
 
 
 
 
x 
x[e] 
 
 
 
 
 
x 
x 
x 
 
Pituitary markers 
 
x[e]  
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Urinalysis 
x 
x[e]  
 
 
 
x 
x 
x 
x[e]  
 
 
 
 
x 
x 
x 
x 
Radioactive PK and dosimetry [h][i]  
 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI 
x[o] 
 
 
 
 
 
 
 
 
 
 
 
 
 
x[n]  
x 
x[p] 
Somatostatin receptor scan 
x[q] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole body scan 
 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
 
 
 
SPECT/CT 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x[r] 
Survival 
 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
x 
x 
177Lu-OPS201 infusion 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
CCI
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PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
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Screening 
Visit 
Visit 1 
FU Visit 
1 
Visits 2/3 
FU 
Visits  
2 + 3[a] 
End of 
Core Trial 
Visit/ 
EW Visit[b] 
LTFU 
Visits 
(up to 2 
years)  
Week -4 
to -1 
Day 1 Day 2 Day 3 
Day4 
to 5 
Day 
7 to 8 
Day 
15 (±2 
days) 
Day 29 
(±5 
days) 
Day 1 Day 2 Day 3 
Day 4 
to 5 
Day 7 
to 8 
Day 15 
(±2 
days) 
Day 29 
(±5 
days) 
CT=computed tomography; DNA=deoxyribonucleic acid; DOTA=tetraxetan; ECG=electrocardiogram; EOCT=end of core trial; EW=early withdrawal; FU=follow-up; LTFU=long-term 
follow-up; 177Lu=lutetium-177; MRI=magnetic resonance imaging; OPS201=somatostatin analogue peptide JR11 coupled to DOTA; PK=pharmacokinetics; RNA=ribonucleic acid; 
SPECT=single photon emission computed tomography; SRS=somatostatin receptor scintigraphy; TAC=time-activity curve. 
a 
follow-up Visit 2 takes place 4 weeks after Visit 2 Day 1; Follow-up Visit 3 takes place 4 weeks after Visit 3 Day 1. Before the administration of Cycles 2 and 3 the criteria in Section 11.3 
must be checked. In the event of withdrawal (discontinuation) from treatment the EOCT Visit and the Long-term Follow-up Visits will be performed as planned with the EOCT Visit, 8 
weeks after the last administration of 177Lu-OPS201. 
b The Early Withdrawal Visit will take place 8 weeks after the last administration study medication. 
c 
during Long-term Follow-up, only antitumour treatments for NETs will be recorded. 
d a serum pregnancy test will be performed at the Screening Visit. A serum or urine pregnancy test will be performed predose on Day 1 of Visits 1 to 3 
e 
predosing: safety assessment results must be checked before 177Lu-OPS201 administration (with the exception of Quality of Life); these can be performed one day before administration. 
f 
24-hour ECG (Holter) to start 15 to 30 minutes before the amino acid infusion. 
g 
prior to infusion and at infusion completion (0), 30±5 min, 60±10 min, 4 hours ±10 min after the end of 177Lu-OPS201 infusion. 
h 
blood sampling to determine TACs will be performed before the infusion (baseline), at the stop of infusion (0), 5, 30 minutes, 1, 4, 24, 48, 72 to 96 and 144 to 168 hours after the stop of 
infusion of 177Lu-OPS201 (Visit 1). Blood sampling for Visits 2 and 3 will be performed before the infusion (baseline), at the stop of infusion (0), 1, 4, 24, 48, 72 to 96 hours and 144 to 
168 hours postinfusion. 
i 
urine will be collected for the following time periods: Visit 1 only: 0 to 6 hours, 6 to 24 hours, and 24 to 48 hours postinfusion. 
n 
at Follow-up Visit 2 only. 
o ceCT/MRI not older than 1 month on Visit1 Day 1.  
p 
central read of ceCT/MRI is performed during Core Trial and local read is performed during the 2-year LTFU period. 68Ga-PET scan may be performed during the Core Trial and the 2-year 
LTFU period, if deemed necessary by the investigator. 
q 
sstr scan should be performed (unless already performed within 6 months prior to Day 1) Local SRS eligibility read is performed at screening. 
r up to 6 months after the last study drug administration, all AEs/SAEs will be collected unless new NET therapies are started, then only AEs/SAEs related to the study 
drug/procedure will be collected. From 6 months after the last study drug administration until 2 years after the EOCT/EOAC/EW Visit, withdrawal of consent, lost to 
follow-up or death, all AEs/SAEs related to the study drug/procedure will be collected. 
CCI


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PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
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Table 8 
Study Procedures and Assessments Part B 
Screening 
Visit 
Visit 1 
FU Visit 1 
Visits 2/3 + additional optional V4, 
V5[v] 
FU Visits 2 + 3 + 
additional 
optional V4, V5[a] 
EOCT/EW Visit 
during the Core 
Trial (±5 days) [b] 
EOAC/EW 
Visit during 
additional 
cycles [b] [v] 
LTFU 
Visits 
(up to 2 
years) 
Week -4 
to -1 
Day 1 Day 2 Day 3 
Day 
4 to 
5 
Day 
7 to 
8 
Day 
15 
(±2 
days) 
Day 
29 
(±5 
days) 
Day 
42  
(±5 
days) Day 1 Day 2 Day 3 
Day 4 
to 5 
Day 7 
to 8 
Day 
15 
(±2 
days) 
Day 29 
(±5 
days) 
Day 42 
(±5 
days) 
Study informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
check 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x[c] 
Pregnancy test[d] 
x 
x[e] 
 
 
 
 
 
 
 
x[e] 
 
 
 
 
 
 
 
 
 
 
Physical examination 
x 
x[e] 
 
 
 
 
 
x 
 
x[e] 
 
 
 
 
 
x 
 
x 
x 
x 
Height* and weight** 
x* 
x**[e] 
 
 
 
 
 
 
 
x**[e
] 
 
 
 
 
 
 
 
x** 
x** 
 
ECG (12-lead) 
x 
x[e] 
 
 
 
 
 
x 
 
x[e] 
 
 
 
 
 
x 
 
x 
x 
x 
24 hour ECG (Holter) 
 
x[f] 
 
 
 
 
 
 
 
x[f] 
 
 
 
 
 
 
 
 
 
 
Vital signs 
x 
x[g] 
x 
x 
x 
x 
x 
x 
x 
x[e] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Performance status 
x 
x[e] 
 
 
 
 
 
 
 
x[e] 
 
 
 
 
 
 
 
x 
x 
 
Quality of Life 
Questionnaire 
 
x[e] 
 
 
 
 
 
 
 
x[e] 
 
 
 
 
 
 
 
x 
x 
 
Haematology/Biochemistry 
x 
x[e] 
x 
x 
x 
x 
x 
x 
x 
x[e] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Tumour markers 
x 
x[e] 
 
 
 
 
 
x 
 
x[e] 
 
 
 
 
 
x 
 
x 
x 
x 
 
 
Pituitary markers 
 
x[e] 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Urinalysis 
x 
x[e] 
 
 
 
x 
x 
x 
x 
x[e] 
 
 
 
 
x 
x 
x 
x 
x 
x 
Radioactive PK and 
dosimetry[h][i]  
 
x 
x 
x 
x 
x 
 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
CCI


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PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
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Screening 
Visit 
Visit 1 
FU Visit 1 
Visits 2/3 + additional optional V4, 
V5[v] 
FU Visits 2 + 3 + 
additional 
optional V4, V5[a] 
EOCT/EW Visit 
during the Core 
Trial (±5 days) [b] 
EOAC/EW 
Visit during 
additional 
cycles [b] [v] 
LTFU 
Visits 
(up to 2 
years) 
Week -4 
to -1 
Day 1 Day 2 Day 3 
Day 
4 to 
5 
Day 
7 to 
8 
Day 
15 
(±2 
days) 
Day 
29 
(±5 
days) 
Day 
42  
(±5 
days) Day 1 Day 2 Day 3 
Day 4 
to 5 
Day 7 
to 8 
Day 
15 
(±2 
days) 
Day 29 
(±5 
days) 
Day 42 
(±5 
days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OPS201 PK[l] [m] 
 
x 
x 
x 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI 
x[r] 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
x 
x[s] 
Somatostatin receptor scan 
x[t] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole body scan 
 
x[u] 
x 
x 
x 
x 
 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
SPECT/CT 
 
x 
x 
x 
x 
x 
 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x [w] 
Survival 
 
x 
 
 
 
 
 
x 
 
x 
 
 
 
 
 
x 
 
x 
x 
x 
177Lu-OPS201 infusion 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
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PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
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Screening 
Visit 
Visit 1 
FU Visit 1 
Visits 2/3 + additional optional V4, 
V5[v] 
FU Visits 2 + 3 + 
additional 
optional V4, V5[a] 
EOCT/EW Visit 
during the Core 
Trial (±5 days) [b] 
EOAC/EW 
Visit during 
additional 
cycles [b] [v] 
LTFU 
Visits 
(up to 2 
years) 
Week -4 
to -1 
Day 1 Day 2 Day 3 
Day 
4 to 
5 
Day 
7 to 
8 
Day 
15 
(±2 
days) 
Day 
29 
(±5 
days) 
Day 
42  
(±5 
days) Day 1 Day 2 Day 3 
Day 4 
to 5 
Day 7 
to 8 
Day 
15 
(±2 
days) 
Day 29 
(±5 
days) 
Day 42 
(±5 
days) 
CT=computed tomography; DNA=deoxyribonucleic acid; DOTA=tetraxetan; ECG=electrocardiogram; EOCT=end of core trial; FU=follow-up; 177Lu=lutetium-177; LTFU=long-term 
follow-up; MRI=magnetic resonance imaging; OPS201=somatostatin analogue peptide JR11 coupled to DOTA; PK=pharmacokinetics; RNA=ribonucleic acid; SPECT=single photon 
emission computed tomography; SRS=somatostatin receptor scintigraphy; TAC=time-activity curve.  
a 
follow-up Visits take place 4 weeks and 6 weeks after administration of 177Lu-OPS201 at Day 1. Before the administration of Cycles 2 and 3 (and additional optional Cycles 4 and 5) the 
criteria in Section 6.4.2 must be checked. In the event of withdrawal from treatment, the EW Visit will be performed 8 weeks after the last administration of 177Lu-OPS201 and the LTFU 
visits will be performed as planned after the EOCT/EOAC/EW Visit. Additional tests in the presence of toxicity are to be done as clinically indicated.  
b Subjects who are to receive additional cycles of therapy will undergo the EOCT assessment after Cycle 3. Where possible, the EOCT visit and Visit 4, Day 1 (additional cycle) can be 
combined. An additional EOAC assessment will be done 8 weeks after the last dose of therapy. The EW Visit will take place 8 weeks after the last administration study medication. 
c 
during Long-term Follow-up, only antitumour treatments for NETs will be recorded. 
d a serum pregnancy test will be performed at the Screening Visit. A serum or urine pregnancy test will be performed predose on Day 1 of Visits 1 to 3 
e 
predosing: safety assessment results must be checked before 177Lu-OPS201 administration (with the exception of Quality of Life); these can be performed one day before administration. 
f 
24-hour ECG (Holter) to start 15 to 30 minutes before the amino acid infusion. 
g prior to infusion and at infusion completion (0), 30±5 min, 60±10 min, 4 hours ±10 min after the end of 177Lu-OPS201 infusion. 
h urine will be collected for the following time periods: Visit 1 only: 0 (start of the infusion) to 4 hours, 4 to 24 hours, and 24 to 48 hours postinfusion (only 0 (start of the infusion) to 4 hours 
for US and Canada sites). 
i 
blood sampling to determine TACs will be performed before the infusion (baseline), at the stop of infusion (0), 5, 30 minutes, 1, 4, 24, 48, 72 to 96 and 144 to 168 hours after the stop of 
infusion of 177Lu-OPS201 (Visit 1). Blood sampling for Visits 2 and 3 will be performed before the infusion (baseline), at the stop of infusion (0), 1, 4, 24, 48, 72 to 96 hours and 144 
to168 hours postinfusion.  
l 
blood samples for assessment of OPS201 plasma levels will be collected at Visit 1 (first infusion): before the infusion (baseline), at the end of the infusion (0), 5±1 minute, 30±3 minutes, 
60±5 minutes and at 4 hours±10 minutes, 6 hours±30 minutes, 8 hours ±30 minutes, 24±1 hours and 48±1 hours after the administration of 177Lu-OPS201. 
m Urine samples for assessment of OPS201 urine levels will be collected Visit 1 only at the following time periods: 0 (start of the infusion) to 4 hours, 4 to 24 hours, and 24 to 48 hours 
postinfusion (only 0 (start of the infusion) to 4 hours in US and Canada sites). 
n a tumour biopsy will be taken at screening following confirmation of subject eligibility (if an archived biopsy is not available from up to 6 months before baseline, Visit 1 Day 1) and at 
Follow-up Visit 2 (i.e. at the same time point as RECIST assessment after Visit 2 or at disease progression, if this occurs earlier). If no biopsy material has been collected at Visit 1 Cycle 1, 
no further biopsy should not be performed for the purpose of the study (as it could not be compared to a baseline). 
r 
ceCT/MRI not older than 1 month on Visit 1 Day 1. To be performed also at each cycle of therapy (+2 weeks or up to +4 weeks in case of AEs), at the EOCT/EOAC/EW visit (±5 days) 
and at each long-term follow-up visit (±2 weeks) 
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Screening 
Visit 
Visit 1 
FU Visit 1 
Visits 2/3 + additional optional V4, 
V5[v] 
FU Visits 2 + 3 + 
additional 
optional V4, V5[a] 
EOCT/EW Visit 
during the Core 
Trial (±5 days) [b] 
EOAC/EW 
Visit during 
additional 
cycles [b] [v] 
LTFU 
Visits 
(up to 2 
years) 
Week -4 
to -1 
Day 1 Day 2 Day 3 
Day 
4 to 
5 
Day 
7 to 
8 
Day 
15 
(±2 
days) 
Day 
29 
(±5 
days) 
Day 
42  
(±5 
days) Day 1 Day 2 Day 3 
Day 4 
to 5 
Day 7 
to 8 
Day 
15 
(±2 
days) 
Day 29 
(±5 
days) 
Day 42 
(±5 
days) 
s 
central read of ceCT/MRI is performed during Core Trial and additional optional cycles; local read is performed during the 2-year LTFU period. 68Ga-PET scan may be performed 
during the treatment period (Core Trial and Additional Cycles) and the 2-year LTFU period, if deemed necessary by the investigator. 
t 
sstr scan should be performed (unless already performed within 6 months prior to Day 1) Local SRS eligibility read is performed at screening. 
u postdosing imaging at 4 hours ±10 min. In case of misadministration (such as spillage or interruption of the infusion), an additional whole body scan is required shortly after the end of 
infusion and before the first bladder emptying (see Section 9.2.1 Whole Body Scan). 
v 
w up to 6 months after the last study drug administration, all AEs/SAEs will be collected unless new NET therapies are started, then only AEs/SAEs related to the study 
drug/procedure will be collected. From 6 months after the last study drug administration until 2 years after the EOCT/EOAC/EW Visit, withdrawal of consent, lost to 
follow-up or death, all AEs/SAEs related to the study drug/procedure will be collected. 
 
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The total volume of blood drawn for all evaluations throughout this study is up to 306.0 mL in 
Part A and up to 563.5 mL in Part B across 23 visits (Part A) or 41 visits (Part B) and will not 
exceed 77.5 mL at any one visit and 158.5 mL within 1 month (see Section 5.3 and Table 9). 
The total amount will be greater for subjects participating in Part B, which includes OPS201 
PK, blood for 
 in all sites (5 mL of whole blood for serum) 
and 
 
 The total volume of blood for biobanking is 33 mL, which is an 
optional assessment.  
5.2 
Study Visits 
The schedule of visits and main procedures at each visit are summarised in the study flowchart 
(see Section 3.1). If the time buffers of the visits are utilised, later visits must be shifted 
accordingly. 
5.2.1 
Screening Visit 
Week -4 to -1 
Depending on the SRS, a hospitalisation of up to 2 days may be necessary.  
• 
written informed consent 
- 
study informed consent and optional informed consent for biobanking 
• 
clinical assessments 
- 
demographic details 
- 
medical history and concurrent (baseline) conditions 
- 
concomitant and prior medications (taken up to 28 days before the Screening 
Visit) 
- 
physical examination 
- 
height 
- 
vital signs and 12-lead ECG 
- 
clinical laboratory tests (biochemistry, haematology, and urinalysis) 
- 
circulating tumour marker (blood) 
- 
serum ȕ-human chorionic gonadotropin (HCG) pregnancy test for women of 
childbearing potential (not surgically sterile or 2 years postmenopausal) 
- 
review of inclusion and exclusion criteria. 
- 
performance status. 
• 
CT/MRI (not older than 1 month on the first day of the Screening Visit) 
• 
sstr scan (unless already performed within 6 months of Visit 1 Day 1) 
• 
5.2.2 
Visit 1 
During Visit 1, patient may be hospitalised on Day 1 for 24 hours and up to Day 8. The duration 
of the hospital stay is left at the discretion of the investigator and will depend on the individual 
subject and the regulatory requirements at the study site. Later assessments can be performed 
on an outpatient basis.  
All postdosing time points are defined from stop of infusion (0). 
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5.2.2.1 
Visit 1, Day 1 (Week 0) 
Safety assessments (predosing results must be checked before 177Lu-OPS201 administration; 
these can be performed 1 day before administration) 
• 
physical examination 
• 
weight 
• 
vital signs and 12-lead ECG 
• 
performance status 
• 
clinical laboratory tests (biochemistry, haematology, pituitary marker and urinalysis) 
• 
serum ȕ-HCG or urine pregnancy test for women of childbearing potential (not surgically 
sterile or 2 years postmenopausal) 
• 
AEs/concomitant medications 
• 
24 hour ECG (Holter) (to start before amino acid infusion). 
Efficacy assessments 
• 
Quality of Life Questionnaire (QLQ-C30; GI.NET21) 
• 
tumour markers. 
Administration of 177Lu-OPS201  
See Section 6.2. 
Safety assessments (postdosing) 
• 
vital signs (stop of infusion, 0.5 hours ±5 minutes, 1 hour ±10 minutes, 4 hours 
±10 minutes) 
• 
AEs/Concomitant medications 
Dosimetric measurements  
• 
blood sampling (2 mL) before and at stop of infusion (0) and 5 minutes±1 minute, 
0.5 hours±3 minutes, 1 hour±5 minutes, 4 hours±10 minutes postinfusion 
• 
whole body imaging at 4 hours±10 minutes 
• 
SPECT/CT imaging (Part B only) at 4 hours±10 minutes 
• 
urine collection 0 to 6 hours and 6 to 24 hours postinfusion (Part A), 0 (start of the 
infusion) to 4 hours, 4 to 24 hours postinfusion at visit 1 only (0 (start of the infusion) to 
4 hours only for US and Canada sites) (Part B) 
OPS201 PK assessments (Part B only) 
• 
blood samples for assessment of OPS201 plasma levels will be collected at the following 
time points at visit 1 only: before the infusion (baseline), at the end of the infusion (0), 
5 minutes±1 minute, 
30 minutes±3 
minutes, 
60 minutes±5 minutes 
and 
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4 hours±10 minutes, 
6 hours±30 minutes, 
and 
8 hours±30 minutes 
after 
the 
administration of 177Lu-OPS201. 
• 
urine collection for assessment of OPS201 urine levels will be collected at the following 
time periods at visit 1 only: from 0 (start of the infusion) to 4 and 4 to 24 after the start 
of infusion (0 (start of the infusion) to 4 hours only for US and Canada sites). 
Efficacy assessments 
• 
Survival 
5.2.2.2 
Visit 1, Day 2 
Safety assessments (at 24±1 hour) 
• 
clinical laboratory tests (biochemistry, haematology, pituitary marker) 
• 
vital signs 
• 
AEs/concomitant medications. 
Dosimetric measurements (at 24±1 hour) 
• 
blood sampling at 24±1 hours 
• 
whole body imaging 
• 
SPECT/CT imaging 
• 
urine collection 24 to 48 hours postinfusion at visit 1 only (not applicable for US and 
Canada sites) 
OPS201 PK assessments (Part B only) 
• 
blood samples for assessment of OPS201 plasma levels will be collected 24 hours 
(±1 hour) after the administration of 177Lu-OPS201 at visit 1 only. 
• 
urine collection for assessment of OPS201 urine levels will be collected from 24 to 48 
hours after the start of infusion at visit 1 only (not applicable for US and Canada sites). 
5.2.2.3 
Visit 1, Day 3 
Safety assessments (at 48 hours±1 hour) 
• 
clinical laboratory tests (biochemistry, haematology) 
• 
Vital signs 
• 
AEs/concomitant medications. 
Dosimetric measurements (at 48 hours±1 hour) 
• 
blood sampling 
• 
whole body imaging 
• 
SPECT/CT imaging (Part B only) 
• 
urine collection 24 to 48 hours at visit 1 only (continued) (not applicable for US and 
Canada sites). 
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OPS201 PK assessments (Part B only) 
• 
blood samples for assessment of OPS201 plasma levels will be collected 48 hours 
(±1 hour) after the administration of 177Lu-OPS201 at visit 1 only. 
• 
urine collection for assessment of OPS201 urine levels will be collected 24 to 48 hours 
at visit 1 only (continued) (not applicable for US and Canada sites). 
5.2.2.4 
Visit 1, Day 4 (-Day 5) 
Safety assessments (at 72 to 96 hours) 
• 
laboratory tests (biochemistry, haematology) 
• 
vital signs 
• 
AEs/concomitant medications. 
Dosimetric measurements (at 72 to 96 hours) 
• 
blood sampling 
• 
whole body imaging 
• 
SPECT/CT imaging (Part B only).   
5.2.2.5 
Visit 1, Day 7 (-Day 8) 
Safety assessments (at 144 to 168 hours postinfusion) 
• 
clinical laboratory tests (biochemistry, haematology and urinalysis)  
• 
vital signs 
• 
AEs/concomitant medications. 
Dosimetric measurements (at 144 to 168 hours postinfusion) 
• 
blood sampling 
• 
whole body imaging 
• 
SPECT/CT imaging (Part B only). 
5.2.2.6 
Visit 1, Day 15 (±2 Days) 
Safety assessments 
• 
clinical laboratory tests (biochemistry, haematology and urinalysis)  
• 
vital signs 
• 
AEs/concomitant medications. 
5.2.3 
Follow-up Visit 1 
Follow-up Visit 1 should be Week 4 (Day 29±5) and Week 6 (Day 42±5) if no previous visit 
window was extended.  At Week 6, only safety assessments such as clinical laboratory tests 
(biochemistry, haematology and urinalysis) will be performed. 
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5.2.3.1 
Week 4 (Day 29±5) 
Safety assessments 
• 
physical examination 
• 
clinical laboratory tests (biochemistry, haematology, and urinalysis) 
• 
vital signs and 12-lead ECG 
• 
AEs/concomitant medications. 
Efficacy assessments 
• 
survival 
• 
tumour markers. 
5.2.3.2 
Week 6 (Day 42±5) - Part B only 
Safety assessments 
• 
clinical laboratory tests (biochemistry, haematology and urinalysis) 
5.2.4 
Visit 2 
During Visit 2, patient may be hospitalised on Day 1 for 24 hours and up to Day 4. The duration 
of the hospital stay is left at the discretion of the investigator and will depend on the individual 
subject and the regulatory requirements at the study site. Later assessments may be performed 
on an outpatient basis. 
5.2.4.1 
Visit 2, Day 1 (Week 8 (+2 Weeks or Up to +4 Weeks in Case of AEs which have Not 
Adequately Recovered)) 
Safety assessments (predosing results must be checked before 177Lu-OPS201 administration; 
can be performed one day before) 
• 
physical examination 
• 
weight 
• 
vital signs and 12-lead ECG 
• 
performance status 
• 
clinical laboratory tests (biochemistry, haematology, and urinalysis) 
• 
serum or urine pregnancy test for women of childbearing potential (not surgically sterile 
or 2 years postmenopausal). 
• 
AEs/concomitant medications 
• 
control of withdrawal from treatment criteria (see Section 6.4)  
• 
24-hour ECG (Holter) (to start before amino acid infusion). 
Efficacy assessments 
• 
survival 
• 
quality of life questionnaire (QLQ-C30; GI.NET21) 
• 
tumour markers 
• 
CT/MRI (same method as in Screening Visit); +2 weeks or up to +4 weeks in case of 
AEs 
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Administration of 177Lu-OPS201 
See Section 6.2. 
Safety assessments (postdosing) 
• 
vital signs (stop of infusion, 30±5 minutes 60±10 minutes, 4 hours ±10 minutes) 
• 
AEs/concomitant medications. 
Dosimetric measurements  
• 
blood sampling before and at stop of infusion at 60±5 minutes, 4 hours ±10 minutes 
• 
whole body imaging at 4 hours ±10 minutes. 
• 
SPECT/CT imaging (Part B only) at 4 hours ±10 minutes. 
5.2.4.2 
Visit 2, Day 2 
Safety assessments at 24 hours ±1 hour 
• 
clinical laboratory tests (biochemistry, haematology) 
• 
vital signs 
• 
AEs/concomitant medications. 
Dosimetric measurements at 24 hours ±1 hour 
• 
blood sampling 
• 
whole body imaging 
• 
SPECT/CT imaging. 
5.2.4.3 
Visit 2, Day 3 
Safety assessments at 48 hours ±1 hour 
• 
clinical laboratory tests (biochemistry, haematology) 
• 
vital signs 
• 
AEs/concomitant medications. 
Dosimetric measurements at 48 hours ±1 hour 
• 
blood sampling 
• 
whole body imaging 
• 
SPECT/CT imaging (Part B only). 
5.2.4.4 
Visit 2, Day 4 (-Day 5) 
Safety assessments 
• 
clinical laboratory tests (biochemistry, haematology) 
• 
vital signs 
• 
AEs/concomitant medications. 
Dosimetric measurements (at 72 to 96 hours postinfusion) 
• 
blood sampling 
• 
whole body imaging 
• 
SPECT/CT imaging (Part B only). 
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5.2.4.5 
Visit 2, Day 7 (-Day 8) 
Safety assessments (at (144 to 168 hours postinfusion) 
• 
clinical laboratory tests (biochemistry and haematology)  
• 
vital signs 
• 
AEs/concomitant medications. 
Dosimetric measurements (at 144 to 168 hours postinfusion) 
• 
blood sampling 
• 
whole body imaging 
• 
SPECT/CT imaging (Part B only). 
5.2.4.6 
Visit 2, Day 15 (±2 Days) 
Safety assessments 
• 
clinical laboratory tests (biochemistry, haematology and urinalysis)  
• 
vital signs 
• 
AEs/concomitant medications. 
5.2.5 
Follow-up Visit 2 
Follow-up Visit 2 should be Week 12 (Day 29±5) and Week 14 (Day 42±5) if no previous visit 
window was extended.  At Week 14, only safety assessments such as clinical laboratory tests 
(biochemistry, haematology and urinalysis) will be performed. 
5.2.5.1 
Week 12 (Day 29±5) 
Safety assessments 
• 
physical examination 
• 
clinical laboratory tests (biochemistry, haematology, and urinalysis) 
• 
vital signs and 12-lead ECG 
• 
AEs/concomitant medications. 
Efficacy assessments 
• 
survival 
• 
tumour marker 
• 
tumour biopsy taken at Follow-up Visit 2 or at disease progression. If no biopsy material 
has been collected at Visit 1 Cycle 1, no further biopsy should be performed for the 
purposes of the study (as it could not be compared to a baseline). 
5.2.5.2 
Week 14 (Day 42±5) - Part B only 
Safety assessments 
• 
clinical laboratory tests (biochemistry, haematology and urinalysis) 
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5.2.6 
Visit 3 
During Visit 3, a patient may be hospitalised on Day 1 for 24 hours and up to Day 4. The 
duration of the hospital stay is left at the discretion of the investigator and will depend on the 
individual subject and the regulatory requirements at the study site. Later assessments may be 
performed on an outpatient basis.  
5.2.6.1 
Visit 3, Day 1 (Week 8 (+2 Weeks or Up to +4 Weeks in Case of AEs which have Not 
Adequately Recovered)) 
Visit 3, Day 1, should take place 8 weeks after Visit 2 (+2 weeks or up to +4 weeks in case of 
AEs which have not adequately recovered). This should be Week 16 (+2 weeks or up to 
+4 weeks in case of AEs which have not adequately recovered), otherwise Week 16 should be 
changed to the appropriate week number. 
Safety assessments (predosing, results must be checked before 177Lu-OPS201 administration; 
can be performed one day before) 
• 
physical examination 
• 
weight 
• 
vital signs and 12-lead ECG 
• 
performance status 
• 
clinical laboratory tests (biochemistry, haematology, and urinalysis) 
• 
serum or urine pregnancy test for women of childbearing potential (not surgically sterile 
or 2 years postmenopausal). 
• 
AEs/concomitant medications 
• 
control of withdrawal from treatment criteria (see Section 6.4) 
• 
24 hour ECG (Holter) (start before amino acid infusion). 
Efficacy assessments 
• 
survival 
• 
quality of life questionnaire (QLQ-C30; GI.NET21)  
• 
tumour markers 
• 
CT/MRI (same method as in Screening Visit); +2 weeks or up to +4 weeks in case of 
AEs 
Exploratory biomarkers  
Administration of 177Lu-OPS201 
See Section 6.2. 
Safety assessments (postdosing) 
• 
vital signs (stop of infusion, 30±5 minutes 60±10 minutes, 4 hours ±10 minutes 
• 
AEs/concomitant medications. 
Dosimetric measurements  
• 
blood sampling before and at stop of infusion, 1 hour ±5 minutes, 4 hours ±10 minutes 
• 
whole body imaging at 4 hours ±10 minutes 
• 
SPECT/CT imaging (Part B only) at 4 hours ±10 minutes.   
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5.2.6.2 
Visit 3, Day 2 
Safety assessments at 24 hours ±1 hour 
• 
clinical laboratory tests (biochemistry, haematology) 
• 
vital signs 
• 
AEs/concomitant medications. 
Dosimetric measurements at 24 hours ±1 hour 
• 
blood sampling 
• 
whole body imaging 
• 
SPECT/CT imaging.   
5.2.6.3 
Visit 3, Day 3 
Safety assessments at 48 hours ±1 hour 
• 
clinical laboratory tests (biochemistry, haematology) 
• 
vital signs 
• 
AEs/concomitant medications. 
Dosimetric measurements at 48 hours ±1 hour 
• 
blood sampling 
• 
whole body imaging 
• 
SPECT/CT imaging (Part B only).   
5.2.6.4 
Visit 3, Day 4 (-Day 5) 
Safety assessments (at 72 to 96 hours) 
• 
clinical laboratory tests (biochemistry, haematology) 
• 
vital signs 
• 
AEs/concomitant medications. 
Dosimetric measurements (at 72 to 96 hours postinfusion) 
• 
whole body imaging 
• 
blood sampling 
• 
SPECT/CT imaging (Part B only).   
5.2.6.5 
Visit 3, Day 7 (-Day 8) 
Safety assessments (at 144 to 168 hours postinfusion) 
• 
clinical laboratory tests (biochemistry and haematology)  
• 
vital signs 
• 
AEs/concomitant medications. 
Dosimetric measurements (at 144 to 168 hours postinfusion) 
• 
blood sampling 
• 
whole body imaging 
• 
SPECT/CT imaging (Part B only).   
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5.2.6.6 
Visit 3, Day 15 (±2 Days) 
Safety assessments 
• 
clinical laboratory tests (biochemistry, haematology and urinalysis) 
• 
vital signs 
• 
AEs/concomitant medications. 
5.2.7 
Follow-up Visit 3 
Follow-up Visit 3 should be Week 20 (Day 29±5) and Week 22 (Day 42±5) if no previous visit 
window was extended. This visit should take place 4 weeks ±5 days after Visit 3. At Week 22, 
only safety assessments such as clinical laboratory tests (biochemistry, haematology and 
urinalysis) will be performed. 
5.2.7.1 
Week 20 (Day 29±5) 
Safety assessments 
• 
physical examination 
• 
clinical laboratory tests (biochemistry, haematology and urinalysis) 
• 
vital signs and 12-lead ECG 
• 
AEs/concomitant medications. 
Efficacy assessments 
• 
survival 
• 
tumour markers 
5.2.7.2 
Week 22 (Day 42±5) - Part B only 
Safety assessments 
• 
clinical laboratory tests (biochemistry, haematology and urinalysis) 
5.2.8 
End of Core-trial Visit  
The EOCT Visit should take place 8 weeks after Visit 3. This should be Week 24 (Day 1±5) if 
no previous visit window was extended. Subjects who are to receive additional cycles of therapy 
will undergo the EOCT assessment after Cycle 3. Where possible, the EOCT visit and Visit 4, 
Day 1 (additional cycle) can be combined. An additional EOAC assessment will be done 
8 weeks after the last dose of therapy (Part B only). 
Safety assessments (at EOCT/EOAC Visit) 
• 
vital signs and 12-lead ECG  
• 
physical examination 
• 
weight 
• 
performance status 
• 
clinical laboratory tests (biochemistry, haematology, pituitary markers and urinalysis) 
• 
AEs/concomitant medications (see Section 8.1.4.1). 
Efficacy assessments (at EOCT/EOAC Visit) 
• 
CT/MRI (same method as in Screening Visit); ±5 days' window acceptable 
• 
quality of life questionnaire (QLQ-C30; GI.NET21) 
• 
survival 
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• 
tumour markers. 
5.2.9 
Long-term Follow-up Visits (1 to 8) 
Long term follow-up visits will be carried out every 3 months for 2 years starting 12 weeks 
after the EOCT/EOAC/EW Visit (see Section 3.1.4). In the long-term follow-up phase, 
deviations (±2 weeks) from the time schedule are not recorded as significant deviations. 
Tumour assessments will be assessed every 3 months (±2 weeks) until whichever occurs first: 
documented disease progression (radiological or clinical as per the investigator's judgment), 
2 years after the EOCT/EOAC/EW Visit, withdrawal of consent, lost to follow-up or death. 
Safety assessments, and the subject’s status, will be performed every 3 months (±2 weeks) until 
whichever occurs first: 2 years after the EOCT/EOAC/EW Visit, withdrawal of consent, lost to 
follow-up or death. 
After the long-term follow-up period is completed i.e. 2 years after the EOCT/EOAC/EW Visit, 
all subjects will be invited to participate in a safety surveillance study, as part of a separate 
study protocol. All subjects will be asked to sign a new informed consent form to enter this 
study. The purpose of the safety surveillance study is to monitor any long-term effects of 
177Lu-OPS201 up to 5 years from the first dose of 177Lu-OPS201. 
Efficacy assessments  
• 
CT/MRI (same method as in Screening Visit); ±2 weeks' window allowable 
• 
survival 
• 
tumour markers. 
Long-term safety assessment 
• 
vital signs and 12-lead ECG  
• 
physical examination 
• 
laboratory tests (biochemistry, haematology, and urinalysis) 
• 
AEs/concomitant medications (NET only) (see Section 8.1.4.1).  
5.2.10 
Early Withdrawal Visit  
This visit will be performed if a subject withdraws from trial participation (treatment and any 
Follow-up procedures) and consents to this last visit. The assessments at this visit correspond 
to the EOCT/EOAC Visit. 
If the study subject withdraws early from the trial, the EW Visit should be performed 8 weeks 
after the last administration study medication). 
Safety assessments 
• 
vital signs and 12-lead ECG  
• 
physical examination 
• 
weight 
• 
performance status 
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• 
clinical laboratory tests (biochemistry, haematology, pituitary markers, specific renal 
safety biomarkers and urinalysis) 
• 
AEs/concomitant medications (see Section 8.1.4.1) 
Efficacy assessments 
• 
CT/MRI (same method as in Screening Visit); ±5 days' window allowable 
• 
survival 
• 
quality of life questionnaire (QLQ-C30; GI.NET21) 
• 
tumour markers. 
5.3 
Laboratory Assessments 
The total volume of blood to be collected from any subject during the core trial will be up to 
306 mL (Part A) or up to 563.5 mL (Part B) across 23 visits (Part A) or 41 visits (Part B) and 
will not exceed 77.5 mL at any one visit and 152.5 mL within 1 month (see Table 6). The total 
amount will be greater for subjects participating in Part B, which includes OPS201 PK. The 
total volume of blood for biobanking is 33 mL, which is an optional assessment. 
Table 9 
Volume of Blood During the Core Trial  
Test 
Volume per 
Sample 
Maximum 
number of 
Samples 
(Part A) 
Maximum 
number of 
Samples 
(Part B) 
Haematology 
2 mL 
23 
42 
Biochemistry 
5 mL 
23 
42 
Tumour markers 
4 mL 
8 
8 
Pituitary biomarkers  
6 mL 
3 
3 
Blood sampling for 
radiopharmaceutical PK 
2 mL 
26 
42 
OPS201 PK blood 
2 mL 
NA 
10 
TOTAL number of samples 
 
91 
166 
TOTAL Volume 
 
306 mL 
563.5 mL 
 
5.4 
Functional Imaging: Somatostatin Receptor Scan 
Functional imaging by SRS will be performed at the Screening Visit. 
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The selection of the peptide depends on the regulatory requirement in the specific country of 
this multinational trial and will be the responsibility of the investigator. A PET/CT scan with 
68Ga-labeled SSA is preferable.  
The screening SRS will be performed within 1 month before Visit 1 Day 1. If a historic SRS is 
available, and not older than 6 months prior to Visit 1 Day 1, this scan can be used.  
For Part A, the eligibility of subjects will require the presence of: 
• 
At least one lesion that is 20 mm in the longest dimension (as measured on correlative 
CT or MRI); 
• 
And with SUVmax 2× the SUVmean of the liver background on 68Ga-PET imaging, or a 
score of “3” or “4” according to the Krenning scale (see Table 10) on SPECT imaging. 
For Part B the eligibility of subjects will require the presence of: 
• 
At least two lesions that are 20 mm in the longest dimension (as measured on correlative 
CT or MRI); 
• 
And with SUVmax 2× the SUVmean of the liver background on 68Ga-PET imaging, or 
a score of “3” or “4” according to the Krenning scale (see Table 10) on SPECT imaging 
of the two identified lesions. 
Table 10 Krenning Scale 
Score 
Uptake 
0 
No abnormality/no uptake 
1 
Faint uptake 
2 
Clear uptake in tumour but less than in liver 
3 
Uptake greater in tumour than liver 
4 
Uptake much greater in tumour than liver 
6 
TREATMENT OF SUBJECTS 
6.1 
Investigational Medicinal Product Preparation Storage and Accountability 
6.1.1 
Investigational Medicinal Product Storage and Security 
All study material will be kept in a secure, restricted-access location and in accordance with 
applicable regulatory requirements, within the radiopharmacy of the Nuclear Medicine 
Department. 
Spillage: All due precautions and site procedures should be implemented to prevent spillage or 
leakage of radiodiagnostics or radiotherapeutics. Infusion bags, i.v. lines, venous access should 
all be secured and the connections thoroughly checked. The infusion line should be taped in a 
loop and taped to the subject to prevent direct tension between the line and the venous access. 
Despite precautions, if spillage or leakage should occur, then the site procedures must be 
implemented to protect the subject, staff and members of the public from radiation exposure. 
The subject should be moved from the area of the spillage or leakage while the area is 
decontaminated. Details of the spillage or leakage should be recorded (including how the 
incident happened, the time of the incident, an estimate (if possible) of the amount of substance 
lost) and the measures taken. In addition, the incident is to be reported in the same manner as 
an adverse event using the Medical Dictionary for Regulatory Activities (MedDRA) preferred 
term (PT) Product Leakage and as appropriate PT Occupational exposure to radiation (if there 
is exposure to staff) and PT Exposure to radiation (if there is exposure to the subject or members 
of the public). Such “special situation” events should be reported to the sponsor in same 
timelines as an SAE (within 24 hours) using the Ipsen’s SAE form, even if the event did not 
result in any AE. See Section 9.2.1 for additional scanning requirements in case of spillage (or 
interruption of infusion). 


