Clinical trial NCT03773133
Conditions: Small Cell Lung Cancer and Breast Cancer
Sponsor: Ipsen
Start date: 2019-05-14; Completion date: 2019-10-10
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study consists of two phases. The phase I study is designed to investigate the safety and tolerability of Satoreotide tetraxetan following fractionated i.v. administrations in pre-treated subjects with locally advanced or metastatic cancers expressing sstr2 as identified by Satoreotide trizoxetan Positron Emission Tomography (PET/CT) scans. This phase will encompass both radioactivity escalation and peptide mass dose evaluation. Phase II will assess the efficacy of Satoreotide tetraxetan in subjects in selected indications, in a basket design.

Detailed description:

Arms: arm 1: i.v. administrations of up to three radioactivity levels of Satoreotide tetraxetan.
Interventions: intervention 1: Satoreotide tetraxetan intervention 2: Satoreotide trizoxetan
Intervention descriptions: intervention 1: Radioactivity delivered in 2 administrations (cycles): one loading dose followed by a lower maintenance dose, 6 weeks apart until progression or unacceptable toxicity (up to 4 additional cycles could be administered depending on efficacy and tolerability). intervention 2: Imaging companion: 1 administration at screening and one administration at End of core Trial cycle.

Protocol documents:
Prot_000.pdf: 
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PROTOCOL TITLE: A MULTICENTRE, OPEN-LABEL PHASE I/II STUDY TO 
EVALUATE THE SAFETY, TOLERABILITY, BIODISTRIBUTION AND 
ANTI-TUMOUR ACTIVITY OF 177LU-OPS201 WITH COMPANION IMAGING 
68Ga-OPS202 PET/CT IN PREVIOUSLY TREATED SUBJECTS WITH LOCALLY 
ADVANCED OR METASTATIC CANCERS EXPRESSING SOMATOSTATIN 
RECEPTOR 2 (SSTR2) 
 
(Sub-study of Master Protocol Ipsen 001 Version 1.0 dated 02 February 2018) 
 
STUDY PROTOCOL 
STUDY number: D-FR-01072-002 
68Ga-OPS202 and 177Lu-OPS201 
EudraCT number: 2017-005173-39/NCT Number: XXXX 
Version 2.0: 07 March 2019 
Study Sponsor: 
Ipsen Pharma, 65 quai Georges Gorse, 92100 Boulogne-Billancourt, France 
Tel:  +33 (0)1 58 33 50 00 
Fax:  +33 (0)1 58 33 50 01 
Sponsor Signatory:  
  
Ipsen Bioscience, Inc. 
650 East Kendall Street 
Cambridge, MA 02142 
United States 
Tel: 
 
Pharmacovigilance/Emergency Contact: 
, Global Pharmacovigilance, Ipsen Innovation 
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. 
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Sponsor Medical Monitor:  
 
Ipsen Bioscience, Inc. 
650 East Kendall Street 
Cambridge, MA 02142 
United States 
Tel: 
 
 
 
Sponsor Clinical Pharmacologist:  
 
 
Ipsen Innovation 
 
Global Drug Development 
 
ZI de Courtaboeuf 5, Avenue du Canada 
91940 Les Ulis, France 
 
Tel: 
 
 
 
 
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INVESTIGATOR’S AGREEMENT 
 
Investigator Agreement and Signature: 
I have read and agree to Protocol D-FR-01072-002 entitled a multicentre, open-label phase I/II 
study to evaluate the safety, tolerability, biodistribution and anti-tumour activity of 
177Lu-OPS201 with companion imaging 68Ga-OPS202 PET/CT in previously treated subjects 
with locally advanced or metastatic cancers expressing somatostatin receptor 2 (sstr2). 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: 
 Ipsen Bioscience Inc
 
SIGNATURE: 
  
  
DATE: 
OFFICE: 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
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COORDINATING INVESTIGATOR’S AGREEMENT 
 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol D-FR-01072-002 entitled a multicentre, open-label phase I/II 
study to evaluate the safety, tolerability, biodistribution and anti-tumour activity of 
177Lu-OPS201 with companion imaging 68Ga-OPS202 PET/CT in previously treated subjects 
with locally advanced or metastatic cancers expressing somatostatin receptor 2 (sstr2). 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: 
University Hospital Essen,  
Department of Nuclear Medicine,  
Hufelandstraße 55 
D-45147 Essen,  
Germany 
 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
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COORDINATING INVESTIGATOR’S AGREEMENT 
 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol D-FR-01072-002 entitled a multicentre, open-label phase I/II 
study to evaluate the safety, tolerability, biodistribution and anti-tumour activity of 
177Lu-OPS201 with companion imaging 68Ga-OPS202 PET/CT in previously treated subjects 
with locally advanced or metastatic cancers expressing somatostatin receptor 2 (sstr2). 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: 
University of Texas MD Anderson Cancer Center,  
Department of Investigational Cancer Therapeutics,  
Division of Cancer Medicine,  
1515 Holcombe Blvd Houston,  
TX 77030-4009,  
United States of America 
 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
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SUMMARY OF CHANGES 
The current version of the protocol was released on 07 March 2019 and includes Amendment 1. 
For all protocol amendment/s, amendment form/s 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 
Amendment 
Release date 
Amendment form 
1 
07 March 2019 
Appendix 2 
 


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SYNOPSIS 
Name of sponsor/company: IPSEN 
Name of finished product:  
177Lu-OPS201 – 177Lu-satoreotide tetraxetan  
68Ga-OPS202 – 68Ga-satoreotide trizoxetan 
Name of active ingredient(s):  
177Lu-OPS201 – INN for OPS201 is satoreotide tetraxetan 
68Ga-OPS202 – INN for OPS201 is satoreotide trizoxetan 
Title of study: a multicentre, open-label phase I/II study to evaluate the safety, tolerability, 
biodistribution and anti-tumour activity of 177Lu-OPS201 with companion imaging 
68Ga-OPS202 PET/CT in previously treated subjects with locally advanced or metastatic 
cancers expressing somatostatin receptor 2 (sstr2). 
(Sub-study of Master Protocol Ipsen 001 Version 1.0 dated 02 February 2018) 
Study number: D-FR-01072-002 
Number of planned centres:  
Phase I: Approximately 8 centres in Europe and United States of America 
Phase II: Approximately 30 centres in Europe, North America and Asia-Pacific 
Planned study period: 
Phase I: FPI: Q4 2018 - LPO: Q2 2020 (core 
treatment part) 
Phase II: FPI: Q4 2020 - LPO: Q1 2022 (core 
treatment part) - Q4 2023  
(2-year follow-up part) 
Phase of development: 
Phase I/II 
Objectives:  
Primary objective 
Phase I  
To evaluate the safety