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6.1.2 
Investigational Medicinal Product Preparation 
For production in radiopharmacies: 
The hospital radiopharmacy will order the required 177Lu, on demand, following the local 
procedures of the hospital. 
OPS201 precursor for radiopharmaceutical preparation will be supplied in glass vials as an 
acetate salt powder. OPS201 precursor will be manufactured, handled and stored in accordance 
with Good Pharmacy Practice. 
The hospital radiopharmacist will perform the radiolabelling of OPS201 precursor to obtain the 
radiolabelled study medication according to the radiolabelling procedure provided in a 
177Lu-OPS201 radiolabelling procedure manual (see IRPP dossier). Upon completion of 
radiopharmacy procedures, the study medication will be labelled according to GMP and any 
applicable local laws/regulations, and the radiopharmacist will hand over or ship the study 
medication to the investigator or a designated and suitably qualified deputy for administration. 
The radiolabelling, dispensing and quality control is described in the site specific IRPP manual 
for the 177Lu-OPS201 Radiolabelling Procedure. 
For production in central contract manufacturing organisation: 
The IRPP will be supplied as a ready-to-use solution for injection. 
6.1.3 
Investigational Medicinal Product Accountability 
The sponsor will supply to the trial site sufficient materials to conduct the study after receipt of 
all required documentation, including written approval from the IEC/IRB and Regulatory 
Authority, as appropriate.  
At the end of the study, when applicable, any unused quantities of precursor for 
radiopharmaceutical preparation will be returned to the sponsor or will be locally eliminated 
according to all requirements for the destruction of radioactive materials. The return or 
elimination of any unused precursor will be documented appropriately. 
The investigator is obliged to keep sufficient documentation of the delivery, use and destruction 
or return of unused, used or partially used packages of IRPP. The documentation must include 
dates, quantities, subject numbers, batch numbers or other identification number. The 
investigator may assign some or all of the investigator’s duties for drug accountability to an 
appropriate radiopharmacist. 
The investigator should maintain records that document adequately that the subjects were 
administered the doses specified in the protocol and reconcile all IRPP received for the trial. 
The local study monitor will be responsible for checking the drug accountability records 
maintained by the site during the monitoring visits. 
The medication provided for this study is for use only as directed in the protocol. It is the 
investigator/Institution’s responsibility to establish a system for handling study drug, so as to 
ensure that: 
• 
Deliveries of IRPP are correctly received by a responsible person; 
• 
Such deliveries are recorded; 
• 
Study treatments are handled and stored safely and properly as stated on the label; 
• 
Study drug is only dispensed to study subjects in accordance with the protocol; and 
• 
Any unused study drug is destroyed locally or returned for destruction in liaison with the 
Clinical Research Associate (CRA). 
Throughout the study, it must be possible to reconcile delivery records with records of usage 
and any destroyed/returned stock. Records of usage should include the identification of the 


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subject to whom the study treatment was dispensed, and the quantity and date of dispensing. 
The radioactivity should also be recorded before and after administration. This record is in 
addition to any drug accountability information recorded on the eCRF. Any discrepancies must 
be accounted for on the appropriate forms. Certificates of delivery and return must be signed, 
preferably by the investigator or a radiopharmacist, and copies retained in the Radiopharmacy 
File. The return or destruction of unused drug will be conducted after written approval by the 
sponsor, with appropriate documentation and drug accountability procedures completed 
following destruction. 
6.2 
Study Drugs Administered 
Subjects will be treated with three cycles of 177Lu-OPS201 PRRT with an interval of 8 weeks 
+2 weeks, or up to +4 weeks in case of AEs which have not adequately recovered. If any side 
effects are adequately recovered within the 4 weeks, the next treatment cycle can be initiated; 
if not, no further PRRT treatment will be administered and the subject will undergo the EOCT 
Visit followed by the Long-term Follow-up Visits. 
The absorbed organ doses (blood and image based), especially the bone marrow and kidney 
doses as a limiting organs, will be analysed after each treatment cycle so that the radioactivity 
for the following cycles for this particular subject can be reduced in order to not exceed 
cumulative absorbed organ dose limits. 
The study will be performed in two phases. 
Part A (15 subjects) 
Initially, six subjects will be treated. Each subject will receive three cycles of 4.5 GBq (target 
radioactivity 4.5 GBq±10%) 177Lu-OPS201 (target dose 300±50 g), every 8 weeks (+2 weeks 
or up to +4 weeks in case of AEs which have not adequately recovered). An SRC meeting will 
be held before exposing the remaining nine subjects to the entire number of planned 
administrations (see Section 3.8 for DLT rules). 
Part B (up to 40 subjects) 
Table 11 provides the specific radioactivity and peptide mass dose for each cohort in Part B. 
Table 11 Radioactivity and Peptide Mass Dose in Each Cohort and Cycle – Part B 
Cohorts 
Planned dose escalation 
Nominal OPS201 dose 
per cycle (g) 
OPS201 range per 
cycle (g)[a] 
Nominal radioactivity 
and range 
(GBq) 
Cumulative 
radioactivity 
(3 cycles, GBq) 
1 
300 
[250 to 350] 
6.0±10% 
18.0 
2[b] 
300 
[250 to 350] 
7.4±10% 
22.2 
3 
300 (Cycle 1) 
700 (Cycle 2) 
300 (Cycle 3) 
300 (Cycle 4 and 5)[c] 
[250 to 350] 
[550 to 850] 
[250 to 350] 
[250 to 350] 
4.5±10% 
13.5 
4 
700 
[550 to 850] 
6.0±10% 
18.0 
5 
700 
[550 to 850] 
7.4±10% 
22.2 
6 
300 (Cycle 1) 
1300 (Cycle 2) 
300 (Cycle 3) 
300 (Cycle 4 and 5)[c] 
[250 to 350] 
[1100 to 1500] 
[250 to 350] 
[250 to 350] 
4.5±10% 
13.5 
7[b] 
1300 
[1100 to 1500] 
6.0±10% 
18.0 
8[b] 
1300 
[1100 to 1500] 
7.4±10% 
22.2 
DOTA=tetraxetan; GBq=gigaBecquerel; IRPP=investigational radiopharmaceutical product; OP201=somatostatin analogue 
peptide JR11 coupled to DOTA. 


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a 
IRPP will be provided either through local or centralised manufacturing. OPS201 ranges include the ranges validated for 
local IRPP manufacturing in radiopharmacy of selected centres and the general validated range for centralised IRPP 
manufacturing (i.e. nominal OPS201 dose±15%). 
b 
optional. 
c 
For additional cycles, if any 
6.2.1 
Dosage and Administration of Study Medication 
At each PRRT cycle, the study medication will be administered after the conduct of a safety 
examination of the subject. The IRPP (20 mL of 177Lu-OPS201) will be administered once per 
cycle by an i.v. infusion at a rate of 10 mL/h over 120 minutes. Infusion rate modification (up 
or down) would be under the investigator’s judgement and may be temporarily halted or even 
further slowed down if the subject does not tolerate the IRPP infusion. The overall infusion 
duration should not exceed 4 hours.  
Prophylaxis may be considered if the subject is thought to be at increased risk of 
infusion-related reactions as per the site’s standard of care (see also Section 6.3.3 and Section 
6.3.4). Appropriate treatment should be administered should an infusion-related reaction occur 
including somatostatin analogues. At any time, if infusion-related reactions are encountered, 
the infusion should be slowed or interrupted. 
There are no fasting conditions, nor food restrictions that should apply when administering 
177Lu-OPS201 to the subject.  
To protect the kidneys, an amino acid solution is infused with 177Lu-OPS201 (Section 6.3.2). 
The same venous access for IRPP and amino acid solution administration (see Section 6.3.2) 
will be used. Infusion should be done into the contra-lateral arm of the PK sampling. 
The administered radioactivity and mass dose follow the escalation scheme (see Section 3 and 
Section 6.2).  
Note: The rate of infusion can be adjusted based on recommendations from the DRB.  
The same venous access for IRPP and amino acid solution administration (see Section 6.3.2) 
will be used. Infusion should be done into the contra-lateral arm of the PK sampling. 
At any time, if infusion-related reactions are encountered, the infusion should be slowed or 
interrupted. 
Radioactivity evaluation (Part A) 
In Part A, a cumulative radioactivity of 13.5 GBq (4.5 GBq/cycle × three cycles) with a peptide 
mass dose of 300 g will be evaluated.  
Radioactivity and dose escalation (Part B) 
See Table 11 for the peptide mass and radioactivity dosing per cohort. See Section 3.1.3 for the 
rationale of the cohorts and Section 3.8 for dose escalation. 
Subjects who experience a significant toxicity and recover from the toxicity, may be allowed 
to continue to receive study treatment at a lower activity level, subject to review and approval 
by the sponsor. These subjects must be closely monitored for safety. Please refer to Section 6.4 
for Delay of Administration and Withdrawal from Study Treatment. 
6.3 
Concomitant Medication/Therapy 
6.3.1 
Interruption of Somatostatin Analogue Therapy 
Somatostatin analogue therapy for symptom control will be allowed before and during the 
course of the study. If a subject is undergoing therapeutic treatment with any SSA, it is possible 
to interrupt the therapy before the administration of 177Lu-OPS201. 
As a recommendation: if a subject is on a long-acting somatostatin analogue, such as 
Somatuline Autogel® or Sandostatin® LAR, a wash-out period of 28 days is recommended 


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before injection of the study drug. If a subject is on a short-acting somatostatin analogues, such 
as Sandostatin® a wash-out period of 24 hours is recommended before injection of the study 
drug. The decision on the interruption of SSA use is the responsibility of the investigator and 
must be documented.  
The somatostatin analogue can be re-started 24 hours after the infusion of OPS201, but the 
same washout periods should be observed at every cycle of study treatment. Concomitant 
medications should be reviewed periodically as the symptoms associated with the NET might 
be reduced if the tumour comes under control. 
For subjects with severe functional NET symptoms, the investigator is free to pursue SSA 
treatment as preclinical data (presented by Guillaume Nicolas et al. at the EANM congress 
2015/Poster OP307) indicate that the binding of the antagonistic peptide 177Lu-OPS201 is not 
impaired by the use of SSAs. 
In order to determine whether or not the concurrent use of somatostatin analogues has an effect 
on the activity associated with OPS201, response rates amongst those subjects who receive 
concurrent somatostatin analogues will be compared to the response rates amongst those 
subjects whose somatostatin analogues are interrupted at the time of treatment. 
6.3.2 
Amino Acid Infusion: Renal Protection 
It has been shown that the renal absorbed dose, which is the treatment-limiting factor of PRRT, 
can be effectively reduced by the concomitant administration of cationic amino acids. Based on 
the joint IAEA, EANM and SNMMI practical guidance on PRRT in NETs [35] a solution of 
25 g lysine and 25 g arginine in 2 L saline is recommended to be infused concomitant to the 
PRRT administration over 4 hours, starting 30 to 60 minutes before the infusion of 
177Lu-OPS201. The infusion time can be extended to 6 hours in case of e.g. technical infusion 
problems, interruption of infusion due to AEs or subjects’ intolerance of the high-volume load 
in a short time. The guidelines for the infusion of the amino acids should be followed as closely 
as possible, unless there is a contraindication. If the infusion is not complete after 4 hours, a 
long infusion line (2 m) can be used to continue the infusion while the whole-body scan and 
SPECT/CT scan are done (but note the long line can cause increased pressure and result in a 
slowing of the infusion rate which might require correction). The line should be made of PVC 
(Non-DEHP and free of Latex). The infusion of OPS201 must be complete when the long 
infusion line is inserted as the extra length of line would increase the amount of radioactive 
substance in the infusion line and so increase the radiation exposure to the public and to staff. 
Centres experienced in PRRT treatment can use their established amino acid solution, if it is 
covered by the recommendations of the joint IAEA, EANM and SNMMI practical guidance on 
PRRT in NETs and agreed with the sponsor, or Ipsen amino acid solution (auxiliary medicinal 
product OPS301, depending on the availability at the study site). The exact formulation and 
source must be documented in the eCRF. OPS301 has been formulated in compliance with the 
established guidelines and like other similar products is acidic (pH5.5). 
6.3.3 
Antiemetic 
To counteract the known side effects of this amino acid infusion, such as nausea, 8 mg 
dexamethasone (antiemetic) and as-required ondansetron (8 mg i.v.) will be administered 15 to 
30 minutes before the start of the amino acid infusion (unless there are contraindications for 
these drugs). From adoption of the protocol version (v6.0), investigators are advised, if 
required, to control symptoms it is allowed to use antiemetic regime as per site´s standard of 
care and to add extra antiemetic medication including short-term steroids (unless there are 
contraindications for these drugs). Any antiemetic drug administered to the subject must be 
documented in the eCRF. 


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6.3.4
Optional: Loop Diuretic
To facilitate the renal elimination of the radioactive peptide, 20 mg furosemide i.v. (loop 
diuretic) can be administered 30 to 60 minutes prior to the administration of the study 
medication. This is optional and can be decided by the investigator, but must be documented in 
the eCRF.
6.3.5
Administration Scheme 
Figure 14 Administration Schedule for Study Treatment and Concomitant Medication
i.v.=intravenous.
0 h=end of infusion.
Antiemetic and loop diuretic are administered if required.
177Lu-OPS201 infusion takes place over 120 minutes (see Section 6.2.1).
6.3.6
Prior and Further Concomitant Treatments
Subjects will be excluded from the study if they have received any other IRPP. Therapy given 
subsequently to study medication needs to be considered carefully: if radionuclide therapy is 
used, the prior radiation doses to the normal tissues need to be considered; and any therapy 
(such as chemotherapy or radionuclide therapy) should not be started until it is clear that the 
subject has recovered sufficiently from the adverse events associated with study medication.
During the study period other concomitant medications are permitted at the discretion of the 
investigator. With the exception of the therapeutic use of SSAs (see Section 6.3.1), 
NET-specific treatments are not allowed until the end of the core study. In case the investigator 
considers a NET-specific treatment is deemed necessary for the benefit and well-being of the 
subject, they should withdraw the subject from study treatment and perform the Withdrawal 
visit as specified in Section 5.
Vitamins, herbal preparations and other nutritional supplements are permitted during this study.
Prior medications (up to 28 days prior to the Screening Visit) and all medications (including 
herbal products) taken until the EOCT or EOAC Visit, whichever occurs last, must be recorded 
in the subject’s eCRF. The only treatments recorded during the Long-term Follow-up period 
will be further antitumour treatments for NETs. The indication for each drug, generic name, 
administration form, strength, dose, frequency of dosing, route of administration, start date and, 
if applicable, stop date should also be recorded in the eCRF. All medications will be encoded 
according to the Anatomical Therapeutic Chemical/Defined Daily Dose Classification of the 
European Pharmaceutical Market Research Association.


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6.4 
Delay of Administration and Withdrawal from Treatment 
6.4.1 
Part A 
If any of the following occur, no further 177Lu-OPS201 treatment will be administered: 
• 
subject withdraws his/her consent to further treatment; 
• 
cumulative kidney dose exceeds 23 Gy; 
• 
cumulative bone marrow dose exceeds 1.5 Gy, as determined by image-based dosimetry; 
• 
absolute neutrophil count <1.000*109/L (i.e. Grade 3 or higher); 
• 
platelets <50.0*109/L (i.e. Grade 3 or higher); 
• 
if one of the following medical conditions occurs (based on CTCAE v5.0 criteria, see 
Appendix 4) and does not resolve within 4 weeks (resolved=toxicity Grade 2 or lower 
and is at the discretion of the investigator):  
- 
estimated GFR (eGFR) of <45 mL/min/1.73m2; 
- 
liver function tests (total bilirubin and aminotransferases) higher than Grade 3 
(unless there is treatment-related liver toxicity, in which case the study treatment 
should be stopped or interrupted to enable recovery when deterioration of the liver 
function is noted); 
- 
any other AE above Grade 2, except hair loss. 
The investigator can decide at his/her discretion to discontinue the treatment or to reduce the 
administered radioactivity for further safety reason than those here listed above to prevent a 
subject from higher grade toxicity. 
Before the administration of Cycles 2 and 3 these criteria must be checked. In the event of 
withdrawal (discontinuation) from treatment only the EW Visit and the Long-term Follow-up 
will be performed (with the EW Visit, 8 weeks after the last administration of 177Lu-OPS201). 
In some cases, absorbed dose to the bone marrow or kidney may be difficult to evaluate. If there 
is uncertainty about the radiation dose received to critical organs, but without substantial 
toxicity, the decision to administer additional cycles is left at the investigator’s and subject’s 
discretions. The decision may be either to stop the treatment, administer the full dose or a 
reduced dose depending on the benefit-risk balance for the subject. 
In the situation of persisting Grade 3 and higher bone marrow toxicity a bone marrow aspirate 
can be considered if at the discretion of the investigator this could contribute to the evaluation 
of the event.  
6.4.2 
Part B 
If any of the following occur, no further 177Lu-OPS201 treatment will be administered: 
• 
subject withdraws his/her consent to further treatment; 
• 
cumulative kidney dose exceeds 23 Gy; 
• 
cumulative bone marrow dose exceeds 1.5 Gy, as determined by image-based dosimetry; 
• 
platelets <50.0*109/L (i.e. Grade 3 or higher); 
• 
if one of the following medical conditions occurs (based on CTCAE v5.0 criteria, see 
Appendix 4) and does not resolve within 4 weeks (resolved=toxicity Grade 1 or 
recovered, and is at the discretion of the investigator): 
- 
eGFR of <45 mL/min/1.73m2; 
- 
liver function tests (total bilirubin, aminotransferases, alkaline phosphatase and 
gamma glutamyl transferase (GGT) higher than Grade 3 (unless there is treatment-


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related liver toxicity, in which case the study treatment should be stopped or 
interrupted to enable recovery when deterioration of the liver function is noted); 
- 
any other related AE above Grade 2, except hair loss, lymphopenia, nonfebrile 
neutropenia lasting <4 weeks. 
The investigator can decide at his/her discretion to discontinue the treatment or to reduce the 
administered radioactivity for further safety reason than those here listed above to prevent a 
subject from higher grade toxicity. 
Before the administration of Cycles 2 and 3 these criteria must be checked. In the event of 
withdrawal (discontinuation) from treatment only the EW Visit and the long-term follow-up 
will be performed (with the EW Visit, 8 weeks after the last administration of 177Lu-OPS201). 
In some cases, absorbed dose to the bone marrow or kidney may be difficult to evaluate. If there 
is uncertainty about the radiation dose received to critical organs, but without substantial 
toxicity, the decision to administer additional cycles is based on continuing to meet 
requirements of the inclusion criteria, the investigator’s judgement and subject’s discretion and 
must be discussed with and agreed by the sponsor. The decision may be either to stop the 
treatment, administer the full dose or a reduced dose depending on the benefit-risk balance for 
the subject. 
In the situation of persisting Grade 3 and higher bone marrow toxicity, a bone marrow aspirate 
can be considered, at the discretion of the investigator, if this could contribute to the evaluation 
of the event.  
6.5 
Treatment of Overdose 
Accidental overdosing is highly unlikely as medication will be prepared individually for each 
subject by a qualified radiopharmacist. In the event of accidental overdosing of radio-labelled 
product, this may result in increased tissue exposure. The subject should be treated according 
to acceptable protocols by the investigator. This might include measures to increase excretion 
(e.g. hydration or diuretics) and preparation for the treatment of damage to critical organs such 
as the kidney and bone marrow (as kidney failure or myelodysplastic syndrome). There is no 
specific guidance for overdosing. All procedures must be in accordance with the local Radiation 
Protection guidelines. 
Drug overdose is a reportable “Special Situation” and should be reported in the same format 
and within the same timelines as a SAE, even if it did not result in an AE. 
Overdose is defined as any dose administration where >25% in excess of the correct 
radioactivity amount is administered whether or not associated with an AE.  
For monitoring purposes, any case of overdose must be reported in the eCRF’s Safety Section 
in an expedited manner.  
If the pharmacy discovers that an overdose has or may have been administered, they should 
inform the Study investigator and Study Coordinator. 
6.6 
Post Study Treatments 
Following completion of this study, all treatments and interventions will be at the investigator’s 
discretion according to clinical practice and subjects’ needs. 
6.7 
Procedures for Monitoring Subject Compliance 
The investigator will be responsible for monitoring subject compliance. Subjects can be 
withdrawn from the study at any time if the investigator or the sponsor determines that the 
subject is not in compliance with the study protocol. 


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The investigator is obliged to keep sufficient documentation of the delivery, use and destruction 
or return of unused, used or partially used packages of IRPP. The investigator should maintain 
records that document adequately that the subjects were administered the doses specified in the 
protocol and reconcile all IRPP received for the trial.  
Records of usage should include the identification of the subject to whom the study treatment 
was dispensed, the quantity and date of dispensing. Administration compliance will be assessed 
by the trained staff/nurse performing the injection. The radioactivity should also be recorded 
before and after administration. In case of incomplete injection of the IRPP, the residual volume 
left (or the residual radioactivity) in the syringe should be recorded in the eCRF. Any 
discrepancies must be accounted for on the appropriate forms.  
7 
ASSESSMENT OF EFFICACY 
For the timing of assessments in this study, refer to the schedule in Section 5.1. 
7.1 
Efficacy Endpoints and Evaluations 
The efficacy endpoints are presented in Sections 3.2.2.4 and 3.3.1.  
The tumour volume assessment: 
• 
Part A: sstr2 lesions are identified as having visible uptake of 177Lu-IPN01072 on 
SPECT/CT. Only the lesions monitored in dosimetry are included.  
• 
Part B: sstr2 lesions are identified by the prestudy sstr2 scan. The lesions that are 
identified on PET or SPECT by sstr2 scan as measured by CT/MRI scan will be the target 
lesions 
  
 
 
7.2 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data 
Methods for assessing efficacy data is described below. Timing of efficacy assessments are 
discussed in Section 5. Procedures for recording efficacy data are discussed in Section 15.1, 
and methods of analyses are discussed in Section 11.4. 
7.2.1 
Contrast Enhanced CT Imaging/MRI 
Sites will be provided with a study manual including the submission procedures and the 
imaging acquisition guidelines. Tumour response assessments will be performed on-site 
(locally) and off-site (centrally, during the core trial period and additional cycles only). CT/MRI 
images will be used for the tumour response assessments (RECIST v1.1 and other endpoints). 
An imaging charter will be prepared detailing the independent read set-up and the read 
methodology. The imaging charter will also include the methodology for the eligibility read.  
Radiological assessments for tumour response will be performed at the Screening Visit, 
repeated at each cycle of therapy, at the EOCT/EOAC/EW Visit, and every 3 months during 
the 2-year follow-up period or at any time. Additionally, in the event of biological or clinical 
signs of disease progression further radiological assessments can be made based upon 
investigator’s judgment.  
The screening tumour assessments will include pelvis, chest and abdomen, and will be 
performed within 1 month before Visit 1 Day 1. If a historic CT/MRI scan is present that is not 
CCI
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older than 1 month at Visit 1 Day 1, this scan can be used. However, the site should ensure that 
all required anatomies are covered and perform scanning for missing anatomies. Imaging 
parameters used at screening should remain consistent throughout the study. Follow-up imaging 
should include chest, pelvis and abdomen. The chest should be included if lesions were present 
at screening. 
For chest/abdomen/pelvic scans, the scan should extend from the lateral ends of the clavicles 
(to ensure complete coverage of lung apices) down to the lesser trochanters or caudally thereof 
(to ensure complete coverage of inguinal lymph nodes). For abdomen/pelvic scans, the scan 
should begin cranially at the right dome of the diaphragm and extend down to the lesser 
trochanters or caudally thereof (to ensure complete coverage of inguinal lymph nodes). Details 
for image acquisition and provision for central review will be given in a separate imaging 
charter. 
During the Treatment Period (Core Trial and additional cycles in Part B) and the 2-year 
long-term follow-up period, 68Ga-PET scans can be performed, if deemed necessary by the 
investigator. 
7.2.2 
Quality of Life Questionnaire 
A Quality of Life Questionnaire, composed of a general questionnaire for oncological subjects 
(QLQ C30; 28 items with a 4-point scale and two items with a scale from one to seven) and a 
NET-specific questionnaire (Gl.NET21; 20 items with a 4-point scale) in paper-form will be 
completed at baseline (Visit 1, predose), during treatment at Visits 2 and 3 (predose), and at the 
EOCT/EOAC/EW Visit. It is important that the investigator does not influence the subject’s 
responses to the questionnaire in any way.  
8 
ASSESSMENT OF SAFETY  
8.1 
Adverse Events 
Adverse events will be monitored from the time that the subject gives informed consent and 
throughout the study, and will be elicited by direct, nonleading questioning or by spontaneous 
reports. Further details for AE reporting can be found in Section 8.1.2.3.  
8.1.1 
Definition of an Adverse Event 
The definition of an AE below follows ICH GCP guidelines (see also ICH Guideline for 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 
Adverse Event (AE): any untoward medical occurrence in a subject or clinical trial subject 
administered a medicinal product, 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. 
Natural progression or deterioration of NETs including symptoms or malignancy under study 
will be recorded as part of the efficacy evaluation and should not be recorded as an AE/SAE. 
Death due to disease progression will be recorded as part of the efficacy evaluation and will not 
be regarded as an SAE. Neuroendocrine tumour status will be monitored through RECIST v1.1 
evaluation and completion of Quality of Life Questionnaires (QLQ C-30 and GINET.21). Signs 
and symptoms should not be reported as AEs/SAEs if they are clearly related to a relapse or an 
expected change or progression of NETs (symptoms/malignancy). These signs and symptoms 
should only be reported as AEs/SAEs (depending on the investigator’s judgment) if they are: 


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• 
Judged by the investigator to be unusually severe or accelerated NETs or; 
• 
If the investigator considers the deterioration of NETs signs and symptoms to be caused 
directly by the IRPP or OPS301 if applicable. 
If there is any uncertainty about an AE being due solely to the NETs under study, it should be 
reported as an AE/SAE as appropriate. 
Preplanned or elective surgeries or therapies should be recorded in the subject’s source 
documents but are not to be considered AEs unless there was any change to the subject’s 
medical condition during the AE collection period.  
All AEs will be assessed and documented in the eCRF by the investigator. Follow-up of the 
AE, after the last visit of the trial, is required if the AE or its sequelae persist. Follow-up is 
required until the event or its sequelae resolve or stabilise at a level acceptable to the 
investigator and the sponsor’s clinical monitor or his/her designated representative.  
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
The severity of an event is captured in order to subcategorise events. Severity is not seriousness. 
A very severe event can be nonserious, and a serious event can be of a mild severity. For this 
study, the US NCI CTCAE v5.0 should be used for determining an event’s severity.  
All AEs (including SAEs) are to be accurately recorded on the AE page of the subject’s eCRF. 
Each event will be graded for severity using the classifications of CTCAE v5.0 (see Appendix 
4). For events not addressed in the CTCAE v5.0, classifications the following grading will 
apply: 
• 
Mild (Grade 1) - Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated; 
• 
Moderate (Grade 2) - Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activity of daily living (ADL); 
• 
Severe (Grade 3) - Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self-care 
ADL; 
• 
Life-threatening (Grade 4) - Life-threatening consequences; urgent intervention 
indicated; 
• 
Death (Grade 5) related to AE. 
8.1.2.2 
Causality Classification 
The relationship of an AE to IRPP or OPS301 if applicable, administration will be classified 
according to the following: 
• 
Related: reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose response relationship, pharmacology, positive dechallenge and/or 
rechallenge) to assume a causal relationship with IRPP or OPS301 if applicable, 
administration in the sense that it is plausible, conceivable or likely. 
• 
Not related: reports including good reasons and sufficient information (e.g. implausible 
time sequence and/or attributable to concurrent disease or other drugs) to rule out a causal 
relationship with IRPP or OPS301 if applicable, administration. 
Causal relationship of an AE with regards to both administration of IRPP and OPS301 (for 
subjects who received OPS301) should be recorded. The relationship of the study treatment to 
an AE will be determined by the investigator and subsequently reviewed by the sponsor. 


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8.1.2.3 
Assessment of Expectedness 
The reference safety document used in this trial is the Investigator Brochure (IB). 
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 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. 
Subjects may also experience discomfort from lying beneath the camera, e.g. back pain. 
Expected adverse reaction related to amino acid solution: nausea and vomiting are adverse 
reactions commonly reported with the use of cationic amino acid solutions as renal protection 
method. 
Expected adverse drug reactions (ADRs): the definition below follows ICH GCP (see also ICH 
Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting). 
Adverse drug reaction: in the preapproval 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.  
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 ADRs: The sponsor will assess all SAEs whether they are expected or unexpected. 
An unexpected ADR is defined as any adverse drug experience, the nature, specificity or 
severity of which is not consistent with the applicable product information (e.g. IB 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. 
8.1.2.4 
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply: 
• 
They result in a change in IRPP schedule of administration (change in dosage, delay in 
administration, IRPP discontinuation), 
• 
They require intervention or a diagnosis evaluation to assess the risk to the subject, 
• 
They are considered as clinically significant by the investigator, or the laboratory test 
abnormality suggests a disease and/or organ toxicity that is new or has worsened from 
baseline based on sponsor review. 
8.1.2.5 
Abnormal Physical Examination Findings  
All abnormalities in physical examinations are to be recorded as AEs. If an abnormal physical 
examination finding meets any of the criteria for an SAE, it must be reported on an SAE Form.  


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8.1.2.6 
Other Investigation Abnormal Findings 
All abnormal vital signs are to be recorded as AEs. Results of 12-lead ECG will be immediately 
analysed by a cardiologist or qualified investigator, and any clinically relevant findings are also 
to be recorded as AEs. ECG results will also be reviewed centrally. If an abnormal ECG, or 
vital sign finding meets any of the criteria for an SAE, it must be reported on an SAE Form. 
8.1.3 
Adverse Events of Special Interest  
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the IMP and may require close monitoring and rapid communication by the 
investigator to the sponsor. An AESI may be serious or non-serious. The reporting of AESIs 
allows ongoing surveillance of these events in order to characterise and understand them in 
association with the use of this IMP.  
AESIs for 177Lu-OPS201 include events with a potential allergic or immunological mechanism 
which may require more frequent monitoring and/or supportive interventions. These AESIs are 
being closely monitored in the clinical studies with 177Lu-OPS201. If the investigator has any 
questions regarding an AE being an infusion related reaction (IRR), the investigator should 
promptly contact the sponsor’s clinical monitor or his/her designated representative. All AESIs 
will be assessed and reported as AEs on the AE page of the eCRF by the investigator and 
periodically evaluated by the sponsor. 
The signs and symptoms of IRR may include: 
• 
vasovagal reaction 
• 
hypotension 
• 
palpitations 
• 
tachycardia 
• 
sweating 
• 
gastrointestinal (nausea or vomiting, metallic taste in mouth, right upper quadrant pain, 
abdominal cramps or bloating / diarrhoea) 
• 
wheezing 
8.1.4 
Recording and Follow-up of Adverse Events 
At every visit during the study period, the subject will be asked a nonleading question such as 
“Have you had any health problems since you were last asked/seen?” All AEs reported in 
response to questioning, as well as AEs reported spontaneously and occurring at any other time, 
will be recorded on the “Adverse Event” page(s) of the eCRF, regardless of causality. 
If an AE fulfils any of the criteria for a SAE, both the AE pages of the eCRF and the SAE Form 
must be completed.  
All abnormal laboratory results that are clinically significant and, abnormalities in physical 
examinations and vital signs are to be recorded as AEs. Results of 12-lead ECG will be 
immediately analysed by a cardiologist or qualified investigator, and any clinically relevant 
findings are also to be recorded as AEs. ECG results will also be reviewed centrally. If an 
abnormal laboratory (e.g. electrolytes disorders), physical examination, ECG, or vital sign 
finding meets any of the criteria for an SAE, it must be reported on an SAE Form.  
The investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The investigator should also try to separate a primary AE considered as the foremost 
untoward medical occurrence from secondary AEs which occurred as complications 
For both serious and nonserious AEs, documentation must be supported by an entry in the 
subject’s hospital notes. The following information should be captured for all AEs: date of onset 


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and resolution, severity of the event, assessment whether the event was serious or nonserious, 
investigator's opinion of the relationship to investigational drug, treatment required for the AE, 
action taken with IRPP or OPS301 if applicable, and information regarding resolution/outcome. 
8.1.4.1 
Reporting of Adverse Events 
Any AE/SAE occurring during the study, from informed consent up to 6 months after last study 
drug administration, must be reported to the sponsor. 
Up to 6 months after the last study drug administration, all AEs/SAEs will be collected unless 
NET therapies are started, then only AEs/SAEs considered by the investigator to be related to 
the study drug/procedure will be collected. From 6 months after the last study drug 
administration until 2 years after the EOCT/EOAC/EW Visit, withdrawal of consent, lost to 
follow-up or death, all AEs/SAEs related to the study drug/procedure will be collected. 
8.1.5 
Reporting of Serious Adverse Events 
An SAE is classified as any untoward medical occurrence that at any dose: 
• 
Results in death, or; 
• 
Is life threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a more 
severe form, might have caused death, or; 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation, excluding 
admission for social or administrative reasons (see further), or; 
• 
Results in persistent or significant disability / incapacity, where disability is a substantial 
disruption of a person's ability to conduct normal life functions, or; 
• 
Is a congenital anomaly / birth defect in the offspring of a subject who received the IRPP 
or OPS301 if applicable.  
• 
Is an important medical event that may not result in death, be life threatening, or require 
hospitalisation when, based upon appropriate medical judgement, may jeopardise the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-patient hospitalisation, or the development of drug 
dependency or drug abuse.  
In addition to the above criteria, any additional AE that the sponsor or an investigator considers 
serious should be immediately reported to the sponsor and included in the safety database. This 
includes any suspected or confirmed coronavirus COVID-19 (SARS-CoV-2) infection 
(seriousness criteria should be “other medically significant” if no other seriousness criteria are 
present (e.g. hospitalisation)). 
• 
Hospitalisation is defined as any inpatient admission (even if less than 24 hours). For 
chronic or long-term inpatients, inpatient admission also includes transfer within the 
hospital to an acute/intensive care inpatient unit. (NB: only the inpatient admission not 
related to IRRP admission and in link with reportable SAE per protocol definition will 
be recorded in eCRF). 
• 
Prolongation of hospitalisation is defined as any extension of an inpatient hospitalisation 
beyond the stay anticipated/required in relation to the original reason for the initial 
admission, as determined by the investigator or treating physician. For protocol-specified 
hospitalisation in clinical studies, prolongation is defined as any extension beyond the 
length of stay described in the protocol. Prolongation in the absence of a precipitating, 
treatment emergent, clinical AE (i.e. not associated with the development of a new AE 


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or worsening of a pre-existing condition) may meet criteria for "seriousness" but is not 
an adverse experience and thus is not subject to immediate reporting.  
• 
Preplanned or elective treatments/surgical procedures should be noted in the subject’s 
screening documentation. Hospitalisation for a preplanned or elective treatment/surgical 
procedure should not be reported as an SAE unless there are complications or sequelae 
which meet the criteria for seriousness described above. 
Planned hospitalisations that occur exclusively for study procedures must not be documented 
as SAEs. 
Actions and reporting obligations in case of SAEs 
All SAEs (as defined above), regardless of treatment group or of suspected relationship to IRPP 
or OPS301 if applicable, must be reported immediately. Therefore, all pertinent questions in 
the eCRF’s Safety Report Section must be answered and the form signed. This triggers 
immediate notification of the sponsor through an email alert. The SAEs should be reported to 
the sponsor within 24 hours of awareness by completing an Ipsen SAE paper form included in 
the site folder and sending it to the sponsor by e-mail (preferably) or fax.  
 
For SAE reporting:  
Email:
Fax: 
 
The following information is the minimum that must be provided to the sponsor 
pharmacovigilance contact within 24 hours for each SAE: 
• 
study number 
• 
site number 
• 
subject number 
• 
AE 
• 
IRPP (177Lu-OPS201) information with administration date/dose/radioactivity 
• 
OPS301 information with administration date (if applicable) 
• 
investigator's name and contact details. 
If the fall back solution was used for reporting an SAE, an Ipsen SAE form must be filled with 
all available details (as many as possible) within 24 hours and sent to Ipsen within 24 hours. 
The event data must still be entered by the site into the eCRF as soon as technical problems 
have been solved to ensure that all events are consistently entered into the study database.  
Any other relevant documents such as anonymised copies of hospital records may also be 
attached, if available, taking care to redact the subject’s name and address and to add the 
subject’s study number on each page.  
In the event of subject death, a detailed description of the cause of death should be provided. If 
available, autopsy reports, with the subject’s name and address redacted and the subject’s study 
number written on every page, should also be sent to the sponsor using the contact routes above, 
as soon as they become available. Any additional information which becomes known to the 
investigator should be provided in a follow-up report to the numbers above. 
Notification to the IEC/IRB: the sponsor will be responsible for ensuring the notification to 
the IEC/IRB of all relevant events (e.g. SAEs and suspected unexpected serious adverse 
reactions (SUSARs)) according to all applicable regulations. 
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Notification of the regulatory authorities: the sponsor will ensure all relevant events 
(e.g. SAEs, SUSARs) are reported to the regulatory authorities according to all applicable 
regulations. 
Exposure during pregnancy or lactation, see Section 8.1.7 
8.1.6 
Suspected Unexpected Serious Adverse Reactions 
SUSARs are serious adverse events that are not consistent in nature, specificity or severity with 
the reference safety information in the approved IB, and that the investigator and/or sponsor 
identifies as related to IRPP or OPS301 if applicable.   
8.1.7 
Pregnancy 
Pregnancy and lactation are exclusion criteria for this clinical study. If pregnancy occurs during 
the course of the study, the subject must be withdrawn from study and closely followed-up 
during the entire course of the pregnancy and postpartum period.  
If a site becomes aware of a subject’s (or their partner’s) pregnancy or of exposure via 
breastmilk, the sponsor must be notified without delay by entering pertinent data in the Safety 
Section of the eCRF.  
The sponsor will request further information from the investigator as to the course and outcome 
of the pregnancy using the Standard Pregnancy Outcome Report Form.  
The investigator must instruct all female subjects to inform them immediately should they 
become pregnant during the study. The investigator should counsel the subject, discuss the risks 
of continuing with the pregnancy and the possible effects on the foetus. For pregnancies, 
parental and neonatal outcomes must be recorded even if they are completely normal and 
without AEs. Offspring should be followed up for at least 8 weeks after delivery. If the expected 
due date is after the end of the study period, the sponsor will assume responsibility for follow-
up through the due date/8 weeks post-partum, and for the regulatory reporting of any pertinent 
follow-up information.  
If the investigator becomes aware of a pregnancy occurring in the partner of a subject 
participating in the study, this should be reported to the sponsor. After the partner has given 
written consent, she should be counselled and followed as described above. Monitoring of the 
partner should continue until conclusion of the pregnancy. 
8.1.8 
Deaths 
For AEs leading to death, NCI CTCAE Grade 5 is the only appropriate grade (see 
Section 8.1.2.1). Deaths that cannot be attributed to an NCI CTCAE term associated with 
Grade 5 or that cannot be reported within an NCI CTCAE category as ‘Other’ have to be 
reported as one of these three AE options: 
• 
death not otherwise specified (NOS), 
• 
disease progression NOS, 
• 
multi-organ failure, 
• 
sudden death. 
8.1.9 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to the IRPP (see Section 4.6.1). 
If the IRPP is discontinued due to an SAE, it must be reported immediately to the sponsor’s 
designated representative (see Section 8.1.5). In case of suspected or confirmed COVID-19 
infection, the IRPP administration may be temporarily discontinued depending on the subject’s 


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clinical presentation. In some cases, the investigator may request a subject be retested before 
the IRPP administration is resumed. 
In all cases, the investigator must ensure the subject receives appropriate medical follow-up 
(see Section 4.6.1). 
8.1.10 
Investigational Product Complaints  
Pharmaceutical technical complaints associated with the investigational product must be 
reported to the sponsor immediately. If a subject experiences an SAE associated to a 
pharmaceutical technical complaint, it must be specified in an SAE form. The same reporting 
timelines as for SAEs apply. 
8.1.11 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The sponsor will ensure that processes are in place for submission of reports of SUSARs and 
other important safety information occurring during the study to the CA, IECs and other 
investigators concerned by the IRPP. Reporting will be done in accordance with the applicable 
regulatory requirements. 
8.1.12 
Risk-benefit Management 
With the exception of the two studies previously described, this is the first clinical trial with 
177Lu-OPS201 conducted by Ipsen. Thus, this study is subject to the precautions detailed in 
"Guideline on strategies to Identify and Mitigate Risks for First-in-human Clinical Trials with 
IMPs" (EMEA/CHMP/SWP/28367/07). In particular, i.v. administration of a peptide may 
conceivably result in a hypersensitivity reaction. Adequate resources, including an intensive 
care unit, must be available at the site to handle acute reactions, including anaphylactic shock. 
Emergency equipment will be available in the nuclear medicine department and anywhere else 
in the hospital where the study will take place. 
8.2 
Clinical Laboratory Tests 
The certified laboratory of the study site will perform haematology, biochemistry and urinalysis 
laboratory tests. Pituitary markers will be analysed at local laboratory unless this assessment 
cannot be performed locally, it will be analysed in a central laboratory. 
 
A copy of the 
laboratory certification and tabulation of the reference ranges will be provided. 
8.2.1 
Haematology 
Samples will be tested for haemoglobin, haematocrit, mean corpuscular volume, mean 
corpuscular haemoglobin, white blood cell count (total and differential: leukocytes, neutrophils, 
eosinophils, basophils, lymphocytes, monocytes), red blood cells and platelets.  
Haematology will be measured at the Screening Visit, at Visits 1 to 3 (+ optional Visits 4/5) 
(predosing, 24±1 hour (Day 2), 48±1 hour (Day 3), 72 to 96 hours (Day 4 to 5), 144 to 
168 hours (Day 7 to 8) and Day 15±2 days), Follow-up Visits, the EOCT/EOAC/EW Visit and 
the visits in the 2-year long-term follow-up period. 
8.2.2 
Blood Biochemistry 
Samples will be tested for sodium, potassium, chloride, calcium, glucose, creatinine, urea, 
albumin, total bilirubin, AST, ALT, alkaline phosphatase, GGT, C-reactive protein. Creatinine 
clearance will also be calculated. 
The eGFR value will be calculated by the Modification of Diet in Renal Disease (MDRD) 
(preferably isotope dilution mass spectrometry (IDMS)-traceable MDRD) formula [61].  
Biochemistry will be measured at the Screening Visit, at Visits 1 to 3 (+ optional Visits 4/5) 
(predosing, 24±1 hour (Day 2), 48±1 hour (Day 3), 72 to 96 hours (Day 4 to 5), 144 to 
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168 hours (Day 7 to 8) and Day 15±2 days), Follow-up Visits, the EOCT/EOAC/EW Visit and 
the visits in the 2-year long-term follow-up period. 
8.2.3 
Urinalysis 
Sample will be tested for specific gravity, pH, protein, glucose, blood, urobilinogen, 
erythrocytes, leukocytes, ketones, bilirubin, nitrite, albumin. 
To be measured at the Screening Visit, predose and Day 15 at Visits 1 to 3 (+ optional Visits 
4/5), Day 7 to 8 at Visit 1, at Follow-up Visits 1 to 3, at the EOCT/EOAC/EW Visit, and at the 
visits in the 2-year long-term follow-up period. 
8.2.4 
Pregnancy Test 
Prior to each PRRT cycle (Screening Visit and Visits 1 to 3 (+ optional Visits 4/5), predosing) 
each female subject of childbearing potential must undergo a pregnancy test. A serum 
pregnancy test will be performed at the Screening Visit. A serum or urine pregnancy test will 
be performed predose on Day 1 of Visits 1 to 3. 
In the event of pregnancy, the subject is not allowed to receive further PRRT cycles and must 
be withdrawn from the study. The pregnancy must be reported to the sponsor on the SAE form 
until the end of the trial. 
8.2.5 
Pituitary Marker (Marker of Pituitary Function)  
Pituitary markers include free thyroxine (fT4), cortisol, insulin-like growth factor (IGF)-1 and 
thyroid stimulating hormone (TSH). These markers will not be analysed if subjects are 
receiving substitute or therapy concerning the respective pituitary axis (e.g. no analysis of fT4 
and TSH in subjects who receive thyroxine, no analysis of cortisol in subjects who received 
corticosteroids). 
Measured predose at Visit 1, Day 1 at 08:00 (±1 hour) and Visit 1, Day 2 – important to judge 
cortisol value, and at the EOCT/ EOAC/EW Visit. 
8.3 
Physical Examination 
A physical examination (including examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, musculoskeletal, 
cardiovascular and nervous systems) will be carried out by a physician at Screening and each 
study visit up to, and including, the EOCT/EOAC/EW Visit and the visits in the 2-year 
long-term follow-up period. Any clinically significant abnormalities at Screening will be noted 
on the medical history pages of the eCRF. During the study, if in the opinion of the investigator 
there are any clinically significant changes in the physical examination findings 
(abnormalities), they will be recorded as AEs. 
8.4 
Height and Weight 
Subject height will be measured at the Screening Visit, while weight will be assessed predose 
at Visits 1 to 3 (+ optional Visits 4/5) and at the EOCT/EOAC/EW Visit. Body surface area 
will be determined with the Mosteller formula. 
8.5 
Vital Signs 
Body temperature and supine vital signs (blood pressure and heart rate) will be measured on 
the nondominant arm after 5 minutes of supine rest at the following time points: at the 
Screening Visit, at Visits 1 to 3 (+ optional Visits 4/5) (predose, postinfusion: at stop of infusion 
(0), 30±5 minutes, 60±10 minutes, 4 hours ±10 minutes, 24±1 hour (Day 2), 48±1 hour 
(Day 3), 72 to 96 hours (Day 4 to 5), 144 to 168 hours (Day 7 to 8), Day 15, Follow-up Visits, 
the EOCT/EOAC/EW Visit and the visits in the 2-year long-term follow-up period. 


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8.6 
Electrocardiography 
A 12-lead ECG will be performed at the Screening Visit, predose at Visits 1 to 3 (+ optional 
Visits 4/5), at the Follow-up Visits, at the EOCT/EOAC/EW Visit and at the visits in the 2-year 
long-term follow-up period. ECGs will be recorded in triplicate and in the supine position after 
at least 5 minutes of rest. 
During the administration of the PRRT study drug, starting with the injection of the antiemetic 
(i.e. 15 to 30 minutes before the start of the amino acid infusion – see Figure 14), a 24 hour 
ECG (Holter) will be recorded to monitor cardiac safety during the treatment.  
The site will be required to review ECGs as a safety check at each Day 1 before administration. 
This will be done immediately by a qualified investigator at the study site. ECG and Holter 
assessments will be reviewed centrally during the core trial period and local review at the site 
will be performed at the visits in the 2-year long-term follow-up period. Results will be 
provided to the site and retained as source data. 
8.7 
Performance Status 
The performance status of the subjects will be defined by the Karnofsky scoring and assessed 
at the Screening Visit, predose at Visits 1 to 3 (+ optional Visits 4/5) and at the 
EOCT/EOAC/EW Visit: 
• 
100 - Normal; no complaints; no evidence of disease, 
• 
90 - Able to carry on normal activity; minor signs or symptoms of disease, 
• 
80 - Normal activity with effort; some signs or symptoms of disease, 
• 
70 - Cares for self; unable to carry on normal activity or to do active work, 
• 
60 - Requires occasional assistance but is able to care for most of his personal needs, 
• 
50 - Requires considerable assistance and frequent medical care, 
• 
40 - Disabled; requires special care and assistance, 
• 
30 - Severely disabled; hospital admission is indicated although death not imminent, 
• 
20 - Very sick; hospital admission necessary; active supportive treatment necessary, 
• 
10 - Moribund; fatal processes progressing rapidly, 
• 
0 - Dead. 
8.8 
Subject Demographics  
At the Screening Visit the following demographic data will be collected: year of birth, sex, 
childbearing potential, and ethnicity. 
8.9 
Medical History  
Relevant medical history will be recorded in the eCRF at the Screening Visit and includes 
diagnosis and assessments of any current medical condition, especially details of the NET 
diagnosis and prior cancer therapies (e.g. previous surgery, chemotherapy, radiotherapy, SSA 
use), and concomitant health conditions. In case of SAEs, medical history should also be 
reported in the SAE form. 
8.10 
Prior and Concomitant Medication  
Prior medications/therapies will be reported if taken up to 28 days prior to the Screening Visit. 
Concomitant medications/therapies will be reported at every visit throughout the core trial and 
additional optional cycles. Any effort to report prior NET treatment/therapy prior to study entry 
will be reported. The only treatments recorded during the Long-term Follow-up period will be 
further antitumour treatments for NETs. In case of SAEs, concomitant medications should also 
be reported in the SAE form. 


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9 
ASSESSMENTS OF PHARMACOKINETICS 
Timing of sample collections must be accurately recorded in the eCRF. 
9.1 
Pharmacokinetics of the Radiopharmaceutical 
9.1.1 
Blood Sample Collection 
For each subject, total radioactivity concentration in whole blood will be measured. Each 
subject will have blood samples (2 mL) taken as follows: 
Visit 1: 
• 
Before infusion, at stop of infusion (0), 5 minutes ±1 minute, 30 minutes±3 minutes, 
1 hour±5 minutes, 4 hours±10 minutes, 24±1 hours, 48±1 hours, 72 to 96 hours, and 144 
to 168 hours after the stop of infusion. 
Visits 2 and 3: 
• 
Before infusion, at stop of infusion (0), 1 hour±5 minutes, 4 hours±10 minutes, 
24±1 hour, 48±1 hour, 72 to 96 hours and 144 to 168 hours. 
For subjects receiving additional administrations (up to two additional cycles, Part B only), 
blood samples will be taken at each cycle according to the timepoints described above for 
Visits 2 and 3.  
Blood samples should be collected from the contralateral arm used for the study drug infusion, 
or from another anatomical site. 
The accurate time of sample collection and the duration for measuring the radioactivity 
concentration must be recorded. Any issues associated with sample collection or processing 
should be reported to the sponsor’s monitor. 
Complete instructions for sample collection, processing and handling will be provided in a 
“Dosimetry Operation Manual”. 
9.1.2 
Urine Sample Collection 
To determine the renal excretion of 177Lu, urine will be collected during the first 48 hours post 
infusion at the following time periods: 
Visit 1 only:  
• 
Part A: from the start of the infusion to 6 hours, 6 to 24 hours, 24 to 48 hours 
postinfusion 
• 
Part B: from the start of the infusion to 4 hours, 4 to 24 hours, 24 to 48 hours (from the 
start of the infusion to 4 hours postinfusion only for US and Canada sites) 
The accurate time of urine collection and the total urine volume for each collection interval 
must be recorded. All problems associated with sample collection or processing should be 
reported to the sponsor’s monitor. 
Complete instructions for urine collection, processing and handling will be provided in a 
“Dosimetry Operation Manual”. 
9.1.3 
Analytical Procedures 
Total radioactivity concentration in whole blood and urine will be determined on site/locally 
using a gamma counter calibrated for 177Lu according to the dosimetry operational manual 
(DOM). The time point of the sample collection and the time point and the duration for 
measuring the radioactivity concentration must be recorded. Complete instructions will be 
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9.2 
Nuclear Medicine Imaging for Dosimetry 
Radioactive assessments in blood and urine are described in Section 9.1. 
9.2.1 
Whole Body Scan 
To determine the biokinetics, whole body scans (planar scintigraphy) will be obtained after 
bladder emptying at 4 hours±10 minutes, 24±1 hour, 48±1 hour, 72 to 96 hours and 144 to 
168 hours, after the start of the 177Lu-OPS201 administration at Visits 1 to 3. 
For subjects receiving additional administrations (up to two additional cycles, Part B only), 
dosimetry assessments will be performed after each additional administration with nuclear 
medicine imaging described above. 
In case of misadministration (such as spillage or interruption of the infusion for AEs), a whole 
body scan (but not SPECT) will be required shortly after the end of infusion and before the first 
bladder emptying. 
Details on the procedures will be given in a separate DOM. 
9.2.2 
SPECT/CT Scan 
Part A 
For absolute quantification, additional three-dimensional (3D) SPECT/CT will be obtained at 
24 hours±1 hour at Visits 1 to 3. It is mandatory for a valid quantification, that the SPECT/CT 
is calibrated. 
Part B 
For absolute quantification, 3D SPECT/CT will be obtained at 4 hours±10 minutes, 24±1 hour, 
48±1 hour, 72 to 96 hours and 144 to 168 hours, after the start of the 177Lu-OPS201 
administration at Visits 1 to 3. 
For subjects receiving additional administrations (up to two additional cycles, Part B only), 
dosimetry assessments will be performed after each additional administration with nuclear 
medicine imaging described above. 
Details on the procedures will be given in a separate DOM. 
9.3 
Pharmacokinetics of the OPS201 
9.3.1 
Blood Sample Collection 
Part B only. Blood samples (2 mL) for assessment of OPS201 plasma levels will be collected 
at the following time points (at Visit 1 only): 
At Visit 1 (first infusion): before the infusion (baseline), at the end of the infusion (0), 
5±1 minute, 30±3 minutes, 60±5 minutes and at 4 hours±10 minutes, 6 hours±30 minutes, 
8 hours ±30 minutes, 24±1 hours and 48±1 hours after the administration of 177Lu-OPS201. 
Blood samples should be collected from the arm opposite to that of the study drug infusion, or 
from another site. 
The accurate time of sample collection must be recorded. Any issues associated with sample 
collection or processing should be reported to the sponsor’s monitor. 
Complete instructions for sample collection, processing, handling and shipment will be 
provided in the laboratory manual. 
9.3.2 
Urine Sample Collection 
To determine the renal excretion of OPS201, the concentration of OPS201 in urine will be 
determined. 


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The samples for urine OPS201 concentration analysis will be taken from urine collected during 
three different periods at Cycle 1 only: from 0 (start of the infusion) to 4, 4 to 24 and 24 to 
48 hours after the start of infusion (0 (start of the infusion) to 4 hours only for US and Canada 
sites). 
The accurate time of urine collection and the total urine volume for each collection interval 
must be recorded. Any issues associated with sample collection or processing should be 
reported to the sponsor’s monitor. 
Complete instructions for urine collection, processing, handling and shipment will be provided 
in the laboratory manual. 
9.3.3 
Analytical Procedures 
Plasma and urine samples will be analysed to determine concentrations of OPS201 using a 
high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) 
detection, according to a separate protocol established with the dedicated analytical laboratory. 
Residual plasma and urine used for OPS201 PK analysis may also be used for exploratory 
analysis. 
 
Plasma and urine samples remaining from the analysis may be retained by the 
sponsor for additional investigations (i.e. long-term stability, reproducibility).  
10 
EXPLORATORY BIOMARKERS AND BIOBANKING 
10.1 
Exploratory Biomarkers 
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11 
STATISTICS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
are documented in a statistical analysis plan (SAP), v1.0 Final which is dated and completed 
on 09 March 2017 (revisions may be made to this to incorporate changes made to methodology 
of Part B in the protocol v6.0 and up). The SAP may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint and/or its analysis will also be 
reflected in a protocol amendment. 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® (v9.2 or 
higher) 
11.1 
Analyses Populations 
Subjects will be assigned to each analysis set prior to the statistical analysis. The following 
population will be used during statistical analyses: 
• 
Screened Subjects Set: all subjects screened (i.e. who signed the informed consent) 
• 
Eligible Subjects Set: all subjects who comply with the inclusion and exclusion criteria 
(according to the investigator/site) and have entered the study (performed the Screening 
Visit). 
• 
Safety Analysis Set: all subjects who received study medication.  
• 
Intent-to-Treat Set (ITT): all subjects in the Eligible Subjects Set who received study 
medication. 
• 
Per-Protocol Set (PP): all subjects in the ITT Set who complete the study according to 
the protocol with no major protocol deviation. Any protocol deviation will be evaluated 
by the sponsor based on the individual case. Major protocol deviations will be defined in 
the Protocol Deviations Document and identified in a data review meeting before 
database lock.  
• 
Intent-To-Treat Dosimetry Analysis Set (ITT-DAS): all subjects in the ITT Set for 
whom at least one complete set of dosimetry imaging and dosimetry blood sample 
measurements is available. 
• 
Per-Protocol Dosimetry Analysis Set (PP-DAS): all subjects in the ITT-DAS for whom 
no major protocol violations occurred affecting dosimetry variables. 
• 
Radiopharmaceutical Pharmacokinetic Set: For Part A and Part B, all subjects in the 
ITT Set who receive at least one dose of study medication and have at least one measured 
radioactive concentration in blood. 
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• 
OPS201 Pharmacokinetic Set (for Part B only): all subjects in the ITT Set who receive 
at least one dose of study medication and have no major protocol deviations affecting the 
PK variables and who have a sufficient number of OPS201 levels to estimate the main 
PK parameters (i.e. Cmax, Tmax, and AUC). 
11.1.1 
Populations Analysed 
The primary analysis based on the assessment of the safety and tolerability of the study drug 
(primary objective) will be performed on the Safety Analysis Set. 
The efficacy analysis will be performed on the ITT and PP sets. 
11.1.2 
Reasons for Exclusion from the Analyses  
Any major protocol deviation (see Section 13.1.2 for definition) will be described and its impact 
on inclusion in each analysis population (PP, safety and PK populations) for any subject will 
be specified. The final list of protocol deviations impacting the safety, ITT and PP populations 
will be reviewed prior to database lock. The list may be updated, up to the point of database 
lock, to include any additional major protocol deviations impacting inclusion in the PP 
population. 
11.2 
Sample Size Determination 
It is anticipated that a total of up to 55 subjects will be recruited, up to 15 subjects in Part A and 
up to 40 subjects in Part B. This is considered appropriate for an exploratory study and it is not 
based on formal statistical sample size calculation. In the event subjects do not complete 
treatment due to any reasons other than exceedance of organ dose limits or treatment related 
safety issues, additional subjects may be recruited as replacements to ensure an adequate sample 
size in the “per protocol set” for safety evaluation. Subjects with noninterpretable dosimetry 
scans may be replaced upon agreement of the investigator and the sponsor. 
For Cohorts 3 and 6 in Part B, to detect a difference between two peptide doses within the same 
cohort, the total sample size of eight is calculated. Assuming 30% standard deviation of the 
paired difference, there is 80% power to detect a 2-fold-change, and 99% power to detect a 
3-fold change at a 2-sided alpha of 0.05. 
11.3 
Significance Testing and Estimations 
As this is a descriptive safety and tolerability/efficacy study, no formal statistical testing will 
be carried out. 
11.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by external contract research organisations (CROs), 
managed by the sponsor’s Biometry Department. 
Details of the statistical analysis are specified in the SAP. 
The statistical analyses will be conducted using SAS (v9.2 or later). 
Primarily, all variables will be analysed descriptively, as follows: 
• 
Mean, standard deviation, median and range for continuous variables 
• 
Median, range and frequency distribution for discrete (ordinal) variables 
• 
Frequency distribution for nominal variables. 
Secondarily, the variables descriptive statistics will be presented by study part. If appropriate, 
results for total, Part A+B will be presented. In the event of dose escalation, study Parts A and 
B will be compared using nonparametric tests. The test results will be interpreted in an 
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Data collected during the Long-term Follow-up will be analysed by means of a survival analysis 
(Kaplan-Meier method) with the respective plots and descriptive summaries. 
11.4.1 
Demographic and Other Baseline Characteristics  
Descriptive summary statistics (n, mean, standard deviation, median, minimum, maximum) and 
frequency counts of demographic and baseline data (medical history, concomitant disease, 
predosing AEs and ongoing medical history, prior medications and therapies, baseline 
symptoms, etc.) will be presented for the ITT, PP, safety and PK populations. 
11.4.2 
Subject Disposition and Withdrawals  
The numbers and percentages of subjects enrolled and included in each of the ITT, PP, safety 
and PK populations will be tabulated. The reasons for subject exclusions from each of the 
populations will be listed and tabulated. In addition, the numbers of subjects who received study 
treatment, discontinued and completed at each of the study periods (e.g. active follow-up 
period, survival follow-up period) will be tabulated. Primary reasons for discontinuation of 
study treatment will be listed and tabulated. 
11.4.3 
Efficacy Data  
Descriptive summaries will be performed for the efficacy data and the quality of life 
questionnaire data for each time point as applicable. Preliminary antitumour activity will be 
measured by calculating BOR, ORR and DCR. For each response category, the number and 
associated percentage of subjects will be presented by study part, and by cohort (applicable for 
Part B) and overall. Time to PFS will also be estimated using the Kaplan-Meier method to 
calculate the median (associated 95% confidence interval) by study part, by cohort (applicable 
for Part B) and overall. The summaries will be based on the ITT and PP populations. For 
imaging efficacy endpoints, these will be summarised separately for the central and the 
investigator assessment.  
11.4.4 
Biodistribution and Radioactive Pharmacokinetics of the Radiopharmaceutical 
The following biodistribution (i.e. organ PK) parameters will be evaluated: 
• 
maximal uptake (%) at the target lesion, 
• 
maximal uptake (%) in discernible organs and blood, 
• 
AUC of 177Lu-OPS201 in discernible thoracic and abdominal organs, target lesion and 
blood, 
• 
terminal half-life of radioactivity concentrations of the radiopharmaceutical in blood. 
Data analysis and all biodistribution parameters will be further described in the SAP. 
11.4.5 
Pharmacokinetic Data 
The PK analysis of OPS201 will be performed under the responsibility of the sponsor’s Clinical 
PK department. 
Analysis of PK data by a noncompartmental approach will be documented in a separate SAP. 
Individual plasma and urine concentrations of OPS201 will be listed and summarised by time 
points using descriptive statistics for continuous variables (number of available observations, 
mean, median, standard deviation, minimum, maximum, geometric mean and geometric 
coefficient of variation assuming lognormally distributed data). Linear and semi-logarithmic 
plots of individual and mean plasma concentration-time profiles as well as spaghetti plots will 
be reported. 
Any suspicious concentration will be investigated and kept in the PK analysis if possible. All 
excluded concentrations will be justified in the report. 


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If OPS201 levels are measurable in plasma and urine, PK parameters of OPS201 (including, 
but not limited to, Cmax, AUC, t1/2, Cl, Vd, Ae, CLR) will be derived using the noncompartmental 
approach on the individual plasma concentration-time profiles of OPS201 and on the individual 
urine concentrations. 
11.4.6 
Evaluation of Radiation Dosimetry 
Further details on dosimetric assessments and on dosimetric parameters is provided in the SAP.  
For the central dosimetry assessment, the relevant subject data (subjects’ scans and data on 
blood activities) will be uploaded at the central reading centre and transmitted after the last scan 
of each visit to the central dosimetry assessment site in Würzburg. The dosimetric assessments 
will be performed and reported according to the criteria set by the EANM Dosimetry 
Committee guidance document: good practice of clinical dosimetry reporting.[62]. 
Calculations will be conducted on the following parameters (only in organs showing uptake) as 
described in the Dosimetry Calculation Procedure Manual: 
• 
organs receiving the highest absorbed dose 
• 
specific absorbed dose per organ (Gy/GBq) 
• 
cumulative absorbed organ doses (Gy). 
Cumulative absorbed organ doses (Gy)/Organs of highest radioactivity uptake will be identified 
visually. Regions of interest will be placed over these organs to determine the relative 
radioactivity in the respective organs. TACs (describing % injected (radio)activity /region of 
interest (IA/ROI) of the radioactivity amount injected versus time, considering renal excretion 
radioactivity) will be derived. The absorbed doses of the dose limiting organs (kidney and bone 
marrow) will be evaluated and reported to the investigator before the next cycle can be initiated 
to enable radioactivity adaptations in the event the next dose may exceed the organ limits of 
23 Gy (kidney) and 1.5 Gy (bone marrow). The dosimetry result for all other organs will be 
finalised for the final study report with the restriction, that the Part A dosimetry data must be 
available for the SRC meeting. These data can be reviewed at any time if a major safety issue 
occurs. 
11.4.7 
Documentation of Biodistribution Results  
Biodistribution data for target lesion and all abdominal and thoracic organs analysed will be 
listed for each study subject and each sampling time point. In addition, arithmetic mean, 
arithmetic standard deviation, coefficients of variation (CV) and number of data points (N) will 
be provided per sampling point. The parameters described in the Section 11.4.4 will be 
estimated for each subject. Total radioactivity cumulatively excreted in the urine in the interval 
0 to 6 hours, 6 to 24 hours and 24 to 48 hours postinjection will be determined for each subject. 
Measured total 177Lu radioactivity concentrations in whole blood and urine will be listed for 
each study subject and each sampling time point. In addition, means, standard deviation, CV 
and number of data points (N) will be provided per sampling point. Based on the individual 
177Lu blood TACs, the concentration-time profiles of 177Lu-OPS201 and the AUC in blood, will 
be estimated for each subject.  
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The proportion of renally excreted radioactivity, whole blood radioactivity, and dosimetric 
whole body images will be used to calculate the dosimetry of 177Lu-OPS201.  
11.4.8 
Evaluation of Tumour Response 
Tumour response will be evaluated by the site investigator and by an independent central 
review. Response and progression will be evaluated using the revised RECIST guideline (v1.1, 
see Appendix 2) and 
 Only subjects with measurable disease at 
baseline, who have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response. 
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, and permit reproducible repeated 
measurements. On occasion, if the largest lesion does not permit reproducible measurement, 
the next largest lesion which can be measured reproducibly will be selected. A sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will 
be calculated and reported as the baseline sum diameters. If lymph nodes are included in the 
sum, then only the short axis will be added into the sum. The baseline sum of diameters will be 
used as reference to further characterise any objective tumour regression in the measurable 
dimension of the disease. 
All other lesions (or sites of disease) including any measurable lesions over and above the five 
target lesions should be identified as nontarget lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or unequivocal 
progression of each should be noted throughout follow-up. 
Overall objective tumour response will be classified as CR, PR, SD or PD, and unevaluable 
according to RECIST v1.1 at each visit. Based on objective tumour response, BOR, ORR, DoR 
and DCR will be calculated for both the central and the investigator review.  
Time to PFS according to RECIST v1.1 and time to overall response will also be summarised.  
Details of the response evaluation will be given in a separate image review charter. Details of 
the analysis will be specified in the SAP. 
Tumour volume changes as percentage change from baseline will be evaluated for: 
• 
Part A: sstr2 lesions are identified as having visible uptake of 177Lu-IPN01072 on 
SPECT/CT. Only the lesions monitored in dosimetry are included. 
• 
Part B: sstr2 lesions are identified by the prestudy sstr2 scan. The lesions that are 
identified on PET or SPECT by sstr2 scan as measured by CT/MRI scan will be the target 
lesions 
 
This will be provided on a tumour basis and the sum of the percentage change per tumour.  
An onco-radiologist’s global assessment of each subject will be provided to detail the observed 
changes and anything of note that is not captured in the other radiological evaluations, e.g. a 
PR or SD was not scored because of two-pixel differences.  
All radiological assessments will be detailed in an Imaging Review Charter. 
11.4.9 
Adjustment for Country/Centre Effect 
Not applicable, as no randomisation or stratification will be performed in this study. 
11.4.10 Safety Evaluation  
The safety endpoints are indicated in Section 3.2.1 and Section 0. 
All safety analyses and summary tables will be based upon the safety population. 
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All AEs will be coded according to the MedDRA (v20.0 or later) and will be classified by 
MedDRA PT and system organ class (SOC). Adverse event listings will be presented by 
subject, SOC and PT. 
The incidence of all reported AEs/treatment emergent AEs (TEAE), AESIs and SAEs will be 
tabulated by study part and overall. In addition, summary tables will be presented by maximum 
severity, drug relationship, and AEs/TEAEs associated with premature withdrawal of study 
medication or with delayed administration/reduction of 177Lu-OPS201. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
It was not present prior to receiving the first dose of IRPP or OPS301 if applicable or; 
• 
It was present prior to receiving the first dose of IRPP or OPS301 if applicable but the 
intensity increased during the active phase of the study, or; 
• 
It was present prior to receiving the first dose of IRPP or OPS301 if applicable, the 
intensity is the same but the drug relationship became related during the active phase of 
the study.  
All TEAEs will be flagged in the AEs listings. 
Summary incidence tables will be provided, classified by body system, PT and associated NCI 
CTCAE worst grade. In the event of multiple occurrences of the same AEs being reported by 
the same subject, the maximum severity (Grade 5>Grade 4>Grade 3>Grade 2>Grade 
1>missing>not applicable) and the most serious causality (related>not related) will be chosen. 
The number of subjects presenting with at least one DLT will be tabulated and listed. The type 
of DLTs will be also tabulated and listed. 
Concomitant medication will be coded by using WHO Drug Dictionary and will be summarised 
by study part and overall with the number and percentage of subjects receiving concomitant 
medication by drug class and preferred drug name. 
Summary statistics (mean, median, standard deviation and range as appropriate) by study part 
and by overall will be presented for vital signs, blood pressure, heart rate, clinical laboratory 
tests etc. at each assessment with change from Baseline.  
Physical examination: frequencies and severity (not clinically significant, clinically significant) 
of abnormalities will be analysed. 
Descriptive summaries of following ECG and Holter parameters will be calculated: heart rate, 
RR interval, PR interval, QRS interval, QT interval, QTcB, and QTcF. The number and 
percentage of subjects with normal, abnormal (not clinically significant), abnormal (clinically 
significant) findings will be presented. 
For laboratory data, abnormal values will be flagged in the data listings and a list of clinically 
significant abnormal values will be presented.  
Haematological and biochemical toxicities will be recorded and graded according to the NCI 
CTCAE. The NCI CTCAE Grade 3 and 4 haematology and biochemistry parameters by subject 
and by cycle will be tabulated and listed. For white blood cells, neutrophils, platelets and 
haemoglobin, with associated Grade 3 or 4 toxicities, nadir and day to nadir will be calculated. 
Also, descriptive summaries will be performed for the efficacy data, the data from the quality 
of life questionnaire, the dosimetry data, the bone marrow safety data and the renal toxicity data 
for each time point as applicable. 
11.5 
Subgroup Analyses 
Not applicable. 


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11.6 
Interim Analyses/Safety Review Committees/Data Review Boards 
Dosimetry evaluation will be performed on an ongoing basis. After the first six subjects 
included have completed the study Part A (EOCT/EW Visit) an SRC meeting will be held 
before exposing the remaining subjects to the entire number of planned administrations. Safety 
data obtained until 8 weeks after the last administration of the 6th subject will be evaluated 
during this SRC. Prior to Part B, the SRC will review the safety and dosimetry data of the first 
six subjects included in Part A.  
For Part B, a DRB meeting will be held to review the safety and radiation exposure data and 
decide whether to proceed with the enrolment of the next cohort dose level and the cumulative 
radioactivity within a cohort. Each dose escalation (both peptide and radioactivity) will be 
carefully evaluated by a DRB (see Figure 13 and Appendix 3).  
In addition, the SRC/DRB can be convened at any time during the trial to discuss potential 
safety issues. The data set to be reviewed by the SRC/DRB is specified in a specific charter.  
A first interim analysis will be conducted at the cut-off date of 27 September 2019 to inform 
the design of the chemotherapy combination study which has been added to the investigational 
plan. 
A second interim analysis of Part B data will be conducted at the EOCT/EOAC/EW (whichever 
occurs last) after completion of Cohorts 3 and 6. This will provide confirmation of the peptide 
dose to allow future studies to be developed. It will also confirm if Cohorts 2 or 7 and 8 will be 
initiated.  
A third interim analysis, including all dosimetry, safety and efficacy data, will be performed 
after the EOCT/EOAC/EW (whichever occurs last) when the two study parts are completed. 
The interim analyses may be combined based on the overall study status and subject accrual. 
The final analysis will be performed at the end of the 2-year long-term follow-up period.  
12 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
Authorised personnel from external CAs and sponsor authorised Quality Assurance personnel 
may carry out inspections and audits. The purpose of an audit is to ensure that ethical, regulatory 
and quality requirements are fulfilled in all studies performed by the sponsor. 
Auditors and inspectors must have direct access to study documents and site facilities as 
specified in Section 13.4, and to any other locations used for the purpose of the study in question 
(e.g. laboratories). 
In the event of the site being notified directly of a regulatory inspection, the investigator must 
notify the sponsor’s representative immediately to assist with preparations for the inspection. 
13 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Protocol Amendments and Protocol Deviations 
13.1.1 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favourable opinion of a written amendment by the IEC/IRB, except when necessary 
to eliminate immediate safety concerns to the subjects or when the change involves only 
logistics or administration.  
In the event that an amendment to this protocol is required, it will be classified into one of the 
following three categories: 
• 
Nonsubstantial amendments are those that are not considered ‘substantial’ 
(e.g. administrative changes) and as such only need to be notified to the IECs or 
regulatory authorities for information purposes. 


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• 
Substantial amendments are those considered ‘substantial’ to the conduct of the clinical 
study where they are likely to have a significant impact on: 
- 
the safety or physical or mental integrity of the subjects; 
- 
the scientific value of the study; 
- 
the conduct or management of the study; or 
- 
the quality or safety of the study drug used in the study. 
Substantial amendments must be submitted to and approved by the IECs and relevant 
regulatory authorities, according to local regulations, prior to implementing changes. 
Urgent amendments are those that require urgent safety measures to protect the study subjects 
from immediate hazard and as such may be implemented immediately by the sponsor with 
subsequent IECs and regulatory authority notification, forthwith 
The principal investigator and the sponsor will sign the protocol amendment. 
13.1.2 
Protocol Deviations and Exceptions 
All protocol deviations will be identified and recorded by the sponsor or sponsor’s 
representative. 
A major protocol deviation is any significant divergence from the protocol, i.e. nonadherence 
on the part of the subject, the investigator, or the sponsor to protocol specific 
inclusion/exclusion criteria, primary objective evaluation criteria, and/or GCP guidelines. 
Generally, a protocol deviation qualifies as major if: 
• 
The deviation has harmed or posed a significant or substantive risk of harm to the 
research subject 
• 
The deviation compromises the scientific integrity of the data collected for the study 
• 
The deviation is a wilful or knowing breach of human subject protection regulations, 
policies, or procedures on the part of the investigator(s) 
• 
The deviation involves a serious or continuing noncompliance with any applicable 
human subject protection regulations, policies, or procedures 
• 
The deviation is inconsistent with Ipsen’s research, medical, and ethical principles. See 
also Section 11.1.2 for details on the impact of major protocol deviations on the inclusion 
of subjects in each analysis population. 
A minor protocol deviation is any significant divergence from the protocol that does not impact 
the study results. 
As a matter of policy, the sponsor will not grant exceptions to protocol specific entry criteria to 
allow subjects to enter a study. If under extraordinary circumstances such action is considered 
ethically, medically, and scientifically justified for a particular subject, prior approval from the 
sponsor and the responsible IRB/IEC, in accordance with the Standard Operating Procedure 
(SOP), is required before the subject will be allowed to enter the study. If investigative centre 
personnel learn that a subject who did not meet protocol eligibility criteria was entered in a 
study (a protocol violation), they must immediately inform the sponsor. Such subjects will be 
discontinued from the study, except in an exceptional instance following review and written 
approval by the sponsor and the responsible IRB/IEC, according to the applicable SOP. 
13.2 
Information to Study Personnel 
To ensure accurate, complete and reliable data, the sponsor or its representatives will provide 
instructional material to the study sites, as appropriate. A study initiation visit will be conducted 
prior to screening start to instruct the investigators and study coordinators. This session will 


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give instruction on the protocol, the completion of the eCRF and all study procedures. The 
investigator is responsible for giving information about the study to all staff members involved 
in the study or in any element of subject management, both before starting any study procedures 
and during the course of the study (e.g. when new staff become involved). The investigator 
must assure that all study staff members are qualified by education, experience, and training to 
perform their specific responsibilities. These study staff members must be listed on the study 
centre authorisation form, which includes a clear description of each staff member’s 
responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator, and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
13.3 
Study Monitoring 
This study will be monitored at all stages by the clinical research personnel designated by the 
sponsor. Monitoring will include visits and telephone communication to ensure that the 
investigation is conducted according to the Protocol and complies with GCP guidelines and 
applicable regulatory requirements. On-site review of eCRFs will include a review of forms for 
completeness, clarity and consistency with source documents available for each subject. 
Source data as defined by ICH GCP are all original documents, records and data as for example 
hospital records, laboratory notes, subject diaries or imaging data.  
To this end, the investigator agrees to allow regular visits (frequency depending on recruitment) 
by the study monitors and to ensure they have a suitable area in which to work (e.g. a desk) and 
adequate access to study personnel and documents. 
On-site monitoring will include source document verification (SDV). SDV is the procedure 
whereby the data contained in the eCRFs are compared with the primary source data (e.g. 
subject notes, original recordings from automated instruments, X-ray films, ECG tracings, and 
laboratory results) contained in the subject records held at the investigational site and thereby 
verified as accurate. 
The investigator must be aware that:  
• 
SDV is a part of the normal monitoring process. It will be carried out by designated study 
personnel and will be done in such a way as to preserve subject confidentiality, taking 
into account all ethical and legislative requirements. SDV will be carried out by direct 
comparison of entries made in the eCRF with appropriate source data. Direct access to 
source data requires that the subject gives written, documented consent to this. 
• 
Where source data are in the form of a computer print-out (e.g., medical records, ECG 
tracings) they will be made available by the investigator to the monitor. Each will be 
signed and dated by the investigator or a designated person, confirming that the print-out 
is a true and faithful record of the data for that subject. These print-outs will be filed on-
site. 
• 
100% Source data verification is required for this study. A source data location form will 
be agreed with the investigator listing all documents considered to be source data along 
with location and documented in the Initiation Visit Report.  
For all subjects, subject identity (year of birth, sex, initials and subject number), record of entry 
into the study and signature of informed consent must be verified from source documents as a 
minimum.  


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It is important that the subject’s notes record important details about their participation in the 
study. The investigator or designated person will agree, as a minimum requirement, to record 
the following information in the subject’s notes: 
• 
study number, brief description or title of study 
• 
date that the subject gave written consent 
• 
all visit dates 
• 
all SAEs 
• 
all concomitant medications. 
The extent of source data verification and monitor visits frequency will be adapted for 
individual sites in case of lack of quality or a high number of protocol deviations. All 
trial-specific monitoring procedures, monitoring visits, frequency and extent of source data 
verification will be predefined in a trial specific monitoring plan. 
Medical experts and CRAs may request to witness subject evaluations occurring as part of this 
protocol. The investigator and appropriate personnel will be periodically requested to attend 
meetings/workshops 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 Authority or IEC/IRB. If such an audit or inspection occurs, the investigator must agree 
to allow access to the study site, required subject 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 Regulatory Authorities for on-site 
monitoring of all appropriate study documentation, as well as on-site review of the procedures 
employed in the eCRF generation, where clinically appropriate. The investigator will be 
informed about the outcome of the audit. 
Quality control procedures regarding statistical analysis will be documented in the SAP. Quality 
control procedures regarding calibration measures have to be performed according to the 
guidelines of the EANM [63] and will be available for review by the monitor.  
13.4 
Investigator’s Regulatory Obligations 
All clinical work under this protocol will be conducted according to GCP rules. This includes 
that the study may be audited at any time by a quality assurance personnel designated by the 
sponsor, or by regulatory bodies. The investigator must adhere to the GCP principles in addition 
to any applicable local regulations. 
If requested, the investigator will provide the sponsor, applicable regulatory agencies, and 
applicable EC with direct access to any original source documents. 
The investigator(s) should demonstrate due diligence in recruitment and screening of potential 
study subjects. The enrolment rate should be sufficient to complete the study as agreed with the 
sponsor. The sponsor should be notified of any projected delays, which may impact the 
completion of the study. 
13.5 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised Quality Assurance 
personnel may carry out inspections and audits (see Section 12). 
13.6 
Data Quality Assurance 
Monitored eCRFs will be reviewed by the CRO Data Management group for completeness, 
consistency, legibility and protocol compliance. 


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The investigator should provide reasons for any missing data and other protocol deviations on 
the relevant eCRF. Any electronic queries and items not adequately explained will require 
additional electronic manual queries to be raised to the investigator by the CRO monitor and/or 
Data Manager for clarification/correction. The investigator must ensure that queries are dealt 
with promptly. All data changes and clarifications can be viewed in the audit trail function of 
the eCRF. 
14 
ETHICS 
14.1 
Compliance with Good Clinical Practice and Ethical Considerations  
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, the 
Declaration of Helsinki and ICH GCP Guidelines and FDA, 21 CFR Part 11, Electronic 
Records, Electronic Signatures, and FDA, Guidance for Industry: Computerised Systems Used 
in Clinical Trials. 
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided to 
subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the study has started, 
amendments should be made only in exceptional circumstances. Changes that do not affect 
subject safety or data integrity are classified as administrative changes and generally do not 
require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
14.2 
Informed Consent for Participation in the Study 
Prior to study entry, the investigator, or a medically qualified person under the investigator’s 
responsibility, will explain the nature, purpose, benefits and risks of participation in the study 
to each subject, subject’s legally acceptable representative or impartial witness. Written 
informed consent must be obtained prior to the subject entering the study (before initiation of 
any study-related procedure and administration of the IRPP). Sufficient time will be allowed to 
discuss any questions raised by the subject. 
The sponsor will provide a sample informed consent form. The final version controlled form 
adapted as per local requirements must be agreed to by the sponsor, and the IEC/IRB and must 
contain all elements included in the sample form, in language readily understood by the subject. 
Each subject’s original consent form personally signed and dated by the subject or by the 
subject’s legally acceptable representative, and by the person who conducted the informed 
consent discussion, will be retained by the investigator. The investigator will supply subjects 
with a copy of their signed informed consent. 
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject or as a result of protocol 
amendments. In this instance approval should always be given by the IEC/IRB. It is the 
investigator’s responsibility to ensure that all subjects subsequently entered into the study and 
those currently in the study sign the amended form. This is documented in the same way as 
previously described. Subjects who have completed the study should be informed of any new 
information that may impact on their welfare/wellbeing. 


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The investigator should, with the consent of the subject, inform the subject’s primary physician 
about their participation in the clinical study. 
14.2.1 
Optional Informed Consent for 
  
 
 and storage for up to 15 years (where local regulations allow). A 
specific informed consent is required for the collection of these samples and will be explained 
after the subject has given written informed consent for the main study. 
Subjects must receive an explanation that they are completely free to refuse to enter the 
exploratory part of the study and may withdraw from it at any time and for any reason up to 
15 years after the end of the study and will still be allowed to take part in the main study 
14.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
As required by local regulations, the sponsor’s Regulatory Affairs group will ensure all legal 
regulatory aspects are covered, and obtain approval of the appropriate regulatory bodies, prior 
to study initiation in regions where an approval is required. 
The following documents should be submitted to the relevant EC(s) for review and approval to 
conduct the study (this list may not be exhaustive): 
• 
protocol/amendment(s) approved by the sponsor, 
• 
currently applicable IB or package labelling, 
• 
relevant investigator’s curriculum vitae, 
• 
subject information and informed consent document(s) and form(s), 
• 
subject emergency study contact cards, 
• 
recruitment procedures/materials (advertisements), if any. 
The EC(s) will review all submission documents as required, and a written favourable opinion 
for the conduct of the study should be made available to the investigator before initiating the 
study. This document must be dated and clearly identify the version number(s) and date(s) of 
the documents submitted/reviewed and should include a statement from the EC that they 
comply with GCP requirements. 
The study may begin at the investigative site(s) only after receiving this dated and signed 
documentation of the EC approval or favourable opinion. 
During the study, any update to the following documents will be sent to the EC either for 
information, or for review and approval, depending on how substantial the modifications are: 
(1) IB; (2) reports of SAEs; (3) all protocol amendments and revised informed consent(s), if 
any. 
At the end of the study, the EC will be notified about the study completion. 
14.4 
Confidentiality Regarding Study Subjects 
The investigator must record subject identification data for all subjects who provide informed 
consent, regardless of whether they receive any study medication. A subject identification list, 
allocating subject’s clear names to the study identification, must be kept in the Investigator Site 
File (ISF) and must allow for the definite identification of any subject that takes part in the 
study. Study monitors are allowed to review the list, but must not take and keep copies.  
CCI


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The subject’s consent, study participation, the trial visits, relevant medical data, concomitant 
treatment and the occurrence of AEs must be documented in the subject’s medical records. 
The investigator must assure that the privacy of the subjects, including their personal identity 
and all personal medical information, will be maintained at all times. To protect the subject's 
identity, a unique subject identification code will be assigned to each study subject. This unique 
identification number will be assigned automatically by the electronic data capture (EDC) 
system when the subject is first entered and will be used in lieu of the subject's name when the 
investigator reports AEs and/or other trial related data (e.g., eCRFs and other documents or 
image material submitted to the sponsor). Thus, this number will appear on all study-related 
records for a particular subject. Personal information will be treated as confidential, but may be 
reviewed for the purpose of verifying data recorded on the eCRF by the sponsor, coordinating 
investigator, the clinical and medical monitors, the quality assurance unit, the IEC/IRB and 
Regulatory Authorities. The data protection principles of GCP, Directive 95/46/EC and local 
data protection regulations will be observed. 
15 
DATA HANDLING AND RECORD KEEPING 
15.1 
Data Recording of Study Data 
Data obtained will be collected in an eCRF. The eCRF will be completed and monitored in 
accordance with the principles of GCP. 
Source data are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source documents are original documents, data and 
records, such as laboratory printouts, ECG reports, dispensing records, and subject files. 
Imaging data for all subjects will be recorded electronically on digital media. These data and 
print-outs will be considered as source. 
The eCRF includes recordings of all study data from each subject. An eCRF record must be 
completed for every subject who signs an informed consent form and enters the study.  
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 document 
the missing value in the eCRF and, if appropriate, explain, in a comment in the eCRF, why the 
investigation was missed out (e.g. the subject was not well enough to undergo the procedure). 
Details on the statistical analysis of missing data will be described in the SAP. 
15.2 
Data Management 
The designated CRO will be responsible for data processing and quality control. Data 
management will be carried out as described in the CRO’s SOPs. This includes generation and 
resolution of manual electronic data queries. All planned data management procedures will be 
documented in a study specific Data Management Plan prior to start of the trial. All planned 
validation checks will be documented and described in a study specific Data Validation Plan. 
The electronic database is located at the EDC system vendor. Data entry and correction will be 
tracked by a validated electronic audit trail. All systems are validated and compliant to the 
FDA’s ordinance 21 CFR part 11. 
Adverse events, baseline findings, medical/surgical history will be coded using MedDRA 
terminology (v20.0 or later). Medications will be coded using the WHO Drug Dictionary 
(WHO-DD). The processes used for coding will be specified in the Data Management Plan. 
15.3 
Record Archiving and Retention 
Following the end of the study it will be the responsibility of the investigator to guarantee 
adequate storage at the site for all study records, including the hospital notes, according to ICH 


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GCP and regulatory requirements and local regulations. If he/she leaves the employment at 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 archived in such a way that ensures that they are readily available 
upon authorities’ request. 
The ISF must not be destroyed without the sponsor’s approval. The investigator’s contract will 
contain all regulations relevant for the study centre. 
16 
FINANCING AND INSURANCE 
16.1 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and the 
sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
sponsor and investigator responsibilities in relation to the study. Financial remuneration will 
cover the cost per included subject, based on the calculated costs of performing the study 
assessments in accordance with the protocol, and the specified terms of payment will be 
described in the contract. The contract should describe whether costs for pharmacy, laboratory 
and other protocol required services are being paid directly or indirectly. 
Each investigator who is directly involved in the treatment or evaluation of research subjects 
has to provide a financial disclosure according to applicable legal and FDA 21 CRF Part 54 
requirements. All relevant documentation will be filed in the trial master file (TMF) and/or ISF, 
as appropriate. 
16.2 
Insurance, Indemnity and Compensation 
Where required by the laws and regulations of the country in which the study is performed, 
insurance of subjects 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. 
Indemnification 
With respect to any injury caused by the study drug to the subject during this study, the sponsor 
assumes liability by law on behalf of the investigator(s); provided, however, (a) that the 
investigator(s)/delegate have conducted this study in accordance with this protocol and any 
amendments thereto, all instructions delivered by the sponsor, all laws and regulations, accepted 
standards of medical and clinical practice and GCP Guidelines, and scientific practice and 
currently acceptable techniques and know-how; and (b) that the study drug administered to the 
subject in this study has been supplied by the sponsor, and administered/used in accordance 
with this protocol. The indemnity will not cover injuries to the extent caused by the 
investigator(s)’/delegate’s negligence or wilful misconduct, or failure to follow this protocol or 
written instructions (unless deviation to protect safety of the subject) or failure to obtain proper 
informed consent from the subject. The sponsor shall have the sole right to select defence 
counsel, direct the defence, settlement, or other disposition of any claims, and the 
investigator(s)/delegate shall cooperate in the defence of any claim. 
The subjects are covered by insurances held by the sponsor. 
17 
REPORTING AND PUBLICATIONS OF RESULTS 
By signing the study protocol, the investigator agrees to the use of results of the study for the 
purposes of national and international registration. If necessary, the authorities will be notified 
of the investigator’s name, address, qualifications, and extent of involvement. Clinical study 


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reports (CSRs) covering clinical and biometric aspects of the study will be generated at the end 
of the study. 
17.1 
Publication Policy 
The sponsor encourages acknowledgement of all individuals/organisations involved in the 
funding or conduct of the study, including medical writers or statisticians subject to the consent 
of each individual and entity concerned, including acknowledgement of the sponsor. 
The results of this study may be published or communicated to scientific meetings by the 
investigators involved in the study. For multicentre studies, a plan for scientific publication and 
presentation of the results may be agreed and implemented by the study investigators or a 
Steering Committee.  
Selection of authors for scientific publications will follow the International Committee of 
Medical Journal Editors guidelines.[64] In particular, those named as authors, whether 
employed by an Ipsen affiliate or sponsor, or external investigators, ‘should have participated 
sufficiently in the work to take public responsibility for the content’. 
Authorship credit should be based on: 
• 
Substantial contributions to the conception and design, or acquisition of data, or analysis 
and interpretation of data; 
• 
Drafting the article or revising it critically for important intellectual content; 
• 
Final approval of the version to be published; 
• 
Agreement to be accountable for all aspects for the work, thereby ensuring that questions 
related to the accuracy or integrity of any part of the work were appropriately investigated 
and resolved. 
All authors of a manuscript should meet all four criteria. Each author must agree to their 
inclusion in the list of authors. 
Resolution of scientific differences in the presentation or interpretation of study findings will 
be conducted along principles of honest scientific debate. The sponsor shall be promptly 
notified of any amendments subsequently requested by referees or journal editors. 
The sponsor requires that reasonable opportunity be given to review the content and conclusions 
of any abstract, presentation, or paper before the material is submitted for publication or 
communicated. This condition also applies to any amendments that are subsequently requested 
by referees or journal editors. The sponsor will undertake to comment on the draft documents 
within the time period agreed in the contractual arrangements, including clinical trial 
agreements, governing the relationship between the sponsor and authors (or the author’s 
institution). Requested amendments will be incorporated by the author, provided they do not 
alter the scientific value of the material. 
If patentability would be adversely affected by publication, this will be delayed until (i) a patent 
application is filed for the content of the publication in accordance with applicable provisions 
of the clinical trial agreement concerned, (ii) the sponsor consents to the publication, or (iii) the 
time period as may be agreed in the contractual arrangements, including clinical trial 
agreements, governing the relationship between the sponsor and authors (or authors’ institution) 
after receipt of the proposed publication by the sponsor, whichever of (i), (ii) or (iii) occurs 
first. 
The author undertakes to reasonably consider the sponsor's request for delay to the proposed 
publication should the sponsor reasonably deem premature to publish the results obtained at the 
then stage of the study 


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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. 
17.2 
Clinical Study Report  
A final CSR will be prepared according to the ICH guideline on structure and contents of CSRs. 
A final CSR will be prepared where any subject has signed informed consent, regardless of 
whether the study is completed or prematurely terminated. Where appropriate an abbreviated 
report may be prepared. The CSR will comply with any applicable regulatory requirements, 
national laws in force and will be in English. 
A final CSR will be prepared after the last subject completes the 2-year long-term follow-up 
period.  
Analysis of biobank samples will be performed outside the scope of the main study and reported 
separately. 


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18 
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28 
Koenig JA, Edwardson JM, Humphrey PPA. Somatostatin receptors in 
Neuro2A neuroblastoma cells: ligand internalization. Br J Pharmacol 
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29 
Ginj M, Zhang H, Waser B et al. Radiolabeled somatostatin receptor 
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30 
Perrin MH, Vale WW. Corticotropin Releasing Factor Receptors and Their 
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Wild D, Fani M, Behe M et al First Clinical Evidence That Imaging with 
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Cescato R, Erchegyi J, Waser B et al. Design and in vitro characterization of 
highly sst2-selective somatostatin antagonists suitable for radiotargeting. J 
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33 
Han S, Jin G, Wang L et al. The role of PAM4 in the management of pancreatic 
cancer: diagnosis, radioimmunodetection, and radioimmunotherapy. J 
Immunol Res 2014;2014:268479. 


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CONFIDENTIAL 
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Laboratoire National Henri Becquerel. Recommended data 2014. [available at: 
http://www.nucleide.org/DDEP_WG/DDEPdata.htm]. 
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Bodei L, Mueller-Brand J, Baum RP et al. The joint IAEA, EANM, and 
SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) 
in neuroendocrine tumours. European journal of nuclear medicine and 
molecular imaging 2013;40(5):800-16. 
36 
Cescato R, Schulz S, Waser B et al. Internalization of sst2, sst3, and sst5 
receptors: effects of somatostatin agonists and antagonists. J Nucl Med 
2006;47(3):502-11. 
37 
Reubi JC et al. Somatostatin receptor sst1-sst5 expression in normal and 
neoplastic human tissues using receptor autoradiography with subtype-
selective ligands. Eur J Nucl Med. 2001 Jul;28(7):836-46. 
38 
Fani M, Braun F, Waser B et al. Unexpected sensitivity of sst2 antagonists to 
N-terminal radiometal modifications. J Nucl Med 2012;53(9):1481-9. 
39 
Nicolas GP, Mansi R, McDougall L et al. Biodistribution, Pharmacokinetics, 
and Dosimetry of 177Lu-, 90Y-, and 111In-Labeled Somatostatin Receptor 
Antagonist OPS201 in Comparison to the Agonist 177Lu-DOTATATE: The 
Mass Effect. J Nucl Med 2017;58(9):1435-41. 
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Dalm SU, Nonnekens J, Doeswijk GN Comparison of the Therapeutic 
Response to Treatment with a 177Lu-Labeled Somatostatin Receptor Agonist 
and Antagonist in Preclinical Models.J Nucl Med. 2016 Feb;57(2):260-5.  
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Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation 
personal computer software for internal dose assessment in nuclear medicine. 
J Nucl Med 2005;46(6):1023-7. 
42 
Shen S, Meredith RF, Duan J et al. Improved prediction of myelotoxicity using 
a patient-specific imaging dose estimate for non-marrow-targeting (90)Y-
antibody therapy. J Nucl Med 2002;43(9):1245-53. 
43 
Wild D, Fani M, Fischer R et al. Comparison of Somatostatin Receptor Agonist 
and Antagonist for Peptide Receptor Radionuclide Therapy: A Pilot Study. J 
Nucl Medicine 2014;55(8):1248-52. 
44 
Ferrer L, Kraeber-Bodéré F, Bodet-Milin C et al. Three methods assessing red 
marrow dosimetry in lymphoma patients treated with radioimmunotherapy. 
Cancer 2010;116 (4 Suppl):1093-100. 
45 
ICRP 2015, Radiation Dose to Patients from Radiopharmaceuticals: a 
Compendium of Current Information Related to Frequently Used Substances 
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ICRP, 1984. Nonstochastic Effects of Ionizing Radiation. ICRP Publication 41. 
Ann ICRP 14 (3). 
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Kaushansky K. Determinants of platelet number and regulation of 
thrombopoiesis. Hematology Am Soc Hematol Educ Program. 2009:147-52. 
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Bakovic D, Eterovic D, Saratlija-Novakovic Z et al. Effect of human splenic 
contraction on variation in circulating blood cell counts. Clin Exp Pharmacol 
Physiol 2005;32:944-51. 
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Spencer RP, Pearson HA. The spleen as a hematological organ. Semin Nucl 
Med 1975;5:95-102. 


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CONFIDENTIAL 
PROTOCOL: VERSION 10.0 FINAL: 10 AUGUST 2020 
PAGE 125 
 
50 
Bodei L, Cremonesi M, Grana CM et al. Peptide receptor radionuclide therapy 
with 177Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol 
Imaging. 2011;38:2125-35. 
51 
Kwekkeboom 
DJ, 
Bakker 
WH, 
Kooij 
PP 
et 
al. 
[177Lu-
DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in 
patients. Eur J Nucl Med 2001;28:1319-25. 
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Reubi JC, Kvols L, Krenning E et al. Distribution of somatostatin receptors in 
normal and tumor tissue. Metabolism. 1990;39:78-81. 
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Wehrmann C, Senftleben S, Zachert C et al. Results of individual patient 
dosimetry in peptide receptor radionuclide therapy with 177Lu DOTA-TATE 
and 177Lu DOTANOC. Cancer Biother Radiopharm. 2007;22:406-16. 
54 
Sabet A, Ezziddin K, Pape UF et al. Long-Term Hematotoxicity After Peptide 
Receptor Radionuclide Therapy with 177 Lu-Octreotate. J Nucl Med. 
2013;54:1857-61. 
55 
Teunissen JJ, Krenning EP, de Jong FH et al. Effects of therapy with [177Lu-
DOTA0, Tyr3]octreotate on endocrine function. Eur J Nucl Med Mol Imaging. 
2009;36:1758-66. 
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Zatelli MC, degli Uberti EC. Somatostatin receptors: from basic science to 
clinical approach-thyroid. Dig Liver Dis 2004;36:S86-92. 
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Baou N, Bouras M, Droz JP et al. Evidence for a selective loss of somatostatin 
receptor subtype expression in male germ cell tumors of seminoma type. 
Carcinogenesis 2000;21:805-10. 
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Kwekkeboom DJ, Kam BL, van Essen M et al. Somatostatin receptor based 
imaging and therapy of gastroenteropancreatic neuroendocrine tumours. 
Endocr Relat Cancer 2010;17(1):R53-73. 
59 
Nicolas G, Giovacchini G, Muller-Brand J et al. Targeted radiotherapy with 
radiolabelled somatostatin analogues. Endocrinology and metabolism clinics 
of North America 2011;40:187-204, ix-x. 
60 
Caplin ME, Baudin E, Ferolla P et al. Pulmonary neuroendocrine (carcinoid) 
tumors: European Neuroendocrine Tumor Society expert consensus and 
recommendations for best practice for typical and atypical pulmonary 
carcinoids. Ann Oncol 2015:26:1604-20. 
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Filtration 
Rate 
(GFR) 
Calculators. 
[available 
at: 
http://www.niddk.nih.gov/health-information/health-communication-
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Lassmann M, Chiesa C, Flux G et al. EANM Dosimetry Committee guidance 
document: good practice of clinical dosimetry reporting. Eur J Nucl Med Mol 
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EANM Physics Committee, Busemann Sokole E, Plachcinska A et al. Routine 
quality control recommendations for nuclear medicine instrumentation. Eur J 
Nucl Med Mol Imaging 2010;37(3):662-71. 
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preparation/preparing-for-submission.html]. 


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Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45:228-47. 
 

SAP_001.pdf: 
Document Name: dfr01072001 16.1.9 statistical analysis plan v4.1 2021jul09
Approved
Clinical
13-Jul-2021 16:55:16 GMT+0000
Clinical
13-Jul-2021 18:06:54 GMT+0000
Clinical
15-Jul-2021 08:10:13 GMT+0000
Clinical
29-Sep-2021 13:51:58 GMT+0000
PPD
PPD
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IPSEN GROUP 
                                  OPS-C-001 / D-FR-01072-001 
SAP Version 4.1 – Final: 09 July 2021 
1/90 
 
CONFIDENTIAL 
STATISTICAL AND ANALYSIS PLAN 
 
PROTOCOL TITLE: AN INTERNATIONAL MULTI-CENTER, OPEN-LABEL 
STUDY TO EVALUATE SAFETY, TOLERABILITY, BIODISTRIBUTION, 
DOSIMETRY AND PRELIMINARY EFFICACY OF 177LU-OPS201 FOR THE 
THERAPY OF SOMATOSTATIN RECEPTOR POSITIVE NEUROENDOCRINE 
TUMOURS  
(NETs) 
 
PROTOCOL VERSION AND DATE: 
Version 10.0 – 10 August 2020 
 
 
SAP Version 
Date 
Version 1.0 - Final 
29 March 2017 
Version 1.1 – Draft 
28 June 2019 
Version 1.2 Draft 
23 July 2019 
Version 1.3 Draft 
12 August 2019 
Version 2.0 – Final  
21 November 2019 
Version 2.1 Final 
24 March 2020 
Version 3.0 Final 
17 November 2020 
Version 4.0 Final 
17 March 2021 
Version 4.1 Final 
09 July 2021 
 
 


IPSEN GROUP 
                                  OPS-C-001 / D-FR-01072-001 
SAP Version 4.1 – Final: 09 July 2021 
2/90 
 
CONFIDENTIAL 
STUDY NUMBER: 
OPS-C-001 / D-FR-01072-001 
EUDRACT NUMBER 
2015-002867-41 
PROTOCOL TITLE: 
AN INTERNATIONAL MULTI-CENTER, OPEN-
LABEL 
STUDY 
TO 
EVALUATE 
SAFETY, 
TOLERABILITY, 
BIODISTRIBUTION, 
DOSIMETRY AND PRELIMINARY EFFICACY OF 
177LU-OPS201 
FOR 
THE 
THERAPY 
OF 
SOMATOSTATIN 
RECEPTOR 
POSITIVE 
NEUROENDOCRINE TUMOURS  
(NETS) 
SAP VERSION: 
Version 4.1 – Final 
SAP DATE: 
09 July 2021 
 
Further to your review and agreement to the Statistical and Analysis Plan version 
indicated above, please sign to indicate approval for your area of responsibility: 
 
RESPONSIBILITY 
NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Statistician 
IPSEN 
eSignature 
 
Medical Development 
Director 
Ipsen Biopharm Ltd 
eSignature 
 
 
RESPONSIBILITY 
NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Study statistician 
Covance Clinical 
eSignature 
 
Manager statistician 
Covance Clinical 
eSignature 
 
 
IMPORTANT: This completed record (with additional sheets, where required), confirms the 
above-mentioned Statistical and Analysis Plan version became the Final Statistical and 
Analysis Plan 
PPD
PPD
PPD
PPD


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                                  OPS-C-001 / D-FR-01072-001 
SAP Version 4.1 – Final: 09 July 2021 
3/90 
 
CONFIDENTIAL 
 
History of Changes 
Old Version 
Number 
Date Old 
Version 
Date New 
Version 
Reason for Change 
Version  Section 
Was 
Is 
Final 
1.0  
All 
SAP 
 
29 Mar 2017 
21 
November 
2019 
Update according to protocol 
amendment 9 (previous version was 
linked to amendment 4) 
Final 
2.0 
All 
SAP 
21 
November 
2019 
24 March 
2020 
Update to add analyses for efficacy 
and PK 
Final 
3.0 
All 
SAP 
24 March 
2020 
17 
November 
2020 
Main edits to address key changes to 
amendment 10 of the protocol  
Final 
4.0 
All 
SAP 
17 
November 
2020 
17 March 
2021 
Updates following Dry-Run 
comments. 
Final 
4.1 
All 
SAP 
17 March 
2021 
09 July 2021 
RFS update + Table numbering error 
correction. 


IPSEN GROUP 
                                  OPS-C-001 / D-FR-01072-001 
SAP Version 4.1 – Final: 09 July 2021 
4/90 
 
CONFIDENTIAL 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................... 8 
1 
INFORMATION TAKEN FROM THE PROTOCOL ............................................. 12 
1.1 
Study objectives ............................................................................................................. 12 
1.1.1 
Primary objective ......................................................................................... 12 
1.1.2 
Secondary objectives ................................................................................... 12 
1.1.3 
Exploratory objectives ................................................................................. 12 
1.2 
Study design ................................................................................................................... 12 
1.2.1 
General description ..................................................................................... 12 
1.2.1.1 
Part A Design ............................................................................................... 14 
1.2.1.2 
Part B Design ............................................................................................... 15 
1.2.2 
Long-term Follow-up .................................................................................. 16 
1.2.3 
Additional Optional Cycles Part B ............................................................. 17 
1.2.4 
Study population ......................................................................................... 17 
1.2.5 
Study duration ............................................................................................. 18 
1.3 
Methods and procedures .............................................................................................. 18 
1.3.1 
Study treatment ........................................................................................... 18 
1.3.1.1 
Treatment of subjects ................................................................................... 18 
1.3.1.2 
Study drugs administered ............................................................................. 18 
1.3.1.3 
Delay of administration and withdrawal from treatment ............................ 19 
1.3.2 
Efficacy assessments ................................................................................... 21 
1.3.2.1 
Contrast Enhanced CT Imaging/MRI .......................................................... 22 
1.3.2.2 
Evaluation of Tumour Response .................................................................. 22 
1.3.2.3 
Quality of Life Questionnaire - QoL ............................................................ 23 
1.3.3 
Safety assessments ....................................................................................... 23 
1.3.3.1 
Adverse Events ............................................................................................. 23 
1.3.3.2 
Serious Adverse Events ................................................................................ 25 
1.3.3.3 
Clinical Laboratory Tests ............................................................................ 25 
1.3.3.4 
Physical Examination .................................................................................. 27 
1.3.3.5 
Height and Weight ....................................................................................... 27 
1.3.3.6 
Vital Signs .................................................................................................... 27 
1.3.3.7 
Electrocardiography .................................................................................... 27 
1.3.3.8 
Performance Status ...................................................................................... 27 
1.3.3.9 
Subject Demographics ................................................................................. 28 
1.3.3.10 
Medical History ........................................................................................... 28 
1.3.3.11 
Prior and Concomitant Medication ............................................................. 28 
1.3.4 
Pharmacokinetics assessments ................................................................... 28 
1.3.4.1 
Pharmacokinetics of the Radiopharmaceutical ........................................... 28 
1.3.4.2 
Nuclear Medicine Imaging for Dosimetry ................................................... 29 
1.3.4.3 
Pharmacokinetics of the OPS201 ................................................................ 30 


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1.3.4.4 
 ........................................................... 30 
1.3.4.5 
Exploratory biomarkers and biobanking ..................................................... 30 
1.3.5 
Withdrawal/discontinuation ....................................................................... 31 
1.3.6 
Schedule of assessments ............................................................................. 32 
1.3.7 
Planned sample size .................................................................................... 39 
2 
SUBJECT ANALYSIS SETS ...................................................................................... 39 
2.1 
Efficacy .......................................................................................................................... 39 
2.1.1 
Intent-To-Treat Set (ITT) ........................................................................... 39 
2.1.2 
Per Protocol Set (PP) .................................................................................. 39 
2.2 
Safety .............................................................................................................................. 39 
2.3 
Dosimetry ....................................................................................................................... 39 
2.3.1 
Intent-To-Treat Dosimetry Analysis Set (ITT-DAS) ................................. 39 
2.3.2 
Per Protocol Dosimetry Analysis Set (PP-DAS) ........................................ 39 
2.4 
Pharmacokinetics .......................................................................................................... 40 
2.4.1 
Radiopharmaceutical Pharmacokinetic Set ............................................... 40 
2.4.2 
OPS201 Pharmacokinetic Set (Part B only) .............................................. 40 
2.4.2.1 
OPS201 Pharmacokinetic Set in Plasma (Part B only) ............................... 40 
2.4.2.2 
OPS201 Pharmacokinetic Set in Urine (Part B only) ................................. 40 
2.5 
Primary Analysis Set .................................................................................................... 40 
3 
STATISTICAL METHODS ........................................................................................ 40 
3.1 
Statistical analysis strategy .......................................................................................... 40 
3.1.1 
Primary safety endpoint(s) .......................................................................... 40 
3.1.2 
Secondary endpoint(s) ................................................................................. 41 
3.1.2.1 
Biodistribution 
and 
Radioactive 
Pharmacokinetics 
of 
the 
Radiopharmaceutical Endpoints .................................................................. 41 
3.1.3 
Radiation dosimetry endpoint(s) ................................................................. 42 
3.1.4 
 ............................................................................... 42 
3.1.5 
OPS201 Pharmacokinetics (Part B only) ................................................... 42 
3.1.6 
Secondary Efficacy Endpoints .................................................................... 43 
3.1.7 
Exploratory endpoint(s) .............................................................................. 46 
3.1.7.1 
Exploratory Efficacy Endpoints ................................................................... 46 
3.1.7.2 
Exploratory Biomarkers ............................................................................... 47 
3.1.7.3 
Biobanking ................................................................................................... 47 
3.1.7.4 
Modelling ..................................................................................................... 47 
3.1.8 
Multiplicity .................................................................................................. 47 
3.1.9 
Significance testing and estimation ............................................................ 47 
3.2 
Analysis methods ........................................................................................................... 47 
3.2.1 
Safety ........................................................................................................... 47 
3.2.1.1 
Dose Limiting Toxicity ................................................................................. 47 
3.2.1.2 
Adverse events .............................................................................................. 48 
3.2.1.3 
Laboratory data ........................................................................................... 49 
CCI
CCI


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3.2.1.4 
Vital signs, weight and height ...................................................................... 51 
3.2.1.5 
ECG .............................................................................................................. 51 
3.2.1.6 
Physical Examination .................................................................................. 51 
3.2.1.7 
Extent of Exposure ....................................................................................... 51 
3.2.1.8 
Performance status (Karnofsky scoring) ..................................................... 51 
3.2.2 
Radiopharmaceutics and Dosimetry .......................................................... 52 
3.2.3 
Efficacy ........................................................................................................ 55 
3.2.4 
Missing data and outliers ............................................................................ 59 
3.2.4.1 
Missing data ................................................................................................. 59 
3.2.4.2 
Missing or incomplete dates ........................................................................ 59 
3.2.4.3 
Outliers ........................................................................................................ 60 
3.2.5 
Subject disposition ....................................................................................... 60 
3.2.6 
Withdrawals ................................................................................................. 61 
3.2.7 
Demographic and baseline characteristics ................................................ 61 
3.2.8 
Medical and surgical history ...................................................................... 62 
3.2.9 
NET Cancer history .................................................................................... 62 
3.2.10 
Prior surgical procedures and prior Radiotherapies for NET Cancer ..... 62 
3.2.11 
Subject compliance ..................................................................................... 62 
3.2.12 
Prior and concomitant therapies ................................................................ 63 
3.2.12.1 
Prior and concomitant drug therapies ......................................................... 63 
3.2.12.2 
Prior and concomitant non-drug therapies ................................................. 63 
3.2.12.3 
Prior and concomitant Somatostatin Analog treatment for NET ................ 64 
3.2.12.4 
Concomitant Protective Co-Medications for NET ....................................... 64 
3.2.12.5 
Prior and Concomitant Radiopharmaceutical Medications for scanning ... 64 
3.2.12.6 
Prior Chemotherapy for NET Cancer .......................................................... 65 
3.2.12.7 
Concomitant Surgical Procedures ............................................................... 65 
3.2.13 
Derived data ................................................................................................. 65 
3.2.14 
Visit windows ............................................................................................... 65 
3.2.15 
Rules and data formats ............................................................................... 68 
3.2.16 
Pooling of Centres ....................................................................................... 68 
3.2.17 
Interim analysis ........................................................................................... 68 
3.2.18 
Role of the Safety Review Committee (SRC) – Part A ............................... 69 
3.2.19 
Role of the Data Review Board (DRB) – Part B ........................................ 70 
3.2.20 
Covariates and analysis of subgroups ........................................................ 73 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS . 73 
4.1 
Hardware ....................................................................................................................... 73 
4.2 
Software ......................................................................................................................... 73 
4.3 
Validation programs ..................................................................................................... 73 
4.4 
Restitution of the programs ......................................................................................... 74 
5 
CHANGES FROM PROTOCOL ................................................................................ 74 
6 
REFERENCES .............................................................................................................. 74 


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                                  OPS-C-001 / D-FR-01072-001 
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CONFIDENTIAL 
7 
APPENDICES ............................................................................................................... 75 
7.1 
Appendix 1: Derived Data ............................................................................................ 75 
7.2 
Appendix 2: List of TFLs ............................................................................................. 78 
 
LIST OF FIGURES 
Figure 1 
Overview of Study Design for Part A and Part B and Post Study Follow-up
 ............................................................................................................................... 14 
Figure 2 
Study Design- Part A ........................................................................................... 15 
Figure 3 
Study Design- Part B ........................................................................................... 16 
Figure 4 
Part B Cohort Schema with DRB Designations ............................................... 71 
 
LIST OF TABLES 
Table 1 
Radioactivity and Peptide Mass Dose in Each Cohort and Cycle – Part B ... 19 
Table 2 
Study Procedures and Assessments Part A ....................................................... 33 
Table 3 
Study Procedures and Assessments Part B ....................................................... 35 
Table 4 
Time point response ............................................................................................ 43 
Table 5 
Scoring and scale dimension for EORTC QLQ-C30: ...................................... 45 
Table 6 
Scoring and scale dimension EORTC QLQ – GI.NET21: .............................. 46 
Table 7 
Censoring Rules for PFS ..................................................................................... 57 
Table 8 
Event status for various scenarios with missing data ...................................... 58 
Table 9 
Details of each DRB, the Timing, Question and Decision Matrix ................... 72 
 


IPSEN GROUP 
                                  OPS-C-001 / D-FR-01072-001 
SAP Version 4.1 – Final: 09 July 2021 
8/90 
 
CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
Wording Definition 
ADL: 
Activity of Daily Living 
AE: 
Adverse Event/Experience 
Ae 
Amount excreted 
ALT (SGPT): 
Alanine aminotransferase 
AP: 
Alkaline phosphatase 
AST (SGOT): 
Aspartate aminotransferase 
ATC: 
Anatomic Therapeutic Chemical 
AUC: 
Area Under the Curve 
BMI: 
Body Mass Index 
BOR: 
Best Overall Response 
Bq: 
Becquerel 
BSA: 
Body Surface Area 
ceCT: 
contrast enhanced Computer Tomography 
CI: 
Confidence Interval 
ClR 
Renal clearance of the drug from plasma 
CR: 
Complete Response 
CRF: 
Case Report Form 
CRO: 
Contract Research Organisation 
CRP: 
C-Reactive Protein 
CT: 
Computer Tomography 
CT/MRI: 
Computer Tomography/Magnetic Resonance Imaging 
CTC: 
Common Toxicity Criteria  
CTCAE: 
Common Terminology Criteria for Adverse Events 
CV: 
Coefficient of Variation 
DCR: 
Disease Control Rate 
DLT: 
Dose Limiting Toxicity 
DM: 
Data Management 
DNA: 
DeoxyriboNucleic Acid 
e: 
Electronic 
EANM: 
European Association of Nuclear Medicine  
ECG: 
Electrocardiogram 
eCRF:  
Electronic Case Report Form 


IPSEN GROUP 
                                  OPS-C-001 / D-FR-01072-001 
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9/90 
 
CONFIDENTIAL 
ABBREVIATION 
Wording Definition 
eGFR: 
estimated Glomerular Filtration Rate 
EOCT: 
End of Core-Trial 
EOLTFU: 
End of Long-term Follow-up 
EORTC: 
European Organisation for Research and Treatment of 
Cancer 
EW: 
Early Withdrawal 
FAS: 
Full Analysis Set 
FDA: 
Food and Drug Administration 
fe 
Fraction of the intravenously administered drug excreted 
into the urine 
fT4: 
free Thyroxine 
FU: 
Follow-Up 
GBq: 
GigaBecquerel 
GEP NET: 
GastroEnteroPancreatic NeuroEndocrine Tumour 
GGT: 
Gamma-Glutamyl Transferase 
GI.NET: 
GastroIntestinal NeuroEndocrine Tumour 
Gy: 
Gray, SI unit of absorbed radiation dose 
h: 
hour(s) 
HPF: 
High Power Field 
IA: 
Injected radioactivity 
IA / ROI: 
Injected radioactivity/Region Of Interest 
ICH: 
International Conference on Harmonisation  
IGF-1: 
Insulin-like Growth Factor 1 
IRPP: 
Investigational Radiopharmaceutical Product 
IRPPD: 
Investigational Radiopharmaceutical Product Dossier 
ITT: 
Intention-To-Treat  
ITT-DAS: 
Intention-To-Treat Dosimetry Analysis Set 
i.v.: 
Intravenous 
L: 
litre 
LLN: 
Lower Limit of Normality 
MBq: 
MegaBecquerel 
MDRD: 
Modification of Diet in Renal Disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
min: 
minute(s) 


IPSEN GROUP 
                                  OPS-C-001 / D-FR-01072-001 
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10/90 
 
CONFIDENTIAL 
ABBREVIATION 
Wording Definition 
MIRD: 
Medical Internal Radiation Dose 
mL: 
millilitre 
MRI: 
Magnetic Resonance Imaging 
NCI: 
National Cancer Institute 
NCI-CTC: 
National Cancer Institute – Common Toxicity Criteria 
NCI-CTCAE: 
National Cancer Institute – Common Terminology Criteria 
for Adverse Events 
NCRNPD: 
Non-Complete Response/Non-Progressive Disease 
NE: 
Not Evaluable 
NET: 
NeuroEndocrine Tumour 
ORR: 
Overall Response Rate 
PD: 
Progressive Disease 
PET/CT: 
Positron Emission Tomography/Computed Tomography 
PFS: 
Progression Free Survival 
PK: 
Pharmacokinetic 
PP: 
Per Protocol  
PP-DAS: 
Per Protocol Dosimetry Analysis Set 
PR: 
Partial Response 
PRRT: 
Peptide Receptor Radionuclide Therapy 
PV: 
Pharmacovigilance 
QC: 
Quality Control 
QLQ: 
Quality of Life Questionnaire 
QoL: 
Quality of Life 
QRS: 
QRS interval duration 
QT: 
Time interval for ventricular depolarisation and 
repolarisation 
QTc: 
Corrected QT interval 
SAP: 
Statistical Analysis Plan  
SAS: 
Safety Analysis Set 
RECIST: 
Response Evaluation Criteria in Solid Tumours 
ROI: 
Region Of Interest 
SAE: 
Serious Adverse Event 
SAS: 
Safety Analysis Set 
SAS®: 
Statistical Analysis System® 


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ABBREVIATION 
Wording Definition 
SD: 
Stable Disease 
SI: 
Standard International 
SOP: 
Standard Operating Procedure 
SPECT: 
Single Photon Emission Computer Tomography 
SPECT/CT: 
Single Photon Emission Computer Tomography/ Computer 
Tomography 
SRC: 
Safety Review Committee 
SRS: 
Somatostatin Receptor Scan 
Sv: 
Sievert 
TEAE: 
Treatment Emergent Adverse Event 
TFLs: 
Tables, Figures and Listings 
TPR: 
Time Point Response 
TSH: 
Thyroid Stimulating Hormone 
ULN: 
Upper Limit of Normality 
WHO: 
World Health Organization 
WHO- DD: 
World Health Organization – Drug dictionary 
µg: 
Microgram 
68Ga: 
Positron-emitting isotope of Gallium 
177Lu: 
177Lutetium 
177Lu-IPN01072: 
Study medication, 177Lu-labeled somatostatin antagonist for 
Peptide Receptor Radionuclide Therapy 
177Lu-OPS201: 
Study medication, 177Lu-labeled somatostatin antagonist for 
Peptide Receptor Radionuclide Therapy 
 


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1 
INFORMATION TAKEN FROM THE PROTOCOL 
1.1 
Study objectives 
1.1.1 
Primary objective 
The primary objective of this Phase I/II study is to assess the safety and tolerability of Peptide 
Receptor Radionuclide Therapy (PRRT) with 177Lu-OPS201 administered in three cycles in 
subjects with somatostatin receptor (sstr) 2 positive neuroendocrine tumours (NETs) (including 
phaechromocytomas and paragangliomas). 
1.1.2 
Secondary objectives 
This study also aims to achieve the following secondary objectives: 
• 
To evaluate the optimal radioactivity and peptide mass dose to be used in future studies  
• 
To characterise 177Lu-OPS201 whole body biodistribution and pharmacokinetics (PK) of 
the radiopharmaceutical after each administration of 177Lu-OPS201. 
• 
To determine the radiation dosimetry of 177Lu-OPS201 (organ exposure to administered 
radioactivity) after each administration of 177Lu-OPS201 with three different peptide 
mass doses. 
• 
To undertake a preliminary assessment of the therapeutic efficacy of 177Lu-OPS201 
PRRT by determination of Response Evaluation Criteria in Solid Tumours (RECIST) 
version 1.1 status.  
• 
To evaluate the influence of 177Lu-OPS201 PRRT on the subject´s Quality of Life. 
1.1.3 
Exploratory objectives 
• 
To determine the PK of OPS201 in plasma and urine; 
1.2 
Study design 
1.2.1 
General description  
This is an open-label study to evaluate the safety and tolerability of 177Lu-OPS201 for the 
treatment of NETs. This international, multicentre study is planned to be conducted in 
approximately 20 sites with distinguished experience in PRRT or comparable nuclear medicinal 
applications in Europe, USA and Australia. 
The study will be performed in two parts, Part A and Part B. 
 
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                                  OPS-C-001 / D-FR-01072-001 
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A total of up to 55 subjects with histologically confirmed diagnosis of GEP NETs, lung NETs 
or pheochromocytoma or paraganglioma will be recruited in the trial: 
• 
Part A: a minimum of 6 subjects and up to 15 subjects; 
• 
Part B: a minimum of 25 subjects and up to 40 subjects.  
 
Eligible subjects will receive three administrations (or up to 5 cycles in part B) of 177Lu-OPS201 
at 8-week intervals (+2 weeks, or up to +4 weeks in case of AEs which have not adequately 
recovered)  
 
Subject safety and dose escalation (before initiating Part B) will be evaluated by an SRC in Part 
A and a DRB (Part B). 
 
The overall study design is shown in Figure 1, Figure 2 (Part A) and Figure 3 (Part B). 
 
After signing informed consent, subjects will undergo screening (Screening Visit) 
up to 4 weeks before the first administration of 177Lu-OPS201 to check enrolment eligibility 
criteria. A contrast enhanced CT/MRI (baseline for RECIST v1.1 evaluation) will be performed 
and a screening Somatostatin Receptor Scan (SRS) will also be performed (unless already 
performed within 6 months prior to Visit 1 Day 1). Eligibility read for SRS and CT/MRI will 
be performed locally at screening. However, all images, including SRS, will be sent to the 
imaging core laboratory for later evaluation.  
Although the visits are similar in Part A and Part B, there is a change in the amendment version 
6.0 in the CT/MRI imaging which only affects Part B, hence visits for Part A and B are 
described separately. In both Part A and Part B, the end of the core study is defined as the EOCT 
Visit of the last subject. 
 
During the study, subjects will attend the following visits: 
Part A 
Visit 1: On Visit 1 Day 1, subjects will receive the first administration of 177Lu-OPS201 
followed by safety and extended dosimetry evaluations over 8 days, with additional laboratory 
safety tests repeated at Day 15 (±2 days). At 4 weeks (±5 days) after Visit 1 Day 1 (i.e. Follow-
up Visit 1), the safety of the subjects will be assessed. 
Visit 2: 8 weeks after Visit 1 Day 1 (+2 weeks or up to +4 weeks in case of AEs which have not 
adequately recovered) subjects will receive the second administration of 177Lu-OPS201 
followed by safety and dosimetry evaluations over 8 days, with additional laboratory safety 
repeated at Day 15 (±2 days). At 4 weeks (±5 days) after Visit 2 Day 1 (Follow-up Visit 2), the 
safety of the subjects will be assessed. Additionally, subjects will receive a CT/MRI to monitor 
the RECIST v1.1 status and tumour volume changes. 
Visit 3: 8 weeks after Visit 2 Day 1 (+2 weeks or up to+4 weeks in case of AEs which have not 
adequately recovered), subjects will receive the third administration of 177Lu-OPS201 followed 
by safety and dosimetry evaluations over 8 days, with additional laboratory safety tests repeated 
at Day 15 (±2 days). At 4 weeks (±5 days) after Visit 3 Day 1 (Follow-up Visit 3), the safety of 
the subjects will be monitored. 
EOCT Visit: 8 weeks (±5 days) after Visit 3 Day 1, the safety and efficacy of the treatment will 
be evaluated. Subjects enrolled in Part A after the protocol version (v6.0) comes into effect will 
receive a CT/MRI scan to monitor the RECIST v1.1 status and tumour volume.  


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Part B 
Visit 1: On Visit 1 Day 1, subjects will receive the first administration of 177Lu-OPS201 
followed by safety and extended dosimetry evaluations over 8 days, with additional laboratory 
safety tests repeated at Day 15 (±2 days). At Week 4 (Day 29±5 days), Week 6 (Day 42±5 days) 
(i.e. Follow-up Visit 1) and at the intermediate timepoints, the safety of the subjects will be 
assessed.  
Visit 2: 8 weeks after Visit 1 Day 1 (+2 weeks or up to +4 weeks in case of AEs which have not 
adequately recovered) subjects will receive a CT/MRI scan to monitor the RECIST v1.1 status 
and tumour volume. Subjects will then receive the second administration of 177Lu-OPS201 
followed by safety and dosimetry evaluations over 8 days, with additional laboratory safety test 
repeated at Day 15 (±2 days). At Week 4 (Day 29±5 days) Week 6 (Day 42±5 days) (Follow-
up Visit 2) and at intermediate timepoints, the safety of the subjects will be assessed.  
Visit 3: 8 weeks after Visit 2 Day 1 (+2 weeks or up to +4 weeks in case of AEs which have not 
adequately recovered), subjects will receive a CT/MRI scan to monitor the RECIST v1.1 status 
and tumour volume. Subjects will then receive the third administration of 177Lu-OPS201 
followed by safety and dosimetry evaluations over 8 days, with additional laboratory safety test 
repeated at Day 15 (±2 days). At Week 4 (Day 29±5 days) Week 6 (Day 42±5 days)  (Follow-
up Visit 3) and at intermediate timepoints, the safety of the subjects will be monitored. 
EOCT Visit: 8 weeks (±5 days) after Visit 3 Day 1, the safety and efficacy of the treatment will 
be evaluated. Subjects will receive a CT/MRI scan to monitor the RECIST v1.1 status and 
tumour volume.  
Subjects who are to receive additional cycles of therapy will undergo the EOCT assessment 
after Cycle 3. Where possible, the EOCT visit and Visit 4, Day 1 of the first additional cycle 
can be combined. 
 
Figure 1 Overview of Study Design for Part A and Part B and Post Study Follow-up 
 
 
 
EOCT=end of core trial; W=weeks, * Only for Part B. 
 
1.2.1.1 
Part A Design 
In Part A, it is planned to treat up to 15 subjects with three cycles of 4.5 GBq 177Lu-OPS201. 
An SRC will decide, based on the dosimetry and safety data of the initial three and then 


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six subjects, if the remaining nine subjects will continue at the same radioactivity level or if the 
radioactivity has to be adapted. Alternatively, Part A can be closed and Part B initiated. 
Figure 2 shows the study design for Part A. 
Figure 2 Study Design- Part A 
 
 
 
1.2.1.2 
Part B Design  
Part B is a dose escalation both of peptide mass and radioactivity. Up to eight cohorts will be 
enrolled as described below, see Figure 3.  
Part B will encompass radioactivity and peptide mass dose escalation as well as intra-individual 
peptide mass dose evaluation. It consists of up to eight cohorts. In each cohort, each subject 
will receive three cycles of the defined radioactivity and peptide mass dose of 177Lu-OPS201 
(see Table 1). Each cycle will be 8 (+2) weeks apart. In case of AEs which are not adequately 
recovered, a further 4 weeks can be added between dosing.  
After the first three core-treatment cycles, up to two additional cycles of 177Lu-OPS201 can be 
administered if the subject continues to meet the criteria outlined in Section 1.3.1.3 and the 
subject has clinical benefit (defined as CR, PR or SD). The additional cycles are optional and 
must be discussed with the sponsor before administration. 
The population of Cohorts 3 and 6 will enrol eight to 10 subjects to ensure a minimum of eight 
completed subjects. All remaining cohorts (1, 2, 4, 5, 7 and 8) will enrol three to five subjects 
to ensure a minimum of three completed subjects per cohort. A completed subject is defined as 
one who has received at least 3 cycles of study treatment or fewer than 3 cycles if one of the 
following has occurred: exceedance of organ dose limits, treatment-related safety issues or 
disease progression. 


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Figure 3 Study Design- Part B 
 
DRB=Data Review Board; GBq=gigaBecquerel; SRC=safety review committee. 
Each cohort consists of three cycles of treatment. Cohort 2 will not be conducted if 700 μg or 1300 μg peptide mass is shown 
to be optimal. Cohorts 7 and 8 will not be conducted if 1300 µg peptide mass is seen to be too high. Cohorts 3 and 6 require 
10 subjects for eight to be completed. All other cohorts are three to five subjects (minimum of three subjects to be completed). 
1.2.2 
Long-term Follow-up 
The long-term follow-up period will start after the EOCT/end of additional cycles 
(EOAC)/early withdrawal (EW) Visit. 
Tumour assessments will be performed every 3 months (±2 weeks) until whichever occurs first: 
documented disease progression (radiological or clinical as per investigator’s judgement), 2 
years after the EOCT/EOAC/EW Visit, withdrawal of consent, lost to follow-up or death.  
Safety assessments and the subject’s status will be assessed every 3 months (±2 weeks) until 
whichever occurs first: 2 years after the EOCT/EOAC/EW Visit, withdrawal of consent, lost to 
follow-up or death. 
After the long-term follow-up period is completed i.e. 2 years after the EOCT/EOAC/EW Visit, 
all subjects will be invited to participate in a safety surveillance study, as part of a separate 
study protocol. All subjects will be asked to sign a new informed consent form to enter this 
study. The purpose of the safety surveillance study is to monitor any long-term effects of 177Lu-
OPS201 up to 5 years from the first dose of 177Lu-OPS201. 
 
Extra visits, examinations, tests and interventions can be performed at any time if clinically 
indicated, as judged by the investigator. 


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1.2.3 
Additional Optional Cycles Part B 
If a subject tolerates the treatment well and shows clinical benefit (e.g. CR, PR, or SD) up to 
two additional cycles at a radioactivity dose adjusted based on dosimetry results can be 
administered to this subject provided limiting organ absorbed dose levels have not been 
exceeded. Two cycles would consist of 177Lu-OPS201 administration every 8 weeks (+2 weeks, 
or plus up to 4 weeks in case of AEs which are not adequately recovered) with administration 
of the same peptide mass dose as Cycle 1. In this case, subjects will have the same assessments 
as during the core treatment cycles and up to EOAC or early withdrawal except for exploratory 
biomarkers 
. Dosimetry will thus be performed 
after each additional cycle to prevent exceeding limiting organ absorbed doses. For these 
subjects, an EOAC visit will be done 8 weeks (±5 days) after the last 177Lu-OPS201 dose 
administration. In this case, the 2-year long-term follow-up will start at the EOAC (instead of 
EOCT). 
The decision to administer additional cycles or any other antitumoural treatment is at the 
investigator’s and subject’s discretions and must be discussed with and confirmed by the 
sponsor. However, the investigator should follow the following rules before proceeding to any 
additional administration: 
• 
subjects with Dose Limiting Toxicities (DLTs) after first, second or third administration 
will be discontinued from 177Lu-OPS201. 
• 
subject will be eligible for an additional administration of 177Lu-OPS201 only if: 
- 
renal function and blood cell counts are in the range defined in the study inclusion 
criteria (#12 and #13), within the treatment cycle. 
- 
cumulative organ absorbed doses did not exceed 1.5 Gy in BM and 23 Gy in 
kidneys. 
- 
subject is likely to benefit from additional cycles of 177Lu-OPS201 therapy. 
The planned maintenance dose for any cycle may be adjusted such that the limiting organ 
absorbed doses are not exceeded. 
Subjects who are to receive additional cycles of therapy will undergo the EOCT assessment 
after Cycle 3. Where possible, the EOCT visit and Visit 4, Day 1 of the first additional cycle 
can be combined. An additional EOAC assessment will be done 8 weeks after the last dose of 
therapy. 
 
1.2.4 
Study population 
A total of up to 55 subjects with histologically confirmed diagnosis of GEP NETs, lung NETs 
or pheochromocytoma or paraganglioma will be recruited in the trial: 
• Part A: a minimum of 6 subjects and up to 15 subjects;  
• Part B: a minimum of 25 subjects and up to 40 subjects. 
It is intended that potential subjects for this study will be identified from those currently 
attending or being referred to the study centres for the diagnosis and treatment of NETs 
including phaeochromocytomas and paraganglioma. Potentially suitable subjects will be 
approached by the investigating team to ascertain whether they would be interested in 
participating in the study. Interested subjects will be provided with an information sheet and 
undergo consenting procedures prior to any other study procedures. If a subject initially fails 
the Screening process due to a reversible condition, the Screening can potentially be repeated 
once at a later time point (re-enrolment). 
 
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1.2.5 
Study duration 
The estimated core trial duration of Part A is 18 to 21 months (for all subjects) including 6 to 
10 months of treatment for a single subject, while the long-term follow-up lasts for up to 2 years 
after the EOCT/EW Visit. 
The estimated core trial duration of Part B is 14 to 20 months (for all subjects) including 6 to 
10 months of treatment for a single subject, while the long-term follow-up will last for up to 2 
years after the EOCT/EOAC/EW Visit. 
 
1.3 
Methods and procedures 
1.3.1 
Study treatment 
1.3.1.1 
Treatment of subjects 
Subjects will be treated with three cycles and may receive up to 2 additional cycles (Part B 
only) of 177Lu-OPS201 PRRT with an interval of 8 weeks +2 weeks, or up to +4 weeks in case 
of AEs which have not adequately recovered. If any side effects are adequately recovered within 
the 4 weeks, the next treatment cycle can be initiated; if not, no further PRRT treatment will be 
administered and the subject will undergo the EOCT (or EOAC) Visit followed by the Long-
term Follow-up Visits. 
The absorbed organ doses (blood and image based), especially the bone marrow and kidney 
doses as a limiting organs, will be analysed after each treatment cycle so that the radioactivity 
for the following cycles for this particular subject can be reduced in order to not exceed 
cumulative absorbed organ dose limits. 
1.3.1.2 
Study drugs administered 
The study will be performed in two parts.  
Part A (15 subjects) 
Initially, six subjects will be treated. Each subject will receive three cycles of 4.5 GBq (target 
radioactivity 4.5 GBq±10%) 177Lu-OPS201 (target dose 300±50 µg), every 8 weeks (+2 weeks 
or up to +4 weeks in case of AEs which have not adequately recovered). An SRC meeting will 
be held before exposing the remaining nine subjects to the entire number of planned 
administrations.  
Part B (up to 40 subjects) 
The following table provides the specific radioactivity and peptide mass dose for each cohort 
in Part B. 


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Table 1 
Radioactivity and Peptide Mass Dose in Each Cohort and Cycle – Part B 
Cohorts 
Planned dose escalation 
Nominal OPS201 dose 
per cycle (µg) 
OPS201 range per 
cycle (µg)[a] 
Nominal radioactivity 
and range 
(GBq) 
Cumulative 
radioactivity 
(3 cycles, GBq) 
1 
300 
[250 to 350] 
6.0±10% 
18.0 
2[b] 
300 
[250 to 350] 
7.4±10% 
22.2 
3 
300 (Cycle 1) 
700 (Cycle 2) 
300 (Cycle 3) 
300 (Cycle 4 and 5)[c] 
[250 to 350] 
[550 to 850] 
[250 to 350] 
[250 to 350] 
4.5±10% 
13.5 
4 
700 
[550 to 850] 
6.0±10% 
18.0 
5 
700 
[550 to 850] 
7.4±10% 
22.2 
6 
300 (Cycle 1) 
1300 (Cycle 2) 
300 (Cycle 3) 
300 (Cycle 4 and 5)[c] 
[250 to 350] 
[1100 to 1500] 
[250 to 350] 
[250 to 350] 
4.5±10% 
13.5 
7[b] 
1300 
[1100 to 1500] 
6.0±10% 
18.0 
8[b] 
1300 
[1100 to 1500] 
7.4±10% 
22.2 
DOTA=tetraxetan; GBq=gigaBecquerel; IRPP=investigational radiopharmaceutical product; OP201=somatostatin analogue 
peptide JR11 coupled to DOTA. 
a 
IRPP will be provided either through local or centralised manufacturing. OPS201 ranges include the ranges validated for 
local IRPP manufacturing in radiopharmacy of selected centres and the general validated range for centralised IRPP 
manufacturing (i.e. nominal OPS201 dose±15%). 
b 
optional. 
c   For additional cycles, if any 
 
At each PRRT cycle, the study medication will be administered after the conduct of a safety 
examination of the subject. The IRPP (20 mL of 177Lu-OPS201) will be administered once per 
cycle by an i.v. infusion at a rate of 10 mL/h over 120 minutes. Infusion rate modification (up 
or down) would be under the investigator’s judgement and may be temporarily halted or even 
further slowed down if the subject does not tolerate the IRPP infusion. The overall infusion 
duration should not exceed 4 hours.  
Prophylaxis may be considered if the subject is thought to be at increased risk of 
infusion-related reactions as per the site’s standard of care. Appropriate treatment should be 
administered should an infusion-related reaction occur including somatostatin analogues. At 
any time, if infusion-related reactions are encountered, the infusion should be slowed or 
interrupted. 
There are no fasting conditions, nor food restrictions that should apply when administering 
177Lu-OPS201 to the subject.  
 
1.3.1.3 
Delay of administration and withdrawal from treatment 
 
Part A 
If any of the following occur, no further 177Lu-OPS201 treatment will be administered: 
• 
Subject withdraws his/her consent to further treatment 
• 
Cumulative kidney dose exceeds 23 Gy 
• 
Cumulative bone marrow dose exceeds 1.5 Gy as determined by image based dosimetry 
• 
Absolute neutrophil count < 1.000*109 /L (i.e. Grade 3 or higher) 
• 
Platelets < 50.0*109 /L (i.e. Grade 3 or higher) 


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• 
If one of the following medical conditions occurs (based on CTCAE v5.0) and does not 
resolve within 4 weeks (resolved=toxicity Grade 2 or lower and is at the discretion of the 
investigator): 
• 
Estimated glomerular filtration rate (eGFR) of < 45mL/min  
• 
Liver function tests (total bilirubin, aminotransferases) higher than Grade 3 (unless 
there is treatment-related liver toxicity, in which case the study treatment should 
be stopped or interrupted to enable recovery when deterioration of the liver 
function is noted); 
• 
Any other adverse event above Grade 2, except hair loss 
 
The investigator can decide at his/her discretion to discontinue the treatment or to reduce the 
administered radioactivity for further safety reason than those here listed above to prevent a 
patient from higher grade toxicity. 
Before the administration of Cycles 2 and 3 these criteria must be checked. In the event of 
withdrawal (discontinuation) from treatment only the Early Withdrawal (EW) Visit and the 
Long-term Follow-up will be performed (with the EW Visit 8 weeks after the last administration 
of 177Lu-OPS201). 
In some cases, cumulative absorbed dose to the bone marrow or kidney may be difficult to 
evaluate. If there is uncertainty about the radiation dose received to critical organs, but without 
substantial toxicity, the decision to administer additional cycles is left at the investigator’s and 
subject’s discretions. The decision may be either to stop the treatment, administer the full dose 
or a reduced dose depending on the benefit-risk balance for the subject. 
In the situation of persisting Grade 3 and higher bone marrow, toxicity, a bone marrow aspirate 
can be considered if at the discretion of the investigator this could contribute to the evaluation 
of the event. 
 
Part B 
If any of the following occur, no further 177Lu-OPS201 treatment will be administered: 
• 
subject withdraws his/her consent to further treatment; 
• 
cumulative kidney dose exceeds 23 Gy; 
• 
cumulative bone marrow dose exceeds 1.5 Gy, as determined by image-based dosimetry; 
• 
platelets <50.0*109/L (i.e. Grade 3 or higher); 
• 
if one of the following medical conditions occurs (based on CTCAE v5.0 criteria,) and 
does not resolve within 4 weeks (resolved=toxicity Grade 1 or recovered, and is at the 
discretion of the investigator): 
- 
eGFR of <45 mL/min/1.73m2; 
- 
liver function tests (total bilirubin, aminotransferases, alkaline phosphatase and 
gamma glutamyl transferase (GGT) higher than Grade 3 (unless there is treatment-
related liver toxicity, in which case the study treatment should be stopped or 
interrupted to enable recovery when deterioration of the liver function is noted); 
- 
any other related AE above Grade 2, except hair loss, lymphopenia, nonfebrile 
neutropenia lasting <4 weeks. 
 


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The investigator can decide at his/her discretion to discontinue the treatment or to reduce the 
administered radioactivity for further safety reason than those here listed above to prevent a 
subject from higher grade toxicity. 
Before the administration of Cycles 2 and 3 these criteria must be checked. In the event of 
withdrawal (discontinuation) from treatment only the EW Visit and the long-term follow-up 
will be performed (with the EW Visit, 8 weeks after the last administration of 177Lu-OPS201). 
In some cases, absorbed dose to the bone marrow or kidney may be difficult to evaluate. If there 
is uncertainty about the radiation dose received to critical organs, but without substantial 
toxicity, the decision to administer additional cycles is based on continuing to meet 
requirements of the inclusion criteria, the investigator’s judgement and subject’s discretion. The 
decision may be either to stop the treatment, administer the full dose or a reduced dose 
depending on the benefit-risk balance for the subject. 
 
In the situation of persisting Grade 3 and higher bone marrow toxicity, a bone marrow aspirate 
can be considered, at the discretion of the investigator, if this could contribute to the evaluation 
of the event.  
 
1.3.2 
Efficacy assessments 
The following secondary efficacy variables will be assessed: 
• 
Objective tumour response based on RECIST v1.1 (CT/MRI scan) by calculating BOR, 
ORR and DCR  
• 
Progression free survival (PFS) based on RECISIT v1.1 (CT/MRI) 
• 
Influence of 177Lu-OPS201 PRRT on Quality of Life of the Subjects based on change in 
Quality of Life Questionnaire (QLQ)-C30; GI.NET21) from baseline to EOCT. 
 
Evaluation of tumour change in volume from baseline to EOCT/EOAC/EW based on sstr2 
positive lesions  
Efficacy imaging endpoints will be assessed locally by the investigator up to the end of the 2-
year long-term follow-up period and by the central imaging laboratory up to the 
EOCT/EOAC/EW Visit. 
 
 
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1.3.2.1 
Contrast Enhanced CT Imaging/MRI 
Sites will be provided with a study manual including the submission procedures and the imaging 
acquisition guidelines. Tumour response assessments will be performed on-site (locally) and 
off-site (centrally, during the core trial period and additional cycles only). CT/MRI images will 
be used for the tumour response assessments (RECIST v1.1 and other endpoints). An imaging 
charter will be prepared detailing the independent read set-up and the read methodology. The 
imaging charter will also include the methodology for the eligibility read.  
Radiological assessments for tumour response will be performed at the Screening Visit, 
repeated at each cycle of therapy, at the EOCT /EOAC /EW Visit, and every 3 months during 
the 2-year follow-up period or at any time. Additionally, in the event of biological or clinical 
signs of disease progression further radiological assessments can be made based upon 
investigator’s judgment.  
The screening tumour assessments will include pelvis, chest and abdomen, and will be 
performed within 1 month before Visit 1 Day 1. If a historic CT/MRI scan is present that is not 
older than 1 month at Visit 1 Day 1, this scan can be used. However, the site should ensure that 
all required anatomies are covered and perform scanning for missing anatomies. Imaging 
parameters used at screening should remain consistent throughout the study. Follow-up imaging 
should include chest, pelvis and abdomen. The chest should be included if lesions were present 
at screening. 
For chest/abdomen/pelvic scans, the scan should extend from the lateral ends of the clavicles 
(to ensure complete coverage of lung apices) down to the lesser trochanters or caudally thereof 
(to ensure complete coverage of inguinal lymph nodes). For abdomen/pelvic scans, the scan 
should begin cranially at the right dome of the diaphragm and extend down to the lesser 
trochanters or caudally thereof (to ensure complete coverage of inguinal lymph nodes). Details 
for image acquisition and provision for central review will be given in a separate imaging 
charter. 
During the Treatment Period (Core Trial and additional cycles in Part B) and the 2-year long-
term follow-up period, 68Ga-PET scans can be performed, if deemed necessary by the 
investigator. 
1.3.2.2 
Evaluation of Tumour Response 
Tumour response will be evaluated by the site investigator and by an independent central 
review. The central review will be the data used for all imaging efficacy endpoints. Response 
and progression will be evaluated using the revised RECIST guideline (v1.1) and 
 
. Only subjects with measurable disease at baseline, who have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response. 
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, and permit reproducible repeated 
measurements. On occasion, if the largest lesion does not permit reproducible measurement, 
the next largest lesion which can be measured reproducibly will be selected. A sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will 
be calculated and reported as the baseline sum diameters. If lymph nodes are included in the 
sum, then only the short axis will be added into the sum. The baseline sum of diameters will be 
used as reference to further characterise any objective tumour regression in the measurable 
dimension of the disease. 
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All other lesions (or sites of disease) including any measurable lesions over and above the five 
target lesions should be identified as nontarget lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or unequivocal 
progression of each should be noted throughout follow-up. 
Overall objective tumour response will be classified as CR, PR, SD or PD, and unevaluable 
according to RECIST v1.1 at each visit. Based on objective tumour response, BOR, ORR, DoR 
and DCRwill be calculated for both the central and the investigator review. 
Time to PFS according to RECIST v1.1 will also be summarised.  
 
Details of the response evaluation will be given in a separate image review charter.  
 
1.3.2.3 
Quality of Life Questionnaire - QoL 
A Quality of Life Questionnaire, composed of a general questionnaire for oncological subjects 
(QLQ C30; 28 items with a 4-point scale and two items with a scale from one to seven) and a 
NET-specific questionnaire (Gl.NET21; 20 items with a 4-point scale) in paper-form will be 
completed at baseline (Visit 1, predose), during treatment at Visits 2 and 3 (predose), and at the 
EOCT /EOAC /EW Visit. It is important that the investigator does not influence the subject’s 
responses to the questionnaire in any way. 
 
1.3.3 
Safety assessments 
1.3.3.1 
Adverse Events 
Adverse events are defined as any untoward medical occurrence in a subject or clinical trial 
subject administered a medicinal product, 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. 
Adverse events will be monitored from the time that the subject gives informed consent and 
throughout the study, and will be elicited by direct, nonleading questioning or by spontaneous 
reports.  
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By definition, all AEs are regarded as 'treatment emergent', i.e. not seen before treatment or, if 
already present before treatment, worsened after start of treatment. 
Natural progression or deterioration of NETs including symptoms or malignancy under study 
will be recorded as part of the efficacy evaluation and should not be recorded as an AE/SAE. 
Death due to disease progression will be recorded as part of the efficacy evaluation and will not 
be regarded as an SAE. Neuroendocrine tumour status will be monitored through RECIST v1.1 
evaluation and completion of Quality of Life Questionnaires (QLQ C-30 and GINET.21). Signs 
and symptoms should not be reported as AEs/SAEs if they are clearly related to a relapse or an 
expected change or progression of NETs (symptoms/malignancy). These signs and symptoms 
should only be reported as AEs/SAEs (depending on the investigator’s judgment) if they are: 
• 
Judged by the investigator to be unusually severe or accelerated NETs or; 
• 
If the investigator considers the deterioration of NETs signs and symptoms to be caused 
directly by the IRPP or OPS301 if applicable. 
If there is any uncertainty about an AE being due solely to the NETs under study, it should be 
reported as an AE/SAE as appropriate. Preplanned or elective surgeries or therapies should be 
recorded in the subject’s source documents but are not to be considered AEs unless there was 
any change to the subject’s medical condition during the AE collection period. 
All AEs will be assessed and documented in the eCRF by the investigator. Follow-up of the 
AE, after the last visit of the trial, is required if the AE or its sequelae persist. Follow-up is 
required until the event or its sequelae resolve or stabilise at a level acceptable to the 
investigator and the sponsor’s clinical monitor or his/her designated representative. 
Preplanned or elective surgeries or therapies should be recorded in the subject’s source 
documents but are not to be considered AEs unless there was any change to the subject’s 
medical condition during the AE collection period.  
All AEs (including SAEs) are to be accurately recorded on the AE page of the subject’s Case 
Report Form (CRF).  
For both serious and non-serious AEs, documentation must be supported by an entry in the 
patient’s hospital notes. The following information should be captured for all AEs: date of onset 
and resolution, severity of the event, assessment whether the event was serious or non-serious, 
Investigator's opinion of the relationship to investigational drug (OPS201 or OPS301), 
treatment required for the AE, action taken with IRPP or OPS301 if applicable, and information 
regarding resolution/outcome. 
Each event will be graded for severity using the classifications of CTCAE v5.0. For events not 
addressed in the CTCAE v5.0 (as appropriate), classifications the following grading will apply: 
• 
Mild (Grade 1) - Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
• 
Moderate (Grade 2) - Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental Activity of Daily Living (ADL). 
• 
Severe (Grade 3) - Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
• 
Life-threatening (Grade 4) - Life-threatening consequences; urgent intervention 
indicated. 
• 
Death (Grade 5) related to AE. 
 


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The relationship of an AE to IRPP administration will be classified according to the following: 
• 
Related: reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose response relationship, pharmacology, positive dechallenge and/or 
rechallenge) to assume a causal relationship with IRPP administration in the sense that it 
is plausible, conceivable or likely. 
• 
Not related: reports including good reasons and sufficient information (e.g. implausible 
time sequence and/or attributable to concurrent disease or other drugs) to rule out a causal 
relationship with IRPP administration. 
The relationship of the study treatment to an AE will be determined by the investigator and 
subsequently reviewed by the sponsor. 
1.3.3.2 
Serious Adverse Events 
An SAE is classified as any untoward medical occurrence that at any dose: 
• 
Results in death, or; 
• 
Is life threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a more 
severe form, might have caused death, or; 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation, excluding 
admission for social or administrative reasons (see further), or; 
• 
Results in persistent or significant disability / incapacity, where disability is a substantial 
disruption of a person's ability to conduct normal life functions, or; 
• 
Is a congenital anomaly / birth defect in the offspring of a subject who received the 
IRPP or OPS301 if applicable; 
• 
Is an important medical event that may not result in death, be life threatening, or require 
hospitalisation when, based upon appropriate medical judgement, may jeopardise the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-patient hospitalisation, or the development of drug 
dependency or drug abuse.  
 
In addition to the above criteria, any additional AE that the sponsor or an investigator considers 
serious should be immediately reported to the sponsor and included in the safety database. This 
includes any suspected or confirmed coronavirus COVID-19 (SARS-CoV-2) infection 
(seriousness criteria should be “other medically significant” if no other seriousness criteria are 
present (e.g. hospitalisation). 
Planned hospitalisations that occur exclusively for study procedures must not be documented 
as SAEs. 
 
1.3.3.3 
Clinical Laboratory Tests 
 
The certified laboratory of the study site will perform haematology, biochemistry and urinalysis 
laboratory tests. Pituitary markers will be analysed at local laboratory unless this assessment 
cannot be performed locally, it will be analysed in a central laboratory. 
 
 A copy of the 
laboratory certification and tabulation of the reference ranges will be provided. 
 
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1.3.3.3.1 Hematology 
Haematology parameters include haemoglobin, haematocrit, mean corpuscular volume, mean 
corpuscular haemoglobin, white blood cell count (total and differential: leukocytes, neutrophils, 
eosinophils, basophils, lymphocytes, monocytes), red blood cells and platelets.  
Haematology will be measured at the Screening Visit, at Visits 1 to 3 and optional Visits 4 and 
5 (predosing, 24±1 hour (Day 2), 48±1 hour (Day 3), 72 to 96 hours (Day 4 to 5), 144 to 
168 hours (Day 7 to 8) and Day 15±2 days), Follow-up Visits, the EOCT/EOAC/EW Visit and 
the visits in the 2-year long-term follow-up period.  
 
1.3.3.3.2 Blood Biochemistry 
Biochemistry parameters include sodium, potassium, chloride, calcium, glucose, creatinine, 
urea, albumin, total bilirubin, AST, ALT, alkaline phosphatase, GGT, C-reactive protein. 
Creatinine clearance will also be calculated.  
The eGFR value will be calculated by the Modification of Diet in Renal Disease (MDRD) 
formula. 
Biochemistry will be measured at the Screening Visit, at Visits 1 to 3 and optional Visits 4 and 
5 (predosing, 24±1 hour (Day 2), 48±1 hour (Day 3), 72 to 96 hours (Day 4 to 5), 144 to 
168 hours (Day 7 to 8) and Day 15±2 days), Follow-up Visits, the EOCT/EOAC/EW Visit and 
the visits in the 2-year long-term follow-up period.  
 
1.3.3.3.3 Urinalysis 
Urinalysis parameters include specific gravity, pH, protein, glucose, blood, urobilinogen, 
erythrocytes, leukocytes, ketones, bilirubin, nitrite, albumin. 
To be measured at the Screening Visit, predose and Day 15 at Visits 1 to 3 and optional Visits 
4 and 5, Day 7 to 8 at Visit 1, at Follow-up Visits 1 to 3, at the EOCT/EOAC/EW Visit, and at 
the visits in the 2-year long-term follow-up period. 
 
1.3.3.3.4 Pregnancy test 
Prior to each PRRT cycle (Screening Visit, Visits 1 to 3 and optional Visits 4 and 5, predosing) 
each female subject of childbearing potential must undergo a pregnancy test. A serum 
pregnancy test will be performed at the Screening Visit. A serum or urine pregnancy test will 
be performed predose on Day 1 of Visits 1 to 3. 
In the event of pregnancy, the subject is not allowed to receive further PRRT cycles and must 
be withdrawn from the study. The pregnancy must be reported to the sponsor on the SAE form 
until the end of the trial. 
 
1.3.3.3.5 Pituitary Marker (Marker of Pituitary Function)  
Pituitary markers include free thyroxine (fT4), cortisol, insulin-like growth factor (IGF)-1 and 
thyroid stimulating hormone (TSH). These markers results will not be included in the summary 
statistics if subjects are receiving substitute or therapy concerning the respective pituitary axis 
(e.g. no analysis of fT4 and TSH in subjects who receive thyroxine, no analysis of cortisol in 
subjects who received corticosteroids). 
Measured predose at Visit 1, Day 1 at 08:00 (±1 hour) and Visit 1, Day 2 – important to judge 
cortisol value, and at the EOCT/ EOAC/EW Visit.   


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1.3.3.4 
Physical Examination 
A physical examination (including examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, musculoskeletal, 
cardiovascular and nervous systems) will be carried out by a physician at Screening and each 
study visit up to, and including, the EOCT/EOAC/EW Visit and the visits in the 2-year long-
term follow-up period. Any clinically significant abnormalities at Screening will be noted on 
the medical history pages of the eCRF. During the study, if in the opinion of the investigator 
there are any clinically significant changes in the physical examination findings (abnormalities), 
they will be recorded as AEs. 
 
1.3.3.5 
Height and Weight 
Subject height will be measured at the Screening Visit, while weight will be assessed pre-dose 
at Visits 1-3 (and optional Visits 4 and 5) and at the EOCT/EOAC/EW Visit. Body surface area 
(BSA) will be determined with the Mosteller formula [2]. 
Height and weight and associated calculated parameters, will be summarised together with the 
vital signs. 
 
1.3.3.6 
Vital Signs 
Body temperature and supine vital signs (blood pressure and heart rate) will be measured on 
the nondominant arm after 5 minutes of supine rest at the following time points: at the Screening 
Visit, at Visits 1 to 3 and optional Visits 4 and 5 (predose, postinfusion: at stop of infusion (0), 
30±5 minutes, 60±10 minutes, 4 hours ±10 minutes, 24±1 hour (with the exception of Visit 1: 
08:00/Day 2 corresponds approximately 18 to 20 hours), 48±1 hour (Day 3), 72 to 96 hours 
(Day 4 to 5), 144 to 168 hours (Day 7 to 8), Day 15, Follow-up Visits, the EOCT/EOAC/EW 
Visit and the visits in the 2-year long-term follow-up period. 
 
1.3.3.7 
Electrocardiography 
A 12–lead ECG will be performed at the Screening Visit, predose at Visits 1 to 3 and optional 
Visits 4 and 5, at the Follow-up Visits, at the EOCT/EOAC/EW Visit and at the visits in the 2-
year long-term follow-up period. ECGs will be recorded in triplicate and in the supine position 
after at least 5 minutes of rest. 
During the administration of the PRRT study drug, starting with the injection of the antiemetic 
(i.e. 15 to 30 minutes before the start of the amino acid infusion), a 24 hour ECG (Holter) will 
be recorded to monitor cardiac safety during the treatment.  
The site will be required to review ECGs as a safety check at each Day 1 before administration. 
This will be done immediately by a qualified investigator at the study site. ECG and Holter 
assessments will be reviewed centrally during the core trial period and local review at the site 
will be performed during visits in the 2-year long-term follow-up period. Results will be 
provided to the site and retained as source data. 
 
1.3.3.8 
Performance Status 
The performance status of the subjects will be defined by the Karnofsky scoring and assessed 
at the Screening Visit, pre-dose at Visits 1-3, pre-dose at optional Visits 4-5 and at the 
EOCT/EOAC/EW Visit. 
• 
100 - Normal; no complaints; no evidence of disease, 


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• 
90 - Able to carry on normal activity; minor signs or symptoms of disease, 
• 
80 - Normal activity with effort; some signs or symptoms of disease, 
• 
70 - Cares for self; unable to carry on normal activity or to do active work, 
• 
60 - Requires occasional assistance but is able to care for most of his personal needs, 
• 
50 - Requires considerable assistance and frequent medical care, 
• 
40 - Disabled; requires special care and assistance, 
• 
30 - Severely disabled; hospital admission is indicated although death not imminent, 
• 
20 - Very sick; hospital admission necessary; active supportive treatment necessary, 
• 
10 - Moribund; fatal processes progressing rapidly, 
• 
0 – Dead. 
 
1.3.3.9 
Subject Demographics 
At the Screening Visit the following demographic data will be collected: year of birth, sex, 
childbearing potential, and ethnicity. 
 
1.3.3.10 Medical History 
Relevant medical history will be recorded in the eCRF at the Screening Visit and includes 
diagnosis and assessments of any current medical condition, especially details of the NET 
diagnosis and prior cancer therapies (e.g. previous surgery, chemotherapy, radiotherapy, SSA 
use), and concomitant health conditions. In case of SAEs, medical history should also be 
reported in the SAE form. 
 
1.3.3.11 Prior and Concomitant Medication 
Prior medications/therapies will be reported if taken up to 28 days prior to the Screening Visit. 
Concomitant medications/therapies will be reported at every visit throughout the core trial and 
additional optional cycles. Any effort to report prior NET treatment/therapy prior to study entry 
will be reported. The only treatments recorded during the Long-term Follow-up period will be 
further antitumour treatments for NETs. In case of SAEs, concomitant medications should also 
be reported in the SAE form. 
 
1.3.4 
Pharmacokinetics assessments 
1.3.4.1 
Pharmacokinetics of the Radiopharmaceutical 
1.3.4.1.1 Blood Sample Collection 
For each subject, total radioactivity concentration in whole blood will be measured. Each 
subject will have blood samples (2 mL) taken as follows: 
Visit 1: 
• 
Before infusion, at stop of infusion (0), 5 minutes ±1 minute, 30 minutes±3 minutes, 
1 hour±5 minutes, 4 hours±10 minutes, 24±1 hours, 48±1 hours, 72 to 96 hours, and 144 
to 168 hours after the stop of infusion. 
Visits 2 and 3: 
• 
Before infusion, at stop of infusion (0), 1 hour±5 minutes, 4 hours±10 minutes, 
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For subjects receiving additional administrations (up to two additional cycles, Part B only), 
blood samples will be taken at each cycle according to the timepoints described above for 
Visits 2 and 3.  
Blood samples should be collected from the contralateral arm used for the study drug infusion, 
or from another anatomical site. 
The accurate time of sample collection and the accurate time of measurement of the 
radioactivity concentration must be recorded.  
1.3.4.1.2 Urine Sample Collection 
To determine the renal excretion of 177Lu, urine will be collected during the first 48 hours post 
infusion at the following time period: 
Visit 1 only:  
• 
Part A: from the start of the infusion to 6 hours, 6 to 24 hours, 24 to 48 hours 
postinfusion 
• 
Part B: from the start of the infusion to 4 hours, 4 to 24 hours, 24 to 48 hours (from the 
start of the infusion to 4 hours postinfusion only for US and Canada sites) 
The accurate time of urine collection, time of radioactivity measurement and the total urine 
volume must be accurately recorded for each collection interval. 
1.3.4.1.3  Analytical Procedures 
Total radioactivity concentration in whole blood and urine will be determined on site/locally 
using a gamma counter calibrated for 177Lu according to the dosimetry operational manual 
(DOM). The time of the sample collection and the time of measurement of the radioactivity 
concentration must be recorded. 
1.3.4.2 
Nuclear Medicine Imaging for Dosimetry 
1.3.4.2.1 Whole Body Scan 
To determine the biokinetics, whole body scans (planar scintigraphy) will be obtained 
4 hours±10 minutes, 24±1 hour, 48±1 hour, 72 to 96 hours and 144 to 168 hours, after the start 
of the 177Lu-OPS201 administration at Visits 1 to 3. 
For subjects receiving additional administrations (up to two additional cycles, Part B only), 
dosimetry assessments will be performed after each additional administration with nuclear 
medicine imaging described above. 
1.3.4.2.2 SPECT/CT Scan 
Part A 
For absolute quantification, additional three-dimensional (3D) SPECT/CT will be obtained at 
24 hours±1 hour at Visits 1 to 3. It is mandatory for a valid quantification, that the SPECT/CT 
is calibrated. 
Part B 
For absolute quantification, 3D SPECT/CT will be obtained at 4 hours±10 minutes, 24±1 hour, 
48±1 hour, 72 to 96 hours and 144 to 168 hours, after the start of the 177Lu-OPS201 
administration at Visits 1 to 3. 
For subjects receiving additional administrations (up to two additional cycles, Part B only), 
dosimetry assessments will be performed after each additional administration with nuclear 
medicine imaging described above. 
 


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1.3.4.3 
Pharmacokinetics of the OPS201 
1.3.4.3.1 Blood Sample Collection 
Part B only. Blood samples (2 mL) for assessment of OPS201 plasma levels will be collected 
at the following time points (at Visit 1 only): 
At Visit 1 (first infusion): before the infusion (baseline), at the end of the infusion (0), 
5±1 minute, 30±3 minutes, 60±5 minutes and at 4 hours±10 minutes, 6 hours±30 minutes, 
8 hours ±30 minutes ,24±1 hours and 48±1 hours after the administration of 177Lu-OPS201. 
Earlier versions of the protocol may have used other timepoints. 
Blood samples should be collected from the arm opposite to that of the study drug infusion, or 
from another site. 
The accurate time of sample collection must be recorded. Any issues associated with sample 
collection or processing should be reported to the sponsor’s monitor. 
1.3.4.3.2 Urine Sample Collection 
To determine the renal excretion of OPS201, the concentration of OPS201 in urine will be 
determined. 
The samples for urine OPS201 concentration analysis will be taken from urine collected during 
three different periods at Cycle 1 only: from 0(start of the infusion) to 4, 4 to 24 and 24 to 
48 hours after the start of infusion (0 (start of the infusion) to 4 hours only for US and Canada 
sites). 
The accurate time of urine collection and the total urine volume for each collection interval 
must be recorded. Any issues associated with sample collection or processing should be 
reported to the sponsor’s monitor. 
1.3.4.3.3 Analytical Procedures 
Plasma and urine samples will be analysed to determine concentrations of OPS201 using a high-
performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) 
detection, according to a separate protocol established with the dedicated analytical laboratory. 
 
This could include protein binding analysis, metabolite profiling or analysis of 
excipients. Plasma and urine samples remaining from the analysis may be retained by the 
sponsor for additional investigations (i.e. long-term stability, reproducibility).  
 
 
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                                  OPS-C-001 / D-FR-01072-001 
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1.3.5 
Withdrawal/discontinuation 
Since this is a therapeutic study, subjects will be considered to have completed the core-study 
when the final visit of the study treatment period (EOCT Visit) is completed. 
Subjects may decide to withdraw from the study at any time and for any reason without 
prejudice to their further medical care. The Investigator may withdraw a patient from the 
treatment or the study for any of the following reasons: 
• 
Safety Reason/Adverse Event: Clinical or laboratory events occurred that in the medical 
judgment of the Investigator, for the best interest of the subject are reasons for 
discontinuation. This includes serious and non-serious AEs regardless of relation to study 
medication. 
• 
Disease Progression: The Investigator documents disease progression (based on 
RECIST v 1.1 or clinical symptoms) and does not expect any beneficial effect of the 
continuation of the study treatment. 
• 
Protocol Deviation: The subject’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 subject wished to withdraw from further participation in the 
study in the absence of an Investigator-determined medical need to withdraw. If the 
subject gave a reason for withdrawing, it should be recorded in the CRF. 
• 
Lost to Follow-Up: The subject stopped coming for visits, and study personnel were 
unable to contact the subject. 
• 
Other: Any other reasons. 
In the event of pregnancy, the patient is not allowed to receive further PRRT cycles and must 
be withdrawn from the study. 
The Sponsor reserves the right to request the withdrawal of a patient due to protocol deviation 
or other significant reason. 
Although a subject is not obliged to give reason(s) for withdrawing, if a subject is discontinued 
at any time after entering the study, the investigator should make a reasonable effort to ascertain 
the reason(s) while fully respecting the subject’s rights. The investigator will make every effort 
to contact the subject and complete the termination status page on the eCRF and if possible 
conduct an EW Visit that will take place 8 weeks after the last administration study medication. 
In case of discontinuation of treatment/withdrawal from treatment, the EW Visit and the Long-
term Follow-up Visits will be performed as planned. 
The reasons for treatment and/or study discontinuation should be collected. 
Appropriate follow-up of withdrawn subjects will be performed, as required. Attempts to 
contact subjects who withdraw from a study must be documented.  
Withdrawn patients will be replaced if they do not complete treatment (the first three cycles) 
due to any reason other than exceedance of organ dose limits, treatment-related safety issues or 
disease progression. 
 
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1.3.6 
Schedule of assessments 
The schedule of assessments is provided in the study flow chart in Table 2 for Part A and 
Table 3 for Part B. 
Extra visits, examinations, tests and interventions can be performed at any time if clinically 
indicated, as judged by the Investigator. 
 
If the COVID-19 pandemic prevents subjects from coming to the site, subjects can have their 
study visit assessments performed remotely as judged appropriate by the investigator. This must 
be discussed with the sponsor before being implemented. In such a case, the investigator will 
perform a telemedicine visit and will make every effort, where applicable, to contact the 
subject’s general practitioner or specialist physician to ensure all important medical information 
and safety event(s) occurring since the last visit are collected. Guidance on how to collect 
protocol-planned assessments will be provided to the investigator in a separate document. This 
document will be filed in the electronic trial master file. IECs/IRBs will be notified of the 
changes as applicable locally. Of note, as the adapted visit deviates from the regular protocol 
plan, the changes will be recorded as protocol deviations related to COVID-19. 


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Table 2 
Study Procedures and Assessments Part A 
 
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Table 3
Study Procedures and Assessments Part B
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1.3.7 
Planned sample size 
It is anticipated that a total of up to 55 subjects will be recruited. 15 subjects in Part A and 40 
subjects in Part B. This is considered appropriate for an exploratory study and it is not based on 
formal statistical sample size calculation. In the event subjects do not complete treatment due 
to any reasons other than exceedance of organ dose limits or treatment-related safety issues, 
additional subjects will be recruited as replacements to ensure an adequate sample size in the 
“per protocol set” for safety evaluation.  Subjects with non-interpretable dosimetry scans may 
be replaced upon agreement of the investigator and the sponsor. 
For Cohorts 3 and 6 in Part B, to detect a difference between two peptide doses within the same 
cohort, the total sample size of eight is calculated. Assuming 30% standard deviation of the 
paired difference, there is 80% power to detect a 2-fold-change, and 99% power to detect a 3-
fold change at a 2-sided alpha of 0.05. 
 
2 
SUBJECT ANALYSIS SETS 
The following Analysis Sets will be used during statistical analyses  
Screened Subjects Set, i.e. all subjects screened (i.e. who signed the informed consent)   
Eligible Subjects Set, all subjects who comply with the inclusion and exclusion criteria 
(according to the investigator/site) and have entered the study (performed the Screening Visit).  
 
2.1 
Efficacy 
2.1.1 
Intent-To-Treat Set (ITT) 
The Intent-to-Treat Set (ITT) consists of all subjects in the Eligible Subjects Set who received 
study medication. 
 
2.1.2 
Per Protocol Set (PP) 
The Per-Protocol Set (PP) consists of all subjects in the ITT Set who complete the study 
according to the protocol with no major protocol deviation. Any protocol deviation will be 
evaluated by the Sponsor based on the individual case. Major protocol deviations will be 
defined in the Protocol Deviations Document and identified in a data review meeting before 
database lock. 
 
2.2 
Safety 
The Safety Analysis Set (SAS) will consist of all subjects who received study medication. 
 
2.3 
Dosimetry 
2.3.1 
Intent-To-Treat Dosimetry Analysis Set (ITT-DAS) 
The Intent-To-Treat Dosimetry Analysis Set (ITT-DAS) consists of all subjects in the ITT Set 
for whom at least one complete set of dosimetry imaging and dosimetry blood sample 
measurements is available. 
2.3.2 
Per Protocol Dosimetry Analysis Set (PP-DAS) 
The Per Protocol Dosimetry Analysis Set (PP-DAS) will consist of all subjects in the ITT-DAS 
for whom no major protocol violations occurred affecting dosimetry variables. 


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2.4 
Pharmacokinetics 
2.4.1 
Radiopharmaceutical Pharmacokinetic Set 
For Part A and Part B, the Radiopharmaceutical Pharmacokinetic Set will consist of all subjects 
in the ITT Set who receive at least one dose of study medication and have at least one measured 
radioactive concentration in blood.  
2.4.2 
OPS201 Pharmacokinetic Set (Part B only) 
For Part B only, the OPS201 Pharmacokinetic Set will consist of all patients in the ITT Set who 
receive at least one dose of study medication and have no major protocol deviations affecting 
the PK variables and who have a sufficient number of OPS201 levels to estimate the main PK 
parameters (i.e. Cmax, Tmax, and Area Under the Curve (AUC)). 
2.4.2.1 
OPS201 Pharmacokinetic Set in Plasma (Part B only) 
For Part B only, the OPS201 Pharmacokinetic Set will consist of all patients in the ITT Set who 
receive at least one dose of study medication and have no major protocol deviations affecting 
the plasma PK variables and who have a sufficient number of plasma OPS201 levels to estimate 
the main PK parameters (i.e. Cmax, Tmax, and Area Under the Curve (AUC)). 
2.4.2.2 
OPS201 Pharmacokinetic Set in Urine (Part B only) 
For Part B only, the OPS201 Pharmacokinetic Set will consist of all patients in the ITT Set who 
receive at least one dose of study medication and have no major protocol deviations affecting 
the urine PK variables and who have all urine OPS201 levels available to estimate the main 
urine PK parameters (i.e. Ae, fe and ClR). 
 
2.5 
Primary Analysis Set 
The primary analysis based on the assessment of the safety and tolerability of the study drug 
(primary objective) will be performed on the Safety Analysis Set (SAS). 
The efficacy analysis will be performed on the ITT and PP sets. 
Patients will be assigned to each analysis set prior to the statistical analysis. 
 
3 
STATISTICAL METHODS 
3.1 
Statistical analysis strategy 
The statistical analyses will be performed in accordance with ICH E9 guideline [3] and will be 
based on the pooled data from the individual study sites, unless otherwise stated. Statistical 
analyses will be performed by Covance. 
 
3.1.1 
Primary safety endpoint(s) 
Frequencies and/or descriptive summaries of standard safety and tolerability parameters: AEs 
(including SAEs) according to National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) v5.0 and vital signs, laboratory tests (haematology, biochemistry 
and urinalysis, and pituitary markers), 12-lead and Holter electrocardiogram (ECG), DLTs, 
physical examination results and use of concomitant medication throughout the study. 
 


I P S EN G R O U P  
                                  O P S -C -0 0 1 / D -F R -0 1 0 7 2 -0 0 1  
S A P  Versi o n 4. 1 –  Fi n al: 0 9 J ul y 2 0 2 1  
4 1 /9 0  
 
C O N FI D E N TI A L  
3. 1. 2  
Sec o n d ary e n d p oi nt(s)  
3. 1. 2. 1  
Bi o dist ri b uti o n a n d R a di o active P h ar m ac oki netics of t he R a di o p h ar m ace utic al 
E n d p oi nts  
Bi o distri b uti o n 
a n d 
P har mac o ki netics  
(i ncl u di n g 
ra di oacti ve 
deca y) 
of 
t he 
Ra di o p har mace utical  e n d p oi nts are:  
 
(a) 
Ma xi mal u pta ke ( u nit: %) i n lesi o ns.  
T he ma xi mal u pta ke i n lesi o ns will be calc ulate d  f or eac h l esi o n as: 
Ma xi mal u pta ke ( %) = 
 
 (
)
 
 (
) × 1 0 0   
Wit h:  
Ma xi mal acti vit y ( u nit: B q): t he ma xi mal acti vit y i n eac h eli gi ble lesi o n, o n all t he assess me nt 
perf or me d wit hi n eac h c ycl e (at V isits 1 -3 : 4 h o urs, 2 4 h o urs, 4 8 h o urs, 7 2‑9 6 h o urs, a n d 1 4 4 ‑
1 6 8 h o urs p ost i nf usi o n).  
I nje cte d ra dio acti vit y (I A) ( u nit: B q): t he act ual ra di oacti vit y a d mi nistere d/i njecte d.  
 
Ma xi mal u pta ke ( %) i n lesi o ns will be c o m p ute d f or eac h a d m i nistrati o n of 1 7 7L u -O P S 2 0 1 
( visits 1, 2, 3 , 4 a n d 5). U pta ke ( %) at eac h ti me p oi nt will be als o calc ulate d a n d dis pla ye d f or 
t he statistical a nal ysis. 
 
( b) 
Ma xi mal u pta ke ( u nit: %) i n discer ni ble or ga ns.  
T he ma xi mal u pta ke i n discer ni ble or ga ns will b e calc u late d wit h t he sa me f or m ula as f or t he 
lesi o ns.  
Discer ni ble or ga ns will be i de ntifie d d uri n g t he c o urse of t he st u d y.  
Ma xi mal u pta ke ( %) i n discer ni ble or ga ns will be c o m p ute d f or eac h a d mi nistrati o n of 
1 7 7L u -
O P S 2 0 1 ( visits 1, 2 , 3 , 4 a n d 5). U pta k e ( %) at eac h ti me p oi nt will be als o calc ulate d a n d 
dis pla ye d f or t he statistical a nal ysis.  
 
(c) 
Area U n der t he C ur ve ( A U C) of 
1 7 7L u -O P S 2 0 1 i n discer ni ble t h or acic a n d a b d o mi nal 
or ga ns ( u nit: M B q * h), lesi o ns ( u nit: M B q * h) a n d bl o o d ( u nit: M B q/ L * h).  
T he A U Cs of 1 7 7L u -O P S 2 0 1 will be c o m p ute d t hr o u g h s u m of e x p o ne ntial f u ncti o ns fitti n g a n d 
i nte grati o n ( Ref. 1 1 ) as d ecri bed  i n t he D osi metr y Calc ulati o n Pr oce d ure M a n ual. 
A U C of 1 7 7L u -O P S 2 0 1 ra di oacti vit y i n discer ni bl e t h oracic a n d a b d o mi nal or ga ns, lesi o ns a n d 
bl o o d will be c o m p ute d f or eac h a d mi nistrati o n of 1 7 7L u -O P S 2 0 1 . 
Ra di oa cti vit y u pta k e  i n bl o o d i n perce nt a ge of t he I A per liter ( u nit: %/ L) at eac h assess me nt 
ti me p oi nt will be als o dis pla ye d (i.e. at Visit 1: bef ore i nf usi o n , at st o p of i nf usi o n ( 0), 5 
mi n utes  ± 1  mi n ute , 3 0 mi n utes  ± 3  mi n utes , 1 h o ur  ± 5 mi n utes , 4 h o urs ± 1 0 mi n utes,  2 4 ± 1 
h o urs, 4 8 ± 1 h o urs a n d 7 2 -9 6 h o urs  a n d 1 4 4 -1 6 8 h o urs  aft er t h e st o p of i nf usi o n , Visits 2, 3 , 4 
a n d 5: bef ore i nf usi o n , at st o p of i nf usi o n ( 0), 1 h o ur ± 5 mi n utes, 4 h o urs ± 1 0 mi n utes, 2 4 ± 1 
h o ur, 4 8 ± 1 h o ur , 7 2 -9 6 h o urs  a n d 1 4 4-1 6 8 h o urs ). 
 
( d) 
T er mi nal half -life of ra di oacti vit y c o n ce ntr ati o ns i n bl o o d  ( u nit: h). 
T he ter mi nal half -life is defi ne d as t he l o west d eca y rate of t h e A U C fit perf or me d f or bl o o d 
(Ref. 1 1 ). 
 


IPSEN GROUP 
                                  OPS-C-001 / D-FR-01072-001 
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42/90 
 
CONFIDENTIAL 
(e) 
Other biodistribution and radioactive pharmacokinetics of the radiopharmaceutical 
variables 
Cumulatively excreted activity in urine (unit: MBq) in each time period, 0 to 6 hours and 6 to 
24 hours post-infusion (Part A), and 0 to 4 hours, 4 to 24 hours, 24 to 48 hours (Part B). 
 
3.1.3 
Radiation dosimetry endpoint(s) 
Radiation dosimetry endpoints are the following (calculations methods are described in the 
Dosimetry Calculation Procedure Manual): 
(a) 
Absorbed dose in organs/ lesion (unit: Gy). 
 
(b) 
Specific absorbed dose to the lesions (unit: Gy/GBq)  
The specific absorbed dose to the lesions is the absorbed dose by the lesion (unit: Gy) divided 
by the injected radioactivity (unit: GBq) for each lesion selected for dosimetry evaluation. 
Specific absorbed dose to the lesions (unit: Gy/GBq) will be computed for each administration 
of 177Lu-OPS201 (visits 1, 2 and 3) on part A, and on Part B (Cohort 1, 3 and 6), for each lesion 
lesion evaluable in dosimetry (all lesion and by lesion location) when at least 3 patients in the 
same cohort is having a lesion in the same organ, by visit and overall. 
 
(c) 
Specific absorbed dose per organ (unit: Gy/GBq). 
The specific absorbed dose for a given organ is the absorbed dose by this organ (unit: Gy) 
divided by the injected radioactivity (unit: GBq). 
Specific absorbed dose per organ (unit: Gy/GBq) will be computed for each administration of 
177Lu-OPS201 (visits 1, 2 and 3) and any additional cycle. 
 
(d) 
Cumulative absorbed doses in organs and lesions selected for dosimetry evaluation (unit: 
Gy). 
The cumulative absorbed organ dose is calculated as the sum of the absorbed dose over all the 
177Lu-OPS201 administration cycles. In case absorbed dose is missing for at least one of the 
177Lu-OPS201 administration cycles, cumulative absorbed dose is extrapolated from available 
data at the other cycles by dosimetry expert. 
Cumulative absorbed doses will be provided per organ and for lesions selected for dosimetry 
evaluation. 
 
 
3.1.5 
OPS201 Pharmacokinetics (Part B only) 
In subjects in plasma OPS201 PK Set, plasma PK parameters of OPS201 (including, but not 
limited to, maximum observed concentration (Cmax), AUC, elimination half-life (t1/2), apparent 
total body clearance of the drug from plasma (CL), apparent volume of distribution (Vd)) will 
be derived using the non-compartmental approach on the individual plasma concentration-time 
profiles of OPS201. 
CCI


IPSEN GROUP 
                                  OPS-C-001 / D-FR-01072-001 
SAP Version 4.1 – Final: 09 July 2021 
43/90 
 
CONFIDENTIAL 
In subjects in urine OPS201 PK Set, urine PK parameters of OPS201 (including, but not limited 
to, cumulative amount of unchanged drug excreted into the urine (Ae), renal clearance of the 
drug from plasma (CLR)) will be derived using the non-compartmental approach. 
Derivation and analysis of PK data will be documented in a separate Data Analysis Plan. 
 
3.1.6 
Secondary Efficacy Endpoints 
The efficacy endpoints are: 
 
(a) 
Objective tumour response based on RECIST v1.1 (CT/MRI scan)  
- 
Best overall response (BOR) 
The best overall response according to RECIST v1.1 is defined as the best response recorded 
from the initiation of treatment until the EOCT/ EOAC/EW Visit, prior to the assessment of 
PD.  Confirmation of complete or partial response is not required. 
 
The following table provides a summary of the overall response status calculation at each time 
point for subjects who have measurable disease at baseline: 
Table 4 
Time point response 
Target Lesions 
Non-Target Lesions 
New Lesions[a] 
Time Point Response 
(TPR) 
CR 
CR 
No 
CR 
CR 
NCRNPD 
No 
PR 
CR 
NE 
No 
PR[b] 
CR 
NA[c] 
No 
CR 
PR 
NE 
No 
PR[b] 
PR 
CR 
No 
PR 
PR 
NCRNPD 
No 
PR 
PR 
NA[c] 
No 
PR 
SD 
NE 
No 
SD 
SD 
CR 
No 
SD 
SD 
NCRNPD 
No 
SD 
SD 
NA[c] 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
ANY 
Yes/No 
PD 
ANY 
PD 
Yes/No 
PD 
ANY 
ANY 
Yes 
PD 
CR: Complete Response, PR: Partial Response, SD: Stable Disease, PD: Progressive Disease, NE: Not Evaluable, 
NCRNPD: Non-CR/Non-PD, NA: Not Applicable. 
a 
Identification of new lesions at a post-Screening time point will result in a TPR of PD. If an identified 
new lesion subsequently becomes NE, the TPR will be recorded as PD unless the new lesion has proven 
to have resolved. Note: TPRs assessed after a progression event will not contribute to the determination 
of the Best Response. 
b 
If a non-target lesion is classified as NE, a designation of PR may be assigned based on information 
from the target lesions. 
c 
No non-target lesions identified at Screening. 
 
When SD or Non CR/Non Progressive Disease is believed to be the best overall response, it 
needs to be assessed a minimum of 8 weeks [56 days] after start of treatment. Otherwise, the 
best overall response will be NE, unless any Progressive Disease was further documented, in 
which case BOR will be Progressive Disease. 


I P S EN G R O U P  
                                  O P S -C -0 0 1 / D -F R -0 1 0 7 2 -0 0 1  
S A P  Versi o n 4. 1 –  Fi n al: 0 9 J ul y 2 0 2 1  
4 4 /9 0  
 
C O N FI D E N TI A L  
 
- 
O verall Res p o nse Rate ( O R R)  
T he O v erall Res p o ns e R ate ( O R R) is defi ne d as t he pr o p orti o n of p artici p a nts w h o ac hie ve d a 
C o m plete Res p o nse ( C R) or a  Partial Res p o nse ( P R) as best o verall res p o nse acc or di n g t o 
R E CI S T v 1. 1 criteria i n t he I T T Set. S u bjects wit h n o t u m o ur ass ess me nt after t he st art of st u d y 
treat me nt will n ot be e val uate d . 
 
- 
Disease C o ntr ol Rate ( D C R)  
T he D C R is defi ne d as t he pr o p orti o n of partici pa nts w h o ac hie ve d a C o m plete Res p o nse ( C R), 
a Partial Res p o nse ( P R) or a Sta ble Disease ( S D) as best o verall res p o nse acc or di n g t o R E CI S T 
v 1. 1 criteria i n t he I T T Set. S u bjects wit h n o t u m o ur assess me nt after t he start of st u d y treat me nt 
will be  c o nsi dere d as wit h n o disease c o ntr ol . 
- 
S u m of dia meters as perce nta ge c h a n ge  
- 
P erce nta ge c ha n ge fr o m baseli ne i n t he tar get l esi o ns i de ntifie d i n t he 
R E CI S T v 1. 1 assess me nt a n d/ or t h e i nitial lesi o n (s) i de ntifie d at eli gi bilit y 
as bei n g > 2 0  m m i n dia meter , calc ulate d as:  
Perce nta ge  c ha n ge fr o m baseli ne  =  
(
) × 1 0 0   
Wit h  
Di  t he s u m of t he l o n gest dia meters of t he t ar get lesi o ns as per R E CI S T v 1. 1 at t he 
ti me p oi nt/ Visit i. 
D 0  t he s u m of t he l o n gest dia meters of t h e tar get lesi o ns as per R E CI S T v 1.1 at 
baseli ne.  
 
- 
Best p erce nta ge c ha n ge fr o m bas eli ne i n s u m of tar get lesi o ns l o n gest 
dia meters , calc ulate d as:  
Best perce nta ge c h a n ge fr o m baseli ne =  
(
) × 1 0 0   
Wit h : 
D mi n  t he mi ni m u m s u m of t he l o n gest dia met ers as p er R E CI S T v 1. 1 o n all 
meas ure me nt ti me p oi nts.  
D 0  t he s u m of t he l o n gest dia meters of t h e tar get lesi o ns as per R E CI S T v 1. 1 at 
baseli ne.  
C orrelati o ns 
will be c o m p ute d bet wee n d osi metr y para meters ( c u m ulati ve 
a bs or be d d os e) a n d v ol u me a n d di a meter c h a n ges i n lesi o ns at t he last visi t of t he 
c ore trial ( E O C T or E A C T or E W as a p plica ble) .  
 
( b) 
Pr o gressi o n Free S ur vi val ( P F S)  
P F S will be e val uat e d u p t o t w o years  after t he E O C T /E O A C  Visit a n d will be base d o n 
R E CI S T v 1. 1 stat us  assesse d b y i n vesti gat or assess me nt. P F S will be assesse d b y i n de pe n d e nt 
ce ntral r e vie w u p t o E O C T / E O A C /E W Visit ( d uri n g t he c ore st u d y part ). 
 
P F S  is defi ne d as t he ti me fr o m start of st u d y treat me nt u ntil occ urre nce of t u m o ur pr o gressi o n 
or deat h . 
(c) 
Q ualit y of life usi n g E O R T C Q L Q C 3 0 v 3. 0 a n d Q L Q GI. N E T 2 1 ( 2 0 0 6) q u esti o n naires.  
- 
E O R T C Q L Q C 3 0 v 3. 0  


IPSEN GROUP 
                                  OPS-C-001 / D-FR-01072-001 
SAP Version 4.1 – Final: 09 July 2021 
45/90 
 
CONFIDENTIAL 
The European Organisation for Research and Treatment of Cancer (EORTC) score 
questionnaire (QLQ-C30) will be used for quality of life (QoL) evaluation. 
Following the EORTC recommendations, fifteen scales can be derived from the initial 30 
questions: 
• 
A global health status/QoL scale, 
• 
Five functional scales (physical, role, cognitive, emotional and social), 
• 
Nine “symptoms” scales /items (nausea and vomiting, pain, fatigue, 
dyspnoea, insomnia, appetite loss, constipation, diarrhoea and financial 
difficulties).  
Of note, for functional scales, a higher value reflects a better level of function, but for symptoms 
scales /items a higher value reflects worse symptoms; moreover high score for the global health 
status represents a high QoL. 
 
Each scale in the questionnaire will be scored (0 to 100) according to the EORTC 
recommendations in the EORTC QLQ-C30 Scoring Manual. The scoring method is 
summarized below. In this summary, Qi refers to the ith question on the EORTC QLQ-C30. 
Table 5 
Scoring and scale dimension for EORTC QLQ-C30: 
 
Number of items 
(range[a]) 
Item number 
Global health status / QoL 
Global health status/QoL 
2 (6) 
29,30 
Functional scales 
Physical functioning 
5 (3) 
1 to 5 
Role functioning 
2 (3) 
6, 7 
Emotional functioning 
4 (3) 
21 to 24 
Cognitive functioning 
2 (3) 
20, 25 
Social functioning 
2 (3) 
26, 27 
Symptom scales / items 
Fatigue 
3 (3) 
10, 12, 18 
Nausea and vomiting 
2 (3) 
14, 15 
Pain 
2 (3) 
9, 19 
Dyspnoea 
1 (3) 
8 
Insomnia 
1 (3) 
11 
Appetite loss 
1 (3) 
13 
Constipation 
1 (3) 
16 
Diarrhoea 
1 (3) 
17 
Financial difficulties 
1 (3) 
28 
[a] Item range is the difference between the possible maximum and the minimum response to individual items; 
most items take values from 1 to 4, giving range = 3. 
 
For all scales, the RawScore, RS, is the mean of the component items: 
RawScore RS = 
n
I
I
I
n)
...
(
2
1
+
+
+
  
Then for Functional scales: 
 
Score = 
100
)1
(
1





−
−range
RS
 
and for Symptom scales / items and Global health status / QoL: 
Score =
100
)1
(







−
range
RS
 


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                                  OPS-C-001 / D-FR-01072-001 
SAP Version 4.1 – Final: 09 July 2021 
46/90 
 
CONFIDENTIAL 
Missing value (item) consideration for scoring: 
The scale scores will only be calculated if at least half of the items from the scale have been 
answered. Otherwise, no score will be calculated, and the scale score will be set to missing. 
For single-item measures, the score will be missing if the question is not answered. 
 
- 
EORTC QLQ – GI.NET21 (2006) 
The GI.NET21 module is intended for use among subjects with gastrointestinal related (GI.-
related) neuroendocrine tumours, who vary in disease stage and treatments. 
The module comprises 21 questions, consisting of 5 scales and 4 single items, assessing disease 
symptoms, side effects of treatment, body image, disease related worries, social functioning, 
communication and sexuality. The module has been developed according to the EORTC 
guidelines. The GI.NET21 has been translated into several European languages. 
Each question is quoted from 1 (Not at all) to 4 (very much). The scoring algorithm for the 
scales and single items is described below: 
Table 6 
Scoring and scale dimension EORTC QLQ – GI.NET21: 
 
Number of items 
(range[a]) 
Item number 
Scales 
Endocrine symptoms scale 
3 (3) 
31, 32, 33 
G.I. symptoms scale 
5 (3) 
34 to 38 
Treatment related symptom scale 
3 (3) 
39, 40, 46 
Social function scale 
3 (3) 
42, 44, 49 
Disease related worries scale 
3 (3) 
41, 43, 47 
Single items 
Muscle /bone pain symptom 
1 (3) 
48 
Sexual function 
1 (3) 
51 
Information/communication function 
1 (3) 
50 
Body Image 
1 (3) 
45 
[a] Item range is the difference between the possible maximum and the minimum response to individual items; 
most items take values from 1 to 4, giving range = 3. 
 
For all scales, a high score is equivalent to worse or more problems. 
For all scales, the RawScore, RS, is the mean of the component items: 
RawScore RS = 
n
I
I
I
n)
...
(
2
1
+
+
+
 
Then for each of the five scales and for each single item: 
 
Score = 
100
)1
(







−
range
RS
 
Missing value (item) considerations for scoring are the same as for the QLQ-C30 questionnaire 
presented above. 
 
3.1.7 
Exploratory endpoint(s) 
3.1.7.1 
Exploratory Efficacy Endpoints 
CCI


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CONFIDENTIAL 
 
3.1.7.2 
Exploratory Biomarkers 
 
3.1.8 
Multiplicity 
No multiple testing will be performed in this study. 
 
3.1.9 
Significance testing and estimation 
As this is a descriptive safety and tolerability/efficacy study, no formal statistical testing will 
be carried out. If p-values are provided, they will only be provided for exploratory purposes 
only.  
 
3.2 
Analysis methods 
3.2.1 
Safety 
All safety data will be included in the data listings and summary tables will be based on the 
Safety Analysis Set. Summary tables will be presented by study Part, cohort (part B only), 
overall Part B and overall. 
 
3.2.1.1 
Dose Limiting Toxicity 
DLTs (see section 3.2.18) will be listed by study Part, cohort (part B only), radioactivity level 
adapted or not (part B only) and subject. Listings of AEs and abnormal laboratory values 
defined as DLTs will be also provided sorted by study Part, cohort (part B only), radioactivity 
level adapted or not (part B only) and subject. 
 
CCI
CCI


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                                  OPS-C-001 / D-FR-01072-001 
SAP Version 4.1 – Final: 09 July 2021 
48/90 
 
CONFIDENTIAL 
A summary of DLTs will be provided, presenting the number of subjects with DLTs, the 
number of DLTs and the number of DTLs per type of DLTs (presented by decreasing 
frequency), by study Part, cohort (part B only), radioactivity level adapted or not (part B only) 
and overall. 
 
3.2.1.2 
Adverse events 
All AEs will be recorded and graded by investigators using the NCI CTCAE classification v5.0 
and will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 
21.1 or higher and will be classified by MedDRA preferred term and system organ class.  
 
Listings will be presented and sorted by study part, cohort (part B only), radioactivity level 
adapted or not (part B only), subject number, start time of AEs, primary system organ class, 
preferred term and verbatim text for all adverse events recorded during the study.  
 
Listings of all adverse events, serious adverse events (SAE), adverse events leading to 
withdrawal, adverse events leading to dose reduction, adverse events leading to dose 
interruption, adverse events leading to dose delayed, adverse events with CTCAE Grade 3,4 
and 5 and listings of deaths will also be presented. 
 
Treatment Emergent Adverse Events (TEAE) will be flagged (*) in the adverse events listing 
and will be summarised. 
 
A TEAE is defined as any adverse event that occurs up to 6 months (180 days) post last dose 
if: 
(1) 
it was not present prior to receiving the first dose of IRPP (or OPS301 if applicable), 
taking into account the time of administration and the time of AE, or  
(2) 
it was present prior to receiving the first dose of IRPP (or OPS301 if applicable) but the 
intensity/grade increased during the active phase of the study, taking into account the 
time of administration and the time of AE, or 
(3) 
it was present prior to receiving the first dose of IRPP (or OPS301 if applicable), the 
intensity/grade is the same but the causality changed to “related” during the active phase 
of the study, taking into account the time of administration and the time of AE. 
 
Phase of the study will be defined into 3 time periods:  
- 
period 1: treatment intake up to 56 days/8 weeks (corresponding to 8 half-lives of 
the 177Lutetium rounded to the upper number of weeks, 162 hours * 8 + 2 days) 
after last dose 
- 
period 2: 57 days up to 6 months post last dose 
- 
period 3: after 6 months of last dose until 2-year follow-up period /death or lost to 
follow-up 
 
An overall summary table (by period 1, 2 and 1+2) of all treatment emergent adverse events 
will be presented by study part, cohort (part B only) and overall using the Safety Analysis Set. 
This table will be also repeated for period 3. 
 


IPSEN GROUP 
                                  OPS-C-001 / D-FR-01072-001 
SAP Version 4.1 – Final: 09 July 2021 
49/90 
 
CONFIDENTIAL 
All AEs and SAEs occurring during the Screening period and more than 6 months after the last 
dose of study medication will be listed and flagged as occurring before or after (during period 
3) the active phase of the study; however, these will not be defined as TEAEs. 
 
TEAEs will be summarised by study part, cohort (part B only) and overall with the number and 
percentage of subjects with adverse events classified by primary system organ class and 
preferred term. The number of occurrences of a TEAE will also be presented. The summary of 
AEs will also be repeated by time period. A listing of AEs by time period will also be presented.  
 
In addition, summary tables will also be presented for SAEs, TEAEs related to 177Lu-OPS201, 
TEAEs related to OPS301, treatment emergent 177Lu-OPS201 related SAEs, OPS301 related 
SAEs, TEAEs leading to premature discontinuation of study medication, TEAEs leading to 
dose delays, TEAEs leading to dose reduction, TEAEs leading to dose interruption, TEAEs per 
decreasing frequency, TEAEs by associated NCI CTC worst grade and by causality. There will 
also be a separate summary for Adverse Events of Special Interest (AESI) which will be defined 
as any TEAE related to 177Lu-OPS201 which occurs the day of 177Lu-OPS201 administration 
(same date as 177Lu-OPS201 administration and at any cycle).  
 
Summary tables of adverse events will be provided with the number and percentage of subjects 
with adverse events classified by primary system organ class, preferred term (ordered 
alphabetically) and associated CTCAE version 5.0 worst grade. In the event of multiple 
occurrences of the same adverse events being reported by the same subject, the maximum 
intensity (Grade 5 > Grade 4 > Grade 3 > Grade 2 > Grade 1 > missing > not applicable) and 
the most serious causality (related> not related) will be chosen.  
 
3.2.1.3 
Laboratory data 
A separate listing of normal ranges for SI and local laboratories units will be provided by study 
site laboratory, gender and age where relevant. 
 
Laboratory data (including hematology, biochemistry, pituitary markers and urinalysis) will be 
listed in SI and local laboratories units and abnormal values will be flagged (High, [H], Low 
[L], clinically significant [C], CTCAE version 5.0 grade (G)) where applicable. Any 
unscheduled laboratory assessments will be flagged [U] in the listings. In addition, a listing of 
clinically significant abnormal values will be presented. 
As multiple local laboratories are used within the study, a data normalisation method (refer to 
Appendix 1: Derived Data, and Ref. 5, 6, 7) will be used before summarising the data. The 
normalized lab data values will be also included in the lab data listings together with the 
reference normal range limits used for the normalisation.  
 
(a) 
Hematology, Biochemistry and Pituitary Markers 
For hematology, biochemistry and pituitary marker parameters, the baseline will be defined as 
the last measurement collected prior to the first dose of study drug. 
For hematology, biochemistry and pituitary marker parameters, summary statistics, by study 
part, cohort (part B only) and overall, will be presented at each scheduled assessment for 
normalised actual values and changes from baseline. For pituitary markers, all values will be 
displayed in a listing, however the summary tables may exclude any results if it was drawn 
while the subject was receiving medication that may have been deemed to impact the result. 


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The determination of the medications impacting the result will be based upon medical monitor 
review and reflected in a footnote. 
 
Shift tables from Baseline to worst post-baseline and also, each post baseline visit. In the shift 
tables, the number and percentages of subjects with low, normal, or high values will be 
presented by study part, cohort (part B only) and overall. 
 
For hematology and biochemistry, summary statistics by study part, cohort (part B only) and 
overall, will be also provided for nadir and day to nadir by cycle (time from cycle baseline to 
nadir during the same cycle) and on lab toxicities after start of study medication with worst 
CTCAE version 5.0 Grades 3 and 4 (refer to Appendix 1, Derived data). 
Shift tables from Baseline to worst CTCAE version 5.0 Grade of hemoglobin, absolute 
neutrophil count, and platelet count, will be presented by study part, cohort (part B only) and 
overall. 
 
Hematological and biochemistry toxicities will be recorded and graded according to the 
CTCAE criteria, Version 5.0. The CTCAE grade (0 to 4) of hematology and biochemistry by 
cycle and by subject will be listed in the Section 16.2.8. Listings of the laboratory parameters 
in section 14.3.4 will include a listing of all CTCAE Grade 3 and 4 hematological toxicities, a 
listing of CTCAE Grade 3 and 4 hematological toxicities lasting 4 weeks or more, a listing of 
CTCAE Grade 2 hematological toxicities lasting 4 weeks or more, a listing of all CTCAE Grade 
3 and 4 biochemical toxicities, a listing of CTCAE Grade 3 and 4 biochemical toxicities lasting 
4 weeks or more, a listing of CTCAE Grade 2 biochemical toxicities lasting 4 weeks or more, 
a listing of all eGFR of < 45mL/min, a listing of eGFR of < 45mL/min lasting 4 weeks or more, 
a listing of out of range biochemistry parameters that could not be graded using CTCAE grade 
(below LLN – normal – above ULN) and a listing of biochemistry parameters that could not be 
graded using CTCAE grade (below LLN – normal – above ULN) lasting 4 weeks or more.   
 
In addition, figures of absolute leucocyte count, absolute neutrophil count, absolute lymphocyte 
count, platelet count, hemoglobin, AST, ALT, AP, total bilirubin, creatinine, eGFR individual 
normalised values over time will be displayed. 
 
(b) 
Urinalysis 
For categorical urinalysis data (absent/trace/positive and normal/abnormal) frequency tables, 
by study part, cohort (part B only) and overall, will be presented at each scheduled assessment 
as well as the change from baseline with the following categories: improved, stable, worsened 
and abnormal worsening. 
Shift tables from Baseline to each post baseline visit for the number and percentage of subjects 
with normal, abnormal clinical evaluation will be presented by study part, cohort (part B only) 
and overall. 
 
For continuous urinalysis data (specific gravity, PH), summary statistics, by study part, cohort 
(part B only) and overall, will be presented at each scheduled assessment for actual values and 
changes from baseline.  
 


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3.2.1.4 
Vital signs, weight and height 
Vital signs (supine blood pressure, supine heart rate, body temperature, body weight, BMI and 
BSA) will be listed at each assessment by study part, cohort (part B only), radioactivity level 
adapted or not (part B only) and subject. Any unscheduled vital signs assessment will be flagged 
[U] in the listing.   
 
Baseline values will be defined as the last vital signs measurement collected prior to the first 
dose of study drug.  
 
Summary statistics (n, mean, standard deviation, median, minimum and maximum) for supine 
blood pressure, supine heart rate, body weight, BMI and BSA by study part, cohort (part B 
only) and overall, will be presented at each scheduled assessment for actual values and changes 
from baseline. 
 
3.2.1.5 
ECG 
Descriptive summaries of the following ECG and Holter parameters will be calculated: heart 
rate, RR interval, PR interval, QRS interval, QT interval, QTcB, and QTcF. The number and 
percentage of subjects with normal, abnormal (not clinically significant), abnormal (clinically 
significant) findings will be presented for patients in the Safety Analysis Set. 
 
3.2.1.6 
Physical Examination 
Physical examination results (Normal / Abnormal) will be listed at each assessment by study 
part, cohort (part B only), radioactivity level adapted or not (part B only) and subject. Any 
unscheduled physical examination will be flagged [U] in the listings. 
 
3.2.1.7 
Extent of Exposure 
The extent of study treatment exposure will be summarized by cohort, part and overall within 
the safety population.  
The overall study treatment exposure will be summarized by: 
• 
the number of cycles, 
• 
actual cumulative dose defined as the sum of all doses of 177luOPS201 from the first 
dose to the last one. If one administered radioactivity dose is missing, the cumulative 
dose will not be calculated and will be set to missing. 
• 
actual cumulative dose by cycle defined as the sum of all doses taken until the cycle 
presented. If one administered radioactivity dose is missing, the cumulative dose will not 
be calculated and will be set to missing 
• 
duration of exposure (defined in section 7.1) 
• 
overall study duration (defined in section 7.1) 
• 
number of patients with OPS301 at any cycles 
 
3.2.1.8 
Performance status (Karnofsky scoring) 
The performance status of the subjects as defined by the Karnofsky scoring: 
• 
100 - Normal; no complaints; no evidence of disease. 
• 
90 - Able to carry on normal activity; minor signs or symptoms of disease. 


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• 
80 - Normal activity with effort; some signs or symptoms of disease. 
• 
70 - Cares for self; unable to carry on normal activity or to do active work. 
• 
60 - Requires occasional assistance, but is able to care for most of his personal needs. 
• 
50 - Requires considerable assistance and frequent medical care. 
• 
40 - Disabled; requires special care and assistance. 
• 
30 - Severely disabled; hospital admission is indicated although death not imminent. 
• 
20 - Very sick; hospital admission necessary; active supportive treatment necessary. 
• 
10 - Moribund; fatal processes progressing rapidly. 
• 
0 – Dead 
Karnofsky performance status score will be analysed as quantitative variable and qualitative 
variable.  
For Karnofsky performance status score as quantitative variable, descriptive statistics and 95% 
Confidence Interval (CI) of the mean will be presented for the raw data and for the changes 
from baseline during treatment, by study part, cohort (part B only) and overall at each visit 
(Visit 1, 2, 3 and EOCT Visit). 
For Karnofsky performance status score as qualitative variable (class), the number and 
percentage of subjects per score level and per level of change from baseline, summarized as 
Worsening, No change and Improvement, will be provided by study part, cohort (part B only) 
and overall at each visit (Visit 1, 2, 3 and EOCT Visit). The shift from baseline at each visit 
will be also provided. 
 
3.2.2 
Radiopharmaceutics and Dosimetry 
All data will be included in the individual data listings and summary tables will be based on the 
PP-DAS, Radiopharmaceutical Pharmacokinetic Set or ITT-DAS Set depending of the 
parameter. Summary tables will be presented by study part, cohort (part B only), overall part B 
and overall. 
 
(a) 
Biodistribution and Radioactive Pharmacokinetics 
- 
Maximal uptake (unit: %) in lesions. 
Maximal uptake (unit: %) in lesions will be listed by study part, cohort (part B only), 
radioactivity level adapted or not (part B only), subject, cycle and lesion number. Descriptive 
statistics, including geometric mean and geometric Coefficient of Variation (CV), will be 
presented by study part, cohort (part B only) and cycle on the PP-DAS. 
 
Uptake (unit: %) in lesions at each assessment time point will be also displayed, it will be listed 
by study part, cohort (part B only), radioactivity level adapted or not (part B only), subject, 
cycle, lesion number and time point.  
 
- 
Maximal uptake (unit: %) in discernible organs. 
Maximal uptake (unit: %) in discernible organs will be listed by study part, cohort (part B only), 
radioactivity level adapted or not (part B only), subject, cycle and organ. Descriptive statistics, 
including geometric mean and geometric Coefficient of Variation (CV), will be presented by 
study part, cohort (part B only) and cycle on the PP-DAS. 
 


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Uptake (unit: %) in discernible organs at each assessment time point will be also displayed, it 
will be listed by study part, cohort (part B only), radioactivity level adapted or not (part B only), 
subject, cycle, organ and time point, along with dosimetry parameters. Descriptive statistics, 
including geometric mean and geometric Coefficient of Variation (CV), will be presented by 
study part, cohort (part B only), cycle and time point on the PP-DAS. A linear plot of the mean 
of the uptake (%) in discernible organs over time will be displayed by study part, cohort (part 
B only), radioactivity level adapted or not (part B only) and cycle on PP-DAS. 
 
- 
Areas Under the Curve (AUCs) of 177Lu-OPS201 in discernible thoracic and 
abdominal organs (unit: MBq*h), lesions (unit: MBq*h) and blood (unit: 
MBq/L*h). 
 
AUCs of 177Lu-OPS201 in discernible thoracic and abdominal organs (unit: h*MBq) will be 
listed by study part, cohort (part B only), radioactivity level adapted or not (part B only) , 
subject, cycle and organ. Descriptive statistics, including geometric mean and geometric 
Coefficient of Variation (CV), will be presented by study part, cohort (part B only), cycle, organ 
on the PP-DAS. 
 
AUCs of 177Lu-OPS201 in lesions (unit: h*MBq) will be listed by study part, cohort (part B 
only), radioactivity level adapted or not (part B only) , subject, cycle and lesion number. 
 
AUCs of 177Lu-OPS201 in blood (unit: MBq/L*h) will be listed by study part, cohort (part B 
only), radioactivity level adapted or not (part B only), subject and cycle. Descriptive statistics, 
including geometric mean and geometric Coefficient of Variation (CV), will be presented by 
study part, cohort (part B only) and cycle on the Radiopharmaceutical Pharmacokinetic Set. 
 
- 
Uptake in blood (unit: %/L)  
At each assessment time point will also displayed, it will be listed by study part, cohort (part B 
only), radioactivity level adapted or not (part B only), subject, cycle and time point. Descriptive 
statistics, including geometric mean and geometric Coefficient of Variation (CV), will be 
presented by study part, cohort (part B only), cycle and time point on the Radiopharmaceutical 
Pharmacokinetic Set. Graphs of the mean of the uptake in blood (unit: %/L) over time will be 
displayed by study part, cohort (part B only), radioactivity level adapted or not (part B only) 
and cycle on the Radiopharmaceutical Pharmacokinetic Set. 
 
- 
Terminal half-life of radioactivity concentrations of the radiopharmaceutical in 
blood (unit: h). 
Terminal half-life of radioactivity concentrations in blood (unit: h) will be listed by study part, 
cohort (part B only), radioactivity level adapted or not (part B only), subject and cycle. 
Descriptive statistics, including geometric mean and geometric Coefficient of Variation (CV), 
will be presented by study part, cohort (part B only), radioactivity level adapted or not (part B 
only) and cycle on the Radiopharmaceutical Pharmacokinetic Set. 
- 
Cumulatively excreted radioactivity in urine (unit: MBq) in each time period, 0 - 
6 hours, 6 - 24 hours and 24 - 48 hours and overall on the 0-48 hours period (if 
there is no missing collection period). 
Cumulatively excreted radioactivity in urine (unit: MBq) will be listed by study part, cohort 
(part B only), radioactivity level adapted or not (part B only), subject, cycle and time period. 


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Descriptive statistics, including geometric mean and geometric Coefficient of Variation (CV), 
will be presented by study part, cohort (part B only), cycle and time period on the ITT Set. 
 
(b) 
Radiation Dosimetry 
- 
Organs receiving the highest absorbed dose (unit: Gy). 
All organs with their absorbed dose will be listed by study part, cohort (part B only), 
radioactivity level adapted or not (part B only), cycle, organ and subject on the ITT- DAS, and 
highest dose will be flagged. 
 
- 
Specific absorbed dose to the lesions selected for the dosimetry evaluation (unit: 
Gy/GBq). 
Specific absorbed dose to the lesions selected for the dosimetry evaluation will be listed by 
study part, cohort (part B only), radioactivity level adapted or not (part B only), subject, cycle 
and lesion number. Descriptive statistics, including geometric mean and geometric Coefficient 
of Variation (CV), will be presented by study part, cohort (part B only), cycle and lesion 
location on the ITT- DAS and PP-DAS. Descriptive statistics will also be presented on 
combined lesions on the PP-DAS population. 
 
- 
Specific absorbed dose per organ (unit: Gy/GBq). 
Specific absorbed dose per organ will be listed by study part, cohort (part B only), radioactivity 
level adapted or not (part B only), subject, cycle and organ. Descriptive statistics, including 
geometric mean and geometric Coefficient of Variation (CV), will be presented by study part, 
cohort (part B only), cycle and organ on the ITT- DAS and PP-DAS. 
 
- 
Ratio of Specific absorbed dose per organ and lesion. 
Ratio of specific absorbed dose at visits (e.g. visit 2 relative to visit 1, visit 3 relative to visit 1, 
visit 2 relative to visit 3, etc..) will be calculated per organ and per lesion and by study part (Part 
A and B), and by each cohort (applies to part B only), radioactivity level adapted or not (applies 
to part B only), subject, cycle and organ. Descriptive statistics, including geometric mean and 
geometric Coefficient of Variation (CV), will be presented by study part, cohort (part B only), 
cycle and organ on the PP-DAS. 
Boxplots representing the ratio of specific absorbed doses between visits by organ and lesion 
will be produced. 
 
- 
Tumour average/kidney ratio 
Ratio of tumour/average kidney ratio between visits by organ or combined lesions will be 
calculated per lesion and by study part (Part A and B), and by each cohort (applies to part B 
only), radioactivity level adapted or not (applies to part B only), subject and cycle. 
Descriptive statistics, including geometric mean and geometric Coefficient of Variation (CV), 
will be presented by study part, cohort (part B only), cycle and organ on the PP-DAS. 
 
- 
Cumulative absorbed organ doses (unit: Gy) 
Cumulative absorbed organ doses will be listed by study part, cohort (part B only), radioactivity 
level adapted or not (part B only), organ and subject. 


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Descriptive statistics, including geometric mean and geometric Coefficient of Variation (CV), 
will be presented by study part, cohort (part B only) and organ on the ITT- DAS and PP-DAS. 
 
 
(d) 
OPS201 Pharmacokinetics (Part B only) 
Analysis of PK data by non-compartmental approach will be documented in a separate analysis 
plan. A listing of PK sampling time deviation from the scheduled time will be provided on 
OPS201 PK population. A listing of individual OPS201 concentrations per time point will be 
provided on OPS201 PK population. 
 
3.2.3 
Efficacy 
All efficacy data will be included in the data listings and summary tables based on the ITT and 
PP sets. Summary tables will be presented by study part, cohort (part B only), overall part B 
and overall. 
Tumour response will be evaluated by an independent central review and by the site 
investigator.. Response and progression will be evaluated using the revised RECIST guideline 
v1.1 and a modified RECIST (will be analysed for both Part A and B. The efficacy endpoint in 
the protocol only focus on Part B patients) guideline. Only subjects with measurable disease at 
baseline, who have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response. 
Investigator assessment using RECISIT (V1.1) will be the primary assessment whereas central 
RECIST (V1.1) and mRECISIT (part B only) will be sensitivity analysis. 
 
a) 
Overall Response, Best Overall Response and Overall Response Rate 
Overall response at each visit will be tabulated and listed, as well as Best Overall response 
according to RECIST/
. Subjects with concurrent use of somatostatin 
analogues will be flagged in the listing. 
 
For analysis of the ORR, summary tables will be generated, presenting the number and 
proportion of responders by study part, cohort (part B only) and overall on the ITT and PP sets, 
together with two-sided 95% Clopper-Pearson CIs. Subjects with no tumour assessment after 
the start of study treatment will be excluded from the analysis.  
The same analysis might be repeated in the subsets of subjects with and without concurrent use 
of somatostatin analogues, if deemed relevant by the Sponsor. 
The following SAS® code will be used for tables that need exact 95% Clopper-Pearson CIs: 
PROC FREQ DATA=dset NOPRINT; 
  
BY by var; (optional) 
   
TABLES var1 /binomial (exact); 
  
OUTPUT OUT=outname; 
RUN; 
 
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b) 
Disease control rate (DCR) 
The number and proportion of subjects with disease control at end of either EOCT/EOAC (if 
independent central read) or end of long-term follow-up (if investigator) will be presented per 
study part, cohort (part B only) and overall on the ITT and PP sets, together with two-sided 
95% Clopper-Pearson CIs. Subjects with no tumour assessment after the start of study treatment 
will be excluded from the analysis. The DCR will be based on the best overall response over 
all timepoints for independent central review and investigator assessment. 
For investigator data, the DCR rate at selected timepoints (Month 12, 18, 24) will also be 
generated. For DCR at month 12 (resp. 18 and 24 month), the analysis will include all patients 
who are on study at month 12 (resp. 18 and 24 month) defined as 365 days – 28 days (resp. 545 
- 28  and 730- 28) relative to the first dose or patients who had early PD or death prior to that 
time.  The best overall response category of CR, PR or SD in patients who have not had an early 
PD or death up to the timepoint will represent the subjects with disease control  
 
c) 
Sum of Diameters 
Descriptive statistics and 95% CIs of the mean for percentage change from baseline will be 
calculated by study part, cohort (part B only) and overall at Follow-up Visit 2, EOCT, EOAC 
(if any) and Long-Term Follow-up visits on the ITT and PP sets. The length of the longest 
diameter will also be presented. 
Percent change and best percent change in sum of diameters will be listed.  
Percent change of sum of diameters according to RECIST
 will also be plotted by 
study part and cohort (part B only) at Visit 2, EOCT Visit, EOAC Visit (if any) and Long-Term 
follow up visits 1 and 2 on the ITT set. 
Waterfall plots presenting best overall response (RECIST
) versus best percent 
change from baseline of sum of target lesion diameters over the whole study will be performed 
on the ITT set. 
 
d) 
Progression Free Survival (PFS) from independent central review and from 
investigator assessment  
PFS, defined as the time from first study drug administration to progression or death which ever 
occur first, will be analysed. 
 
Disease progression will be assessed by tumour response evaluation according to RECIST 
v1.1/
, measured using the same imaging technique (ceCT scan or MRI) 
for each subject throughout the study.  
 
Event dates are assigned to:  
• 
The first time when progressive disease was noted, or  
• 
Date of death.  
 
In case of progressive disease followed by death, the first event will be considered in the 
analysis.  The date of progression will be recorded as the date of the last radiographic evaluation 
included in the series for that assessment. 
Censoring dates are defined in subjects with no progressive disease or death before end of study 
or withdrawal. In these subjects, the censoring date is defined as the last date on which overall 
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RECIST status was evaluable. This is taken to be the date of the last radiological assessment at 
which the target lesions were evaluated (see Table 7).  
 
Table 7 
Censoring Rules for PFS 
Reason for censoring 
Rule 
No screening evaluable[a] assessment 
Date of first treatment administration 
Two or more not evaluable (NE) consecutive assessments 
before progressive disease or death 
Date of last evaluable disease assessment before the second 
NE assessment 
No progressive disease 
Date of last evaluable disease assessment 
Treatment discontinuation for undocumented progression 
Date of last evaluable disease assessment 
Treatment discontinuation for toxicity or other reason 
Date of last evaluable disease assessment 
Initiation of medications or therapy not permitted 
during the study 
Date of initiation of non-permitted medication or 
therapy 
a 
An assessment is considered NE when no imaging/measurement is done at all at a particular time point, 
or only a subset of lesion measurements are made at the time point. The subject is considered NE at 
that time point. 
 
For central reading assesments, patients will be censored at the timepoint of the last central 
assessment at or before EOCT/EOAC. 
The PFS time will be calculated as the time from first administration of the study drug to either 
progressive disease or death as follows.   
 
PFS time (in months) = [(Date of event – date of first administration of study drug + 1] / 30.4375 
 
Data will be analysed by study part, cohort (part B only) and overall part B on the ITT and PP 
sets. The distribution of PFS times will be estimated using the Kaplan Meier method for each 
study part, cohort (part B only) and overall Part B. The median PFS time will be presented with 
its associated 95% CI, together with the number and percentage of events, by study part, cohort 
(part B only) and overall. The results will also be presented graphically in Kaplan Meier plots. 
 
Completely missing tumour data: when tumour assessment visits are completely missing, FDA 
Guidance “Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics” [4] states 
that "events occurring after two or more missed radiological assessments will be censored in 
the analysis at the last adequate assessment”. 
 
This will be implemented as follows: 
Progressive Diseases (PDs) occurring after two or more missed radiological assessments will 
be censored in the analysis at the last adequate* assessment before the missing assessments:   If 
a subject has one missed radiological assessment before a PD, the PD will be analysed as an 
event (i.e. a PD is analysed as an event if the previous radiological assessment was performed 
within approximately the last 6 months). 
 


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Table 8 
Event status for various scenarios with missing data 
Scan Time 
FU Visit 2  
EOCT/EOAC 
/ EW Visit 
Long-term 
Follow-up 
Visits n 
Long-term 
Follow-up 
Visits n +1  
Event status 
Scenario 1  
missing 
PD 
Event at 
EOCT/EOAC/EW visit  
Scenario 2 
missing 
missing 
PD 
Censored at Baseline 
Scenario 3 
missing 
SD 
PD 
Event at Long-term 
Follow-up Visit n 
Scenario 4 
missing 
missing 
SD 
PD 
Event at Long-term 
Follow-up Visit n+1 
Scenario 5 
SD 
SD 
missing 
PD 
Event at Long-term 
Follow-up Visit n+1 
Scenario 6 
SD 
missing 
missing 
PD 
Censored at FU Visit 2 
 
e) 
Dosing and dosimetry in conjunction with tumour burden 
A figure depicting the following relationship displaying the Pearson’s correlation coefficient 
(and the associated 95% confidence interval): 
• 
• 
 
f) 
Quality of life 
- 
EORTC QLQ C30 v3.0 
For QLQ C30 global health status score, functional scales scores and symptom scales scores, 
descriptive statistics and 95% CIs of the mean will be presented for the raw data and for the 
changes from baseline during treatment, by study part, cohort (part B only) and overall at each 
visit (Visit 1, 2, 3, optional visits (if any) and EOCT/EOAC Visits) on the ITT and PP sets. 
 
For the evaluation of the QLQ C30 scores values at baseline the EORTC QLQ C30 Reference 
Values manual (Ref. 12) or a more up to date reference will be used. 
 
- 
EORTC QLQ – GI.NET21 (2006) 
For GI.NET21 endocrine symptoms scale score, G.I. symptoms scale score, treatment related 
symptom scale score, social function scale score, disease related worries scale score, muscle 
/bone pain symptom item, sexual function item, information/communication function item and 
body Image item, descriptive statistics and 95% CIs of the mean will be presented for the raw 
data and for the changes from baseline during treatment, by study part, cohort (part B only) and 
overall at each visit (Visit 1, 2, 3 and EOCT Visit) on the ITT and PP sets. 
g) 
Duration of Response (DoR) 
DoR refers to the time when complete response (CR) or partial response (PR) is first observed 
until the time of progressed disease (PD) or death for the subjects whose best overall response 
is complete response (CR) or partial response (PR). If the subject did not have an event of PD 
or death, then DoR will be the time of last tumor assessment. 
DoR will be listed. 
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Summaries of DoR will include summary statistics of duration, the number and the associated 
percentage of patients whose DOR is >3, >6, >9 and >12 months for Part A and Part B and 
overall (Part A and B). In case of sufficient responders, the median of DOR (calculated based 
on Kaplan-Meier) and 95% confidence interval of median time will also be summarized. 
 
h) 
Tumour Volume (mL) 
Tumour Volume (mL) is measured for each lesion at each scheduled visit by independent 
central review using RECIST (v1.1) and 
. The sum of the tumour volume (mL) per 
visit will be computed and descriptive statistics of tumour volume, change in tumour volume 
and percentage change in tumour volume will be generated at each scheduled visit on the ITT 
and PP sets. 
 
3.2.4 
Missing data and outliers 
3.2.4.1 
Missing data 
a) 
Efficacy endpoints  
When tumour assessment visits are completely missing, rules from FDA Guidance “Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics” [4] will be implemented as 
described in section 3.2.3.  
Any missing QoL data (EORTC QLQ C30 and QLQ GI.NET21 questionnaires) will be handled 
as described in section 3.2.3. 
b) 
Safety endpoints  
If a value required a retest (for laboratory values, vital signs), the closest non-missing value to 
the scheduled visit will be used in the summary tables.  
If there is a significant number of missing values for a subject (or if there is confirmed data 
appearing spurious), a decision will be made following consultation with the sponsor regarding 
the handling of these data in summaries. This decision will be made during the Data Review 
Meeting and documented. 
Any repeat or additional assessments performed will be included in the individual subject data 
listings. 
For adverse events with missing information for the intensity and causality, the value will not 
be replaced and will be summarized as a separate category. 
c) 
Blood/plasma/serum data 
Any embedded BLQ value (i.e. single BLQ value occurring between 2 quantifiable 
concentrations) and BLQ values following the last quantifiable concentration in a profile will 
be set to missing for the purposes of PK analysis. 
In a single-dose setting, the BLQ data must be substituted by 0 for concentrations measured 
before the first quantifiable concentration. 
In multiple-dose setting, all BLQ must be set as missing in the dataset.  
BLQ values substituted by 0 are included in the PK/NCA calculation whereas missing values 
are ignored. 
In any case, when all concentrations from a concentration-time profile are BLQ, they must be 
substituted by 0 and included in the PK analysis dataset. 
3.2.4.2 
Missing or incomplete dates 
In all listings, missing or incomplete dates should be left as they have been recorded. However, 
for calculation / sorting / assignation based on dates, the following methods will be used: 
CCI


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                                  OPS-C-001 / D-FR-01072-001 
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For partially missing dates for efficacy endpoints derived using tumour assessments, the 
following imputation rules will be used: if the day of the month is missing, but month and year 
are known (UN-MMM-YYYY), it will be imputed by the 1st of the month (01-MMM-YYYY). 
If this implementation rule produces a date before the first study drug administration, then the 
date of start of study treatment will be used. 
The most conservative approach will be systematically considered (i.e. if the onset date of an 
AE/concomitant medication is missing / incomplete, it is assumed to have occurred during the 
study treatment part (i.e. a TEAE for AEs) except if the partial onset date or other data [stop 
date, …] indicates differently). 
 
A missing/incomplete date of medical history or disease diagnosis will be assumed to have 
occurred before any study treatment. 
 
If a partial date and the associated information do not allow to state about the assignation to a 
group / category, all the possible groups / categories will be considered (i.e.: an AE could be 
assigned to several possible doses at event onset according to its partial onset date and stop 
date. Particularly an AE with missing start date will be assigned to each dose received before 
its end date. Similarly, a medication with partial start and stop dates could be considered as 
prior and concomitant treatment). 
 
Where this is possible, the derivations based on a partial date will be presented as superior 
inequalities (i.e.: for an AE started in FEB2004 after the administration performed on 
31JAN2004, the days since last dose will be “≥2”, similarly the duration of ongoing AEs or 
medication will be“≥xx” according to the start and last visit dates). 
 
3.2.4.3 
Outliers 
Any outlier identified prior to database lock which is impossible/implausible will be excluded 
from the analysis. If any outliers are identified after database lock the statistical analysis should 
be performed with the actual values and at least one other analysis eliminating or reducing the 
outlier effect. 
The decision of how to handle these outliers will be made during the Data Review Meeting and 
documented. 
 
3.2.5 
Subject disposition 
A listing of dates of assessments (relative day), including EOCT, EOAC (part B only) and End 
of Long-term Follow-up (EOLTFU) dates and their study exposure will be presented by subject 
for each study part, cohort (part B only) and radioactivity level adapted or not (part B only). 
Subject disposition information will be presented using the eligible subject set. 
 
A summary table will be presented for each subject population presenting the number of 
subjects in each study part and cohort (part B only) at each assessment and identifying the 
number of subjects who withdrew over time. The reasons for exclusions from each of the 
populations will be listed and tabulated. 
 


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                                  OPS-C-001 / D-FR-01072-001 
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CONFIDENTIAL 
A listing of any deviations due to COVID-19 will be generated separately and a table 
summarizing Deviations due to COVID-19 will be produced. 
The number of patients exposed to COVID-19 as well as impacted or infected (see definition 
below) will also be presented. 
 
The number of visits impacted due to COVID-19 with the reasons will be summarized to assess 
the impact of COVID-19 
 
A summary table will present the number of subjects who received study treatment, extent of 
subject exposure in the study and the study drug exposure for each study part and cohort (part 
B only).  
 
The definition of the extent of subject exposure is the time interval between the first inform 
consent signed to the EOCT, EOAC (Part B) or EW visit completed (c.f. in Appendix 1: Derived 
Data).  The definition of Study drug exposure (days) is the time interval between last drug intake 
- date of first drug intake +1 (c.f. in Appendix 1: Derived Data). 
 
3.2.6 
Withdrawals 
Discontinued subjects will be listed and a summary table of the number and percentage of 
subjects who withdrew from the Treatment Period/LTFU and the reasons for withdrawal will 
be presented by study part, cohort (part B only) and overall. 
In addition, the reasons of discontinuation related to COVID-19 will be summarized. 
3.2.7 
Demographic and baseline characteristics 
All demographic and baseline characteristics will be listed by study part, cohort (part B only), 
radioactivity level adapted or not (part B only) and subject. 
Summary statistics will be provided for demographic and baseline characteristics (age, sex, 
ethnicity, race, height, weight, BMI, Karnofsky performance status at screening, physical 
examination at baseline) by study part, cohort (part B only) and overall, for the Safety Analysis 
Sets. 
Start date, defined at 
study / country / site 
End date 
(if applicable) 
Completed or withdrawn 
before start of pandemic 
Non-exposed 
Ongoing at start of pandemic / 
or included during pandemic 
Exposed 
Post-pandemic phase 
Included after the end of 
pandemic 
Non-exposed 
During pandemic phase 
Pre-pandemic 
Impacted 
Infected (including 
suspected) 
or 
Other impact (e.g. due to 
site closure) 
-
Visit / assessment 
d
Non impacted 
Not-Infected  
and 
No impact on visits, 
assessments, treatment 
and end of study 


I P S EN G R O U P  
                                  O P S -C -0 0 1 / D -F R -0 1 0 7 2 -0 0 1  
S A P  Versi o n 4. 1 –  Fi n al: 0 9 J ul y 2 0 2 1  
6 2 /9 0  
 
C O N FI D E N TI A L  
 
N o statistical c o m paris o n of t he treat me nt gr o u ps will be perf or me d . 
 
3. 2. 8  
Me dic al a n d s ur gic al hist ory  
Rele va nt Me dical or S ur gic al Hist or y will be c o d e d usi n g Me d D R A Versi o n 2 1 .1  or hi g h er.  
Listi n gs will pres e nt t he  preferre d ter m a n d v er bati m te xt. T he listi n gs will be s orte d b y st u d y 
part , c o h ort ( part B o nl y) , ra di oacti vit y le vel a da pte d or n ot ( part B o nl y), s u bject, pri mar y 
s yste m or ga n class, preferre d ter m a n d ver bati m te xt.  
A fre q u e nc y ta bl e of t he n u m ber a n d p erce nta ge of s u bjects will be pr o vi de d f or all me dical 
a n d s ur gical hist or y b y pri mar y s yste m or ga n cl ass a n d preferre d ter m b y st u d y part , c o h ort 
( part B o nl y) a n d o verall o n t he Safet y A nal ysis Set.  
 
3. 2. 9  
N E T C a ncer  hist or y 
S u m mar y  statistics will be pr o vi de d b y st u d y part , c o h ort ( part B o nl y) a n d o verall, f or t he 
Safet y A nal ysis Sets  f or i nitial dia g n osis ( G E P N E T, L u n g N E T, P he oc hr o m oc yt o ma a n d 
Para ga n gli o ma), Ki -6 7 i n de x ( %), Mit otic I n de x (/ 1 0 H P F) (i n 3 cat e g ories: < 2 mit oses, 2 -2 0 
mit oses, 
> 2 0 
mit oses), t u m o ur gra di n g ( gra de 1, 2 or 3), t y p e of 
N E T  (N o n -
f u n cti o ni n g/f u n cti o ni n g), hist o pat h ol o gic t y pe, site of pri mar y t u m o ur, W H O gra d e,  ti me si nce 
i nitial dia g n ostic (refer t o A p pe n di x 1: Deri ve d Data ), ti me si nce i nitial dia g n ostic b y cat e g or y 
( ≥3 years vers us > 3 years), ti me si nce hist ol o gicall y c o nfir me d N E T dia g n osis (refer t o 
A p pe n di x 1: Deri ve d Data ), ti me si nce last rela pse (refer t o A p pe n di x 1: Deri ve d Dat a ), ti me 
si nce sca n of p ositi ve s o mat ostati n rece pt or d o c u me ntati o n (refer t o A p pe n di x 1: Deri ve d Data ), 
s o mat ostati n rece pt or i ma gi n g 
met h o d ol o g y, ra di o p har mace utical use d f or s o mat ostati n 
rece pt or i ma gi n g, pre vi o us s ur ger y f or N E T ( Yes vers us N o), n u m ber of pre vi o us s ur ger y f or 
N E T, a n d ti me si nce last pre vi o us s ur ger y f or N E T (refer t o A p pe n di x 1: Deri ve d Data ), T N M 
resi d ual t u m o ur classificati o n after s ur ger y. 
All t hese data will be liste d b y st u d y p art , c o h ort ( part B o nl y) , ra di oacti vit y le vel a da pt e d or 
n ot ( part B o nl y)  a n d s u bject.  
 
3. 2. 1 0  
Pri or  s ur gic al pr oce d ures a n d pri or R a di ot her a p ies f or N E T C a ncer 
N u m ber a n d p erce nta ge of patie nts ha vi n g pri or s ur gical pr oce d ures f or N E T ca n cer, as well as 
t y pe of pr oce d ures will b e ta b ulate d. All data will als o be liste d b y st u d y p art , c o h ort ( part B 
o nl y ), ra di oa cti vit y le v el a da pte d or n ot ( part B o nl y) a n d s u bject , i ncl u di n g i nte nt, d ate of 
s ur ger y a n d ti me si nce last s ur ger y. 
N u m ber a n d perce nta ge of patie nts ha vi n g pri or ra di o thera pies f or N E T ca n cer, as well as t y pe 
of t hera pies will be ta b ulate d. Al l data will be als o liste d i ncl u di n g i nte nt, l ocati o n of t he 
pr oce d ure, start/e n d dat es, t otal d ose recei v e d a n d ti me bet wee n last ra di ot hera p y a n d first st u d y 
dr u g i nf usi o n.  
 
3. 2. 1 1  
S u bject c o m pli a nce  
A listi n g will b e prese nte d f or dr u g a d mi nistrati o n ( d ose, q u a ntit y, d ate) b y c o h ort ( part B o nl y) , 
ra di oacti vit y le v el a da pte d or n ot ( part B o nl y) a n d s u bject f or eac h st u d y part . De viati o ns fr o m 
o bser ve d a n d s c he d ule d ti mes will be prese nte d.   
A listi n g of s u bjects wit h diffic ulties , dela y a n d i nt err u pti o n d uri n g dr u g a d mi nistrati o n will be 
als o pr o vi de d.  


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A listing will be presented for prohibited concomitant medication for any subject who has 
received this prohibited medication. Subjects excluded from the Per Protocol Set due to 
receiving prohibited concomitant medication will be flagged (+). 
 
3.2.12 
Prior and concomitant therapies 
3.2.12.1 Prior and concomitant drug therapies 
Any prior or concomitant therapy or medication given to a subject for another indication within 
4 weeks (28 days) before study drug administration or during study drug administration will be 
indicated on the eCRF. Dose and generic name or tradename will be indicated. All recorded 
data will be included in data listings. 
Prior and concomitant medications will be coded using WHO Drug Dictionary, version June 
2016 or higher.  
Medications which started and stopped before start of study treatment are considered as prior 
medications. 
Medications which started before start of study treatment but are continuing will be considered 
as both prior and concomitant medications. 
 
Listings will include the therapeutic class (i.e., the second level of Anatomical Therapeutic 
Chemical [ATC] classification system code, that is, corresponding to the first 3 figures), 
preferred term (the fourth level of the ATC code, that is, corresponding to the first 5 figures) 
and verbatim text. The listings will be sorted by study part, cohort (part B only), radioactivity 
level adapted or not (part B only), subject id, chronological start date, stop date, therapeutic 
class, preferred name and verbatim name.  
A frequency table of the number and percentage of subjects will be provided for prior 
medications and concomitant medications by therapeutic class and preferred name for each 
study part, cohort (part B only) and overall on the Safety Analysis Set. 
 
3.2.12.2 Prior and concomitant non-drug therapies 
Any prior or concomitant non-drug therapy or medication given to a subject for another 
indication within 4 weeks (28 days) before study drug administration or during study drug 
administration will be indicated on the eCRF. Dose and generic name or tradename will be 
indicated. All recorded data will be included in data listings. 
Prior and concomitant non-drug therapies will be coded using Meddra, version 21.1 or higher.  
Medications which started and stopped before start of study treatment are considered as prior 
medications. 
Medications which started before start of study treatment but are continuing will be considered 
as both prior and concomitant medications. 
Listings will include the therapeutic class (i.e., the second level of Anatomical Therapeutic 
Chemical [ATC] classification system code, that is, corresponding to the first 3 figures), 
preferred term (the fourth level of the ATC code, that is, corresponding to the first 5 figures) 
and verbatim text. The listings will be sorted by cohort, subject id, chronological start date, stop 
date, therapeutic class, preferred name and verbatim name.  
A frequency table of the number and percentage of subjects will be provided for prior and 
concomitant non-drug therapies by therapeutic class and preferred name for each study part, 
cohort (part B only) and overall on the Safety Analysis Set. 


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3.2.12.3 Prior and concomitant Somatostatin Analog treatment for NET   
Prior and concomitant somatostatin analog treatment for NET will be coded using WHO Drug 
Dictionary, version June 2016 or higher.  
Somatostatin analog treatment which started and stopped before start of study treatment are 
considered as prior medications.  Somatostatin analog treatment which started before start of 
study treatment but are continuing will be considered as both prior and concomitant 
medications. 
Listings will include the therapeutic class (i.e., the second level of Anatomical Therapeutic 
Chemical [ATC] classification system code, that is, corresponding to the first 3 figures), 
preferred term (the fourth level of the ATC code, that is, corresponding to the first 5 figures) 
and verbatim text. The listings will be sorted by cohort, subject id, chronological start date, stop 
date, therapeutic class, preferred name and verbatim name.  
A frequency table of the number and percentage of subjects will be provided for prior 
somatostatin analog treatment for NET by therapeutic class and preferred name for each study 
part, cohort (part B only) and overall on the Safety Analysis Set. A similar frequency table will 
be provided for concomitant somatostatin analog treatment for NET. 
 
3.2.12.4 Concomitant Protective Co-Medications for NET 
Concomitant protective co-medications for NET will be coded using WHO Drug Dictionary, 
version June 2016 or higher. 
Listings will include the therapeutic class (i.e., the second level of Anatomical Therapeutic 
Chemical [ATC] classification system code, that is, corresponding to the first 3 figures), 
preferred term (the fourth level of the ATC code, that is, corresponding to the first 5 figures) 
and verbatim text. The listings will be sorted by study part, cohort (part B only), radioactivity 
level adapted or not (part B only), subject id, chronological start date, stop date, therapeutic 
class, preferred name and verbatim name.  
A frequency table of the number and percentage of subjects will be provided for concomitant 
protective co-medications for NET by therapeutic class and preferred name for each study part, 
cohort (part B only) and overall on the Safety Analysis Set. 
 
3.2.12.5 Prior and Concomitant Radiopharmaceutical Medications for scanning 
Prior and concomitant radiopharmaceutical medications for scanning will be coded using WHO 
Drug Dictionary, version June 2016 or higher.  
Radiopharmaceutical medications for scanning which started and stopped before start of study 
treatment are considered as prior medications. Radiopharmaceutical medications for scanning 
which started before start of study treatment but are continuing will be considered as both prior 
and concomitant medications. 
Listings will include the therapeutic class (i.e., the second level of Anatomical Therapeutic 
Chemical [ATC] classification system code, that is, corresponding to the first 3 figures), 
preferred term (the fourth level of the ATC code, that is, corresponding to the first 5 figures) 
and verbatim text. The listings will be sorted by study part, cohort (part B only), radioactivity 
level adapted or not (part B only), subject id, chronological start date, stop date, therapeutic 
class, preferred name and verbatim name.  


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A frequency table of the number and percentage of subjects will be provided for concomitant 
radiopharmaceutical medications for scanning by therapeutic class and preferred name for each 
study part, cohort (part B only) and overall on the Safety Analysis Set. 
 
3.2.12.6 Prior Chemotherapy for NET Cancer 
Prior chemotherapy for NET cancer will be coded using WHO Drug Dictionary, version June 
2016 or higher.  
Listings will include the therapeutic class (i.e., the second level of Anatomical Therapeutic 
Chemical [ATC] classification system code, that is, corresponding to the first 3 figures), 
preferred term (the fourth level of the ATC code, that is, corresponding to the first 5 figures) 
and verbatim text. The listings will be sorted by study part, cohort (part B only), radioactivity 
level adapted or not (part B only), subject id, chronological start date, stop date, therapeutic 
class, preferred name and verbatim name.  
A frequency table of the number and percentage of subjects will be provided for prior 
chemotherapy for NET cancer by therapeutic class and preferred name for each study part, 
cohort (part B only) and overall on the Safety Analysis Set. 
 
3.2.12.7 Concomitant Surgical Procedures 
Concomitant surgical procedures will be coded using MedDRA Version 21.1 or higher. 
Listings will present the preferred term and verbatim text. The listings will be sorted by study 
part, cohort (part B only), radioactivity level adapted or not (part B only), subject, primary 
system organ class, preferred term and verbatim text.  
A frequency table of the number and percentage of subjects will be provided for all concomitant 
surgical procedures by primary system organ class and preferred term for each study part, 
cohort (part B only) and overall on the Safety Analysis Set. 
 
3.2.13 
Derived data 
The derived data are variables which are calculated from the raw data recorded in the eCRF or 
any other support and not included in the database. The derived data will be calculated to be 
included in tables and listings. 
Some specifications of the data derivations necessary for this study are provided in Appendix 
1: Derived Data. 
3.2.14 
Visit windows  
All data will be organised and analysed according to the scheduled visits outlined in the 
protocol. However, actual observation times may differ from the scheduled visit times and 
where this occurs the results should be allocated to the most appropriate visit. Therefore, time 
intervals (e.g. visit windows) have been constructed so that every observation collected can be 
allocated to a particular time point. If more than one record occurs within the same visit window 
where only one assessment is expected then the following rule should be applied: for pre-study 
assessments the last non-missing result prior to study drug administration should be used; for 
post-treatment assessments the closest non-missing result to the scheduled visit should be used. 
 


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CONFIDENTIAL 
Study part 
Scheduled visit 
Time interval (days) 
 
 
 
Pre treatment (Screening) Screening Visit 
Week – 4 to -1 
 
 
 
Active phase 
Visit 1, Day 1 
Day 1 (Week 0) 
Visit 1, Day 2 
Day 2 
Visit 1, Day 3 
Day 3 
Visit 1, Day 4 
Day 4(-Day 5) 
Visit 1, Day 7 
Day 7(- Day 8) 
Visit 1, Day 15 
Day 15 ±2 days 
Follow-up 1 Visit 1 
Week 4 (Day 29 ±5 days) 
Follow-up 2 Visit 1 – Part B 
only 
Week 6 (Day 42±5 days) 
Visit 2, Day 1 
Week 8 +2 weeks (+4 weeks in 
case of reversible toxicity), Day 
1 
Visit 2, Day 2 
Day 2 
Visit 2, Day 3 
Day 3 
Visit 2, Day 4 
Day 4(-Day 5) 
Visit 2, Day 7 
Day 7(- Day 8) 
Visit 2, Day 15 
Day 15 ±2 days 
Follow-up 1 Visit 2 
Week 12 (Day 29±5) 
Follow-up 2 Visit 2 - Part B 
only 
Week 14 (Day 42±5) 
Visit 3, Day 1 
Week 16 +2 weeks (+4 weeks in 
case of reversible toxicity), Day 
1 
Visit 3, Day 2 
Day 2 
Visit 3, Day 3 
Day 3 
Visit 3, Day 4  
Day 4(-Day 5) 
Visit 3, Day 7 
Day 7(- Day 8) 
Visit 3, Day 15 
Day 15 ±2 days 
Follow-up 1 Visit 3 
Week 20 (Day 29±5) 
Follow-up 2 Visit 3 – Part B 
only 
Week 22 (Day 42±5) 
End 
Of 
Core-Trial 
(EOCT)  
End of Core-Trial Visit  
Week 24 (Day 1±5) 


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Study part 
Scheduled visit 
Time interval (days) 
Additional Cycles – Part 
B only 
Additional Cycle 4, Day 1 
Week 24 + 2 weeks (+4 weeks 
in case of reversible toxicity), 
Day 1 
Additional Cycle 4, Day 2 
Day 2 
Additional Cycle 4, Day 3 
Day 3 
Additional Cycle 4, Day 4 
Day 4(-Day 5) 
Additional Cycle 4, Day 7 
Day 7(- Day 8) 
Additional Cycle 4, Day 15 
Day 15 ±2 days 
Follow-up 
1 
Additional 
Cycle 4 
Week 28 (Day 29±5) 
Follow-up 
2 
Additional 
Cycle 4 
Week 30 (Day 42±5) 
Additional Cycle 5, Day 1 
Week 32 + 2 weeks (+4 weeks 
in case of reversible toxicity), 
Day 1 
Additional Cycle 5, Day 2 
Day 2 
Additional Cycle 5, Day 3 
Day 3 
Additional Cycle 5, Day 4 
Day 4(-Day 5) 
Additional Cycle 5, Day 7 
Day 7(- Day 8) 
Additional Cycle 5, Day 15 
Day 15 ±2 days 
Follow-up 
1 
Additional 
Cycle 5 
Week 36 (Day 29±5) 
Follow-up 
2 
Additional 
Cycle 5 
Week 38 (Day 42±5) 
End of Additional Cycles 
(EOAC)– Part B only 
EOAC Visit 
8 weeks after the last dose of 
therapy 
Long term Follow-up 
Long term Follow-up Visits 
(1-8) 
every 3 months (± 2 weeks) for 
2 years starting 12 weeks after 
EOCT/EOAC visit or early 
withdrawal visit, in the long-
term follow-up phase 
Early Withdrawal 
Early Withdrawal Visit 
8 
weeks 
after 
the 
last 
administration 
study 
medication 
Patients will be treated with three cycles of 177Lu-OPS201 PRRT with an interval of 8 (+2) weeks between each 
cycle). If severe side effects occur, the interval can be elongated by 4 weeks. If the side effects are resolved in this 
time, the next treatment cycle can be initiated, if not, no further PRRT treatment will be administered and the 
patient will undergo the EOCT Visit. 


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3.2.15 
Rules and data formats 
Data will be presented using an appropriate number of decimal places (i.e. the number of 
decimal places used does not imply undue precision).  Raw data will be presented to the number 
of decimal places collected, and derived data will be presented to an appropriate number of 
decimal places. The appropriate number of decimal places will be determined by general 
practice, mathematical rationale or scientific rationale (e.g. age should be presented in whole 
numbers).  
For summary statistics, the following will be presented n, number of missing values (based on 
subject who attended the visit), arithmetic mean, standard deviation, median and the range 
(minimum, maximum). 
Mean, median, standard deviation and standard errors of the mean (SE) values will be reported 
to one decimal place greater than the raw/derived data that they summarise. Minimum and 
maximum values will be reported with the same precision as the raw data. 
Percentages will be reported to one decimal place and 0% will not be presented. Percentages 
will be calculated using a denominator of non-missing observations. The denominator will be 
specified in a footnote to the tables for clarification if necessary. 
Lower and upper confidence interval values will be presented to one decimal place more than 
the raw/derived data (i.e., to the same number of decimal places as the mean). 
Percentiles (e.g., 25%, 75%) will be presented to one decimal place more than the raw/derived 
data.  
If any, p-values will be reported to four decimal places (e.g.: p=0.0037), after rounding. P-
values which are less than 0.0001 will be presented as ‘<0.0001’. 
All values below or above a limit of detection (e.g. <0.1 or >100) will be listed as such.   
All text fields must be left justified and numeric or numeric with some text specification (e.g.: 
not done, unknown, <4.5) must be decimal justified. Dates will be presented in the format 
[ddmmmyyyy] and times in the format [hh:mm]. 
 
3.2.16 
Pooling of Centres 
It is not planned to perform a subgroup analysis on individual or groups of centres. 
 
3.2.17 
Interim analysis 
1st Interim analysis 
A first interim analysis will be conducted at the cut-off date of 27 September 2019 to inform 
the design of the chemotherapy combination study which has been added to the investigational 
plan.  
The tables, listings and figures that will be produced for this analysis are flagged “*” in 
Section7.2 – List of TFLs. 
2nd Interim analysis 
A second interim analysis of Part B data will be conducted at the EOCT/EOAC/EW (whichever 
occurs last) after completion of Cohorts 3 and 6. This will provide confirmation of the peptide 
dose to allow future studies to be developed. It will also confirm if Cohorts 2 or 7 and 8 will be 
initiated.  
 


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3rd Interim analysis 
A third interim analysis, including all dosimetry, safety and efficacy data, will be performed 
after the EOCT/EOAC/EW (whichever occurs last) when the two study parts are completed. 
 
The interim analyses may be combined based on the overall study status and subject accrual. 
The final analysis will be performed at the end of the 2-year long-term follow-up period.  
 
Other analyses 
In addition, dosimetry evaluation will be performed on an ongoing basis. After the first six 
subjects included have completed the study Part A (EOCT or Early Withdrawal Visit) an SRC 
meeting will be held before exposing the remaining subjects to the entire number of planned 
administrations. Safety data obtained until 8 weeks after the last administration of the 6th subject 
will be evaluated during this SRC. Prior to Part B, the SRC will review the safety and dosimetry 
data of the first six subjects included in Part A.  
For Part B, a DRB meeting will be held to review the safety and radiation exposure data and 
decide whether to proceed with the enrolment of the next cohort dose level and the cumulative 
radioactivity within a cohort. Each dose escalation (both peptide and radioactivity) will be 
carefully evaluated by a DRB. 
In addition, the SRC/DRB can be convened at any time during the trial to discuss potential 
safety issues. The data set to be reviewed by the SRC/DRB is specified in a specific charter. 
 
3.2.18 
Role of the Safety Review Committee (SRC) – Part A 
The SRC will be composed of all Investigators, who have treated at least one subject in the 
study with study medication, a dosimetry expert evaluating the dosimetry data of the study, an 
independent hematology expert and at least one Sponsor representative. A specific charter will 
be developed to define roles and responsibilities, as well as the data set to be reviewed by the 
SRC. 
 
This study will be performed in two parts: 
 
Part A (15 subjects) 
Initially, 6 subjects will be treated. Each patient will receive: 
• 
3 cycles of 4.5 GBq (target radioactivity of 4.5 GBq±10%)) 177Lu-OPS201 (target dose 
of 300±50 µg), 8 weeks apart (+2 weeks or plus up to 4 weeks in case of AEs which have 
not adequately recovered). 
A SRC meeting will be held before exposing the remaining 9 subjects of Part A to the entire 
number of planned administrations. Safety and dosimetry data from the first 6 subjects (data 
obtained up to 8 weeks after the last administration for each subject) will be evaluated during 
this SRC. 
Dose limiting toxicity (DLT) definition: Investigational medicinal product (IRPP) related AEs 
with a severity of Grade 3 or higher are considered DLT, with the exception of hair loss, 
lymphopenia, nonfebrile neutropenia lasting < 4 weeks and thrombocytopenia lasting < 4 
weeks. 
• 
If DLTs occur in ≤ 33% of the patients (i.e. ≤ 2 of 6 patients), the remaining 9 patients 
will continue at the same radioactivity level. 


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• 
If DLTs occur in > 33% of the patients (i.e. > 2 of 6 patients), the administered 
radioactivity will be reduced to a cumulative radioactivity which did not lead to DLT 
occurrence with this frequency, e.g. the number of administrations will be reduced from 
3 to 2. 
 
Part B (up to 40 subjects) 
Proceeding to next cohort will be determined by the following DLT rules based on three 
evaluable subjects: 
• If DLTs occur in >33% of the subjects of the cohort, the next cohort will not be initiated. 
• If DLTs occur in ≤33% and ≥2 of the three subjects have cumulative absorbed dose in 
each target organs exceeding the acceptability limits (1.5 Gy in bone marrow (BM) and 
23 Gy in kidney), subjects in the next cohort will receive the same cumulative 
radioactivity or less than in the preceding cohort.  
• If DLTs occur in ≤33% and <2 of the three subjects did not reach the cumulative 
absorbed dose in each target organs (1.5 Gy in BM and 23 Gy in kidney), the next cohort 
will be initiated as planned. 
 
3.2.19 
Role of the Data Review Board (DRB) – Part B  
The following are subject stopping rules for Part B.  
If any of the following occur, no further 177Lu-OPS201 treatment will be administered: 
 
• 
subject withdraws his/her consent to further treatment; 
• 
cumulative kidney dose exceeds 23 Gy; 
• 
cumulative bone marrow dose exceeds 1.5 Gy, as determined by dosimetry and dose 
calculation based on imaging; 
• 
absolute neutrophil count <1.000*109/L (i.e. Grade 3 or higher); 
• 
platelets <50.0*109/L (i.e. Grade 3 or higher); 
• 
if one of the following medical conditions occurs (based on Common Terminology 
Criteria for AEs (CTCAE)  v5.0 and does not resolve within four weeks 
(resolved=toxicity Grade 1 or recovered, and is at the discretion of the investigator): 
- 
eGFR of <45 mL/min/1.73m2; 
- 
liver function tests (total bilirubin, aminotransferases, alkaline phosphatase and 
GGT) higher than Grade 3; 
- 
any other AE above Grade 2, except hair loss, lymphopenia, non-febrile 
neutropenia lasting <4 weeks and thrombocytopenia lasting <4 weeks. 
 
The investigator can decide at his/her discretion to discontinue the treatment or to reduce the 
administered activity for further safety reason than those here listed above to prevent a subject 
from higher grade toxicity. 
 
Before the administration of Cycles 2 and 3 these criteria must be checked. In the event of 
withdrawal (discontinuation) from treatment only the EOCT Visit and the Long-term Follow-up 
will be performed (with the EOCT Visit 12 weeks after the last administration of 
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There will be six DRBs that are defined a -priori and show in Figure 4. Each DRB described is 
designated a letter (A to F). The details of the decision making for each DRB is detailed in 
Table 9. 
Figure 4 Part B Cohort Schema with DRB Designations 
 
 


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Table 9 
Details of each DRB, the Timing, Question and Decision Matrix 
DRB 
Designation[a] 
Timing/data 
(EOC=End of cycle) 
 Question(s) for DRB 
Decision Matrix 
DRB-A 
Cohort 3 First three 
subjects EOC-2:  
Start Cohort 6 Cycle 2 with 
1,300 µg peptide mass? 
If >33% in Cohort 3 Cycle 2 then NO to 
Cohort 4.  
DRB-B 
Cohort 3 First three 
subjects, EOC-2  
Start Cohort 4 with 6 GBq? If >65% DLTs in Cohort 3 then NO to 
Cohort 4. 
If >33% and <67% DLTs in Cohort 3 
Cycle 2 then wait for three more 
subjects in Cohort 3 Cycle 2 and re-
evaluate.  
Otherwise start Cohort 4. 
Cohort 4 will not start recruiting until 
Cohorts 1, 3 and 6 are fully recruited 
DRB-C 
Cohort 4 EOC-1 
Start Cohort 5? 
If >33% DLTs in Cohort 4 then NO to 
Cohort 5.  
Continue Cohort 4? 
If >33% DLTs in Cohort 4 then STOP. 
Evaluate peptide mass dosing and lesion 
receptor saturation. Evaluate next cohort 
to start and activity dosing. 
DRB-D 
Cohort 6 EOC-3 All 
subjects  
Cohort 4 EOC-1  
Start Cohort 7? 
If >33% DLT in Cohort 6 Cycle 2 NO 
to Cohort 7 AND 
If lesion receptor saturation in Cohort 6 
Cycle 2, then no to Cohort 7 AND 
If >33% DLTs and <67% DLTs in 
Cohort 4 and receptor modelling 
suggests Cohort 7 mass dose safer, then 
start Cohort 7, otherwise no. 
DRB-E 
Cohort 6 EOC-3 All 
subjects  
Cohort 5 EOC-1 
Start Cohort 8?  
If >33% DLT in Cohort 6 Cycle 2 NO 
to Cohort 8 AND 
If lesion receptor saturation in Cohort 6 
Cycle 2, then no to Cohort 8 AND 
If >33% DLTs <67% DLTs in Cohort 5 
and receptor modelling suggests Cohort 
8 mass dose safer, then start Cohort 8, 
otherwise no. 
DRB-F 
Cohort 1 EOC-3 and 
Cohort 3 EOC-3 and 
Cohort 5 EOC-1  
Start Cohort 2? 
If mass dose modelling suggest 300 ug 
is optimal AND 
If >33% DLTs in Cohort 1, AND 
If >33% DLTs in Cohort 5  
Start Cohort 2 
DLT=dose limiting toxicity; DRB=data review board; EOC=end of cycle; GBq=gigabecquerel. 
Note: At each DRB, safety data available from all cohorts will be evaluated to inform decision making.  
a although the DRBs are written in alphabetical sequence this is not a chronological order; each one will be 
conducted when data becomes available which is dependent on subject recruitment. An ad-hoc DRB can be 
called to ensure continuity of dosing. Although three completed subjects are required for each completed 
cycle for evaluation, all available subject data in that cohort will be used (e.g. If five subjects are enrolled and 
all five complete the end of a cycle prior to the DRB, then all five sets of data will be evaluated). 
This cumulative activity in the cohort being evaluated will be determined by the following DLT 
rules: 
• 
If, in the preceding cohort after the third administration of 177Lu-OPS201, DLTs occur 
in >33% of three subjects (i.e. >1out of the three to five subjects), the activity for the 
next cohort will be reduced to a cumulative administered activity which did not lead to 
DLT occurrence with this frequency. 
• 
If, in the preceding cohort after the third administration of 6GBq 177Lu-OPS201, DLTs 
occur in ≤33% of three subjects and ≥2 of the three subjects have a cumulative absorbed 


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dose in each target organ exceeding the acceptability limits (1.5 Gy in BM and 23 Gy in 
kidney), subjects in the next cohort will receive the same cumulative activity or less than 
in the preceding cohort.  
• 
If, in the preceding cohort after the third administration of 6GBq 177Lu-OPS201, DLTs 
occur in ≤33% of the three subjects and less than two of the three subjects did not reach 
the cumulative absorbed dose in each target organ (1.5 Gy in BM and 23 Gy in kidney), 
the activity in the next cohort will be escalated up to 7.4 GBq per administration, as 
detailed in the table above 
 
Data Review Board 
• 
the DRB will consist of a team of “permanent” decision makers (the core team); 
• 
principal investigators may participate, present and listen in; 
• 
all final decisions will be made by the core team; 
• 
the number of DRB meetings may change as needed and can be called upon rapidly if 
there is a safety issue of concern in a cohort; 
• 
the aim is to have all meetings via conference call, but if the timing does not allow for 
this, then it can be conducted via email exchange or two conference calls with split 
attendees; 
• 
a DRB charter will be developed with further details. 
 
3.2.20 
Covariates and analysis of subgroups 
No adjustment on covariate and no subgroups analysis are planned to be performed. 
 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS 
4.1 
Hardware 
The statistical analysis will be performed using Windows 7 or higher version. 
 
4.2 
Software 
All tables, listings and figures will be produced, and statistical analysis performed using SAS® 
version 9.2 or higher version. All output will be in Microsoft Word Format. 
 
4.3 
Validation programs 
SAS® programs are developed to produce clinical study output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. Covance SOP 
 
 
 provides an overview of the development of such SAS® programs 
and describes the quality control procedures that must be performed for all SAS® programs 
and outputs. Quality control (QC) is defined here as the operational techniques and activities 
undertaken to verify that the SAS® programs produce the proper clinical study output by 
checking for their logic, efficiency and commenting, and by inspection of the produced outputs. 
 will be 
prepared to document the methods of validation.  
Copies of the internal QC forms produced for the validation process and the Covance’s sign-
off forms will be provided to the sponsor to support the validation. 
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4.4 
Restitution of the programs 
All programs (including Macros and analysis datasets) producing the tables, listings and 
statistical output along with associated logs should be given to the sponsor when the tables, 
listings, figures and statistical analysis has been finalised. 
 
5 
CHANGES FROM PROTOCOL 
 
Dosimetry sections: 
Cumulative absorbed dose to the lesions (Gy) has been added as dosimetry endpoint. 
 
AE section: 
AESI definition was updated to “any TEAE related to 177Lu-OPS201 which occurs the day of 
177Lu-OPS201 administration (same date as 177Lu-OPS201 administration and at any cycle). “ 
 
6 
REFERENCES 
 
1 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe 
D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). European journal of cancer 45:228-247. 
2 
Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 
22;317(17):1098 (letter). 
3 
International Conference on Harmonisation (ICH) E9 Guidance on statistical principles 
for clinical trials. Federal register Vol 63, No. 179 (September 1998). 
4 
US Food and Drug Administration. Guidance for Industry: Clinical Trial Endpoints for 
the Approval of Cancer and Drugs and Biologics. Rockville, MD: US Food and Drug 
Administration, US Dept of Health and Human Services; 2007. 
5 
Chuang-Stein C., Summarizing Laboratory Data with different reference ranges in 
multicentre clinical trials. Drug Information Journal, 1992, Vol 26, pp 77-84. 
6 
Karvanon J., The statistical basis of laboratory data normalization. Drug Information 
Journal, 2003, Vol 37, pp 101-107. 
7 
Ruvona F., et al. Generalised lab norms for standardizing data from multiple laboratories. 
Drug Information Journal, 2003, Vol 37, pp 61-79. 
8 
Lassmann M, Chiesa C, Flux G, Bardies M, Committee ED (2011) EANM Dosimetry 
Committee guidance document: good practice of clinical dosimetry reporting. European 
journal of nuclear medicine and molecular imaging 38:192-200. 
9 
Kletting P, Schimmel S, Hänscheid H, Luster M, Fernández M, Nosske D, Lassmann M, 
Glatting G, The NUKDOS software for treatment planning in molecular radiotherapy. Z 
Med Phys. 2015 Sep;25(3):264-74. 
10 
Bolch WE, Eckerman KF, Sgouros G, Thomas SR. MIRD pamphlet No. 21: a 
generalized schema for radiopharmaceutical dosimetry – standardization of 
nomenclature. J Nucl Med 2009;50:477–84. 
11 
Kletting P, Schimmel S, Kestler HA, Hänscheid H, Luster M, Fernandez M, et al. 
Molecular radiotherapy: the NUKFIT software for calculating the time-integrated 
activity coefficient. Med Phys 2013;40(10):102504. 


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12 
Neil W Scott, Peter M Fayers, Neil K Aaronson, Andrew Bottomley, Alexander de 
Graeff, Mogens Groenvold, Chad Gundy, Michael Koller, Morten A Petersen, Mirjam 
AG Sprangers on behalf of the EORTC Quality of Life Group. EORTC QLQ-C30 
Reference Values. July 2008. 
13 
Kim Cocks, Madeleine T. King, Galina Velikova, Marrissa Martyn St-James, Peter M. 
Fayers, and Julia M. Brown. Evidence-Based Guidelines for Determination of Sample 
Size and Interpretation of the European Organisation for the Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30. Journal of Clinical Oncology, Volume 
29, Number 1, January 1, 2011. Pages 89-95. 
14 
Ferté C, Fernandez M, Hollebecque A, et al (2014) Tumour growth rate is an early 
indicator of antitumour drug activity in phase I clinical trials. Clin Cancer Research 
20(1):246-52 
 
7 
APPENDICES  
7.1 
Appendix 1: Derived Data 
 
The following derived data will be calculated and included in the listings: 
 
(1) 
BMI  
BMI (kg/m2) will be derived as Weight (kg)/[Height(cm)/100]2 and rounded to the nearest 
decimal. Underweight is defined as BMI < 18.5, normal as between 18.5 and 25, and overweight 
as ≥ 25. 
 
(2) 
Body Surface Area  
Body Surface Area (m2) will be derived with the Mosteller formula as (Weight (kg) * 
Height(cm) / 3600) ½ and rounded to the nearest decimal. 
 
(3) 
Changes from baseline  
Changes from baseline will be calculated as a difference from baseline (e.g. assessment at the 
visit – assessment at baseline). 
 
(4) 
Adverse event duration 
If the start and end dates of the adverse event are identical then “<1” day will be presented with 
the duration in hh:mm recorded in the eCRF if it is available. If times are available, the duration 
will be calculated as (end date/time – start date/time) and presented in days hh:mm. If at least 
one time is missing and if the duration is greater than 24 hours then it will be calculated as (end 
date - start date)+1 and presented in days. If the recorded end date is CONT. (for continuing), 
the end date will be listed as “ongoing” and the duration will be approximated as “≥(last 
attended visit date – start date)+1” day(s). If the start date or the end date are partial the duration 
will be presented as a superior inequality “≥xx” day(s) [i.e.: ≥2 where start date=31JAN2004 
and end date=FEB2004 or start date=JAN2004 and end date=01FEB2004].  
 
(5) 
Time since last dose for adverse event 
If the start date of the adverse event is identical to the date of last administration, then”<1” day 
will be presented with the time to onset in hh:mm recorded in the eCRF if it is available. If 


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times are available, the time will be calculated as (start date/time – last administration date/time) 
and presented in days hh:mm. If at least one time is missing and if the time to onset is greater 
than 24 hours then it will be calculated as (start date - last administration date)+1 and presented 
in days. If the start date and the associated information do not allow to state about the last dose 
received (partial start date or start at administration day without knowing if it started before or 
after the drug intake), all the possible time since last dose will be presented [i.e.: if a subject 
received a daily administration and reported an AE at second administration day but without 
indication about before or after the drug intake the time since last dose will be as “2 / <1”]. If 
the start date is partial, the time since last dose will be presented as an superior inequality (i.e.: 
for an AE started in FEB2004 after the only administration performed on 31JAN2004, the time 
since last dose will be as “≥2” days). If the start date is missing the time since last dose will not 
be presented although the AE will be assigned to each dose received before its end date. 
 
(6) 
Days since last dose for study drug administration or discontinued subject 
The days since last dose for study drug administration will be calculated as (drug administration 
date/time - previous administration date/time)+1 and presented in days hh:mm. The days since 
last dose for discontinued subject will be calculated as (discontinued date - last administration 
date)+1 and presented in days. 
 
(7) 
Time since initial diagnosis (months) will be calculated as (screening date - date of 
initial diagnosis + 1)/30.4375 
 
(8) 
Time since histologically confirmed NET diagnosis (months) will be calculated as 
(screening date - date of histologically confirmed NET diagnosis + 1)/30.4375 
 
(9) 
Time since scan of positive somatostatin receptor documentation (months) will be 
calculated as (screening date - date of scan of positive somatostatin receptor 
documentation + 1)/30.4375 
 
(10) Time since last relapse/ time since last previous surgery for NET (months) will be 
calculated as (screening date - date of last relapse/surgery + 1)/30.4375 
 
(11) Study exposure 
Study exposure in days will be calculated as (last visit attended - first inform consent signed 
date) + 1. 
 
(12) Duration of Study Drug Exposure  
Duration (days) = (last dose or infusion date - first dose or infusion date +1) 
 
(13) Delay in injection 
A delay in injection is defined as an injection performed more than one day after the scheduled 
injection date. 
The number of days of delay will be positive and calculated as the difference between the actual 
injection date and the scheduled injection date. 
 


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(14) Injection performed in anticipation 
An injection performed in anticipation is defined by an injection performed more than 1 day in 
advance compared to the scheduled date. 
The number of days of anticipated injections will be positive and calculated as the difference 
between the scheduled injection date and the actual injection date. 
 
(15) Concomitant therapy duration 
If times are available, the duration of concomitant treatments/physiotherapy etc. will be 
calculated as (end date/time - start date/time). If at least one time is missing, the duration of 
concomitant treatments will be calculated as (end date - start date) +1. If the recorded end date 
is CONT. (for continuing) then the end date will be listed as “ongoing” and the duration will be 
approximated as “≥(last attended visit date – start date)+1” day(s). If the start date or the end 
date are partial, the duration will be presented as an inequality “≥xx” day(s) [i.e.: ≥2 where start 
date=31JAN2004 and end date=FEB2004 or start date=JAN2004 and end date=01FEB2004] 
but if both are partial or one is missing the duration will not be presented. 
 
(16) Study day 
Study day will be defined as ‘-1’ for the day prior to treatment and as ‘1’ for the day of treatment 
(i.e. day 0 does not exist).  
 
(17) For quantitative statistics of biological values, a standardization method will be used 
in order to take into account the differences between the reference ranges of the different 
laboratories: 
In a general way, standardised values will be assessed using the following formula: 
(
)
L
U
L
LRef
URef
LRef
St
X
X
X
X
X
X
X
X
−
−
−
+
=
.
 
where X = measured value, 
XL = lower limit value for the laboratory of the measured value, 
XU = upper limit value for the laboratory of the measured value, 
XLRef. = lower limit value for the laboratory chosen as a reference, 
XURef. = upper limit value for the laboratory chosen as a reference, 
If a standardised value is negative it will be replaced by 0. 
There is no missing value for any reference value. 
 
(18) A nadir for a subject is defined as the lowest laboratory value during the whole treatment 
period (all cycles combined) among all infusions for that subject and a nadir for a cycle 
is defined as the lowest laboratory value in that cycle. The day to nadir in a cycle is the 
number of days between the nadir and the first date of study medication intake of that 
cycle. 
 
(19) Whole body absorbed dose 
AbsorbedDose_WholeBody [Gy]= AUCWholeBody [Bq.s]X Ebeta / WeightWholeBody [kg] 
With Ebeta = 2.3664E-14 J.Bq-1.s-1.  
 


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(20) Whole body specific absorbed dose 
Specific_AbsorbedDose_WholeBody 
[Gy/GBq] 
= 
AbsorbedDose_WholeBody 
[Gy]/ 
Radioactivity_administered [GBq] 
 
(21) Amount excreted (Ae) for cold PK urine sample 
Ae [ng] = ConcentrationOPS201_urine (ng/mL) x volume urine collected (mL) 
 
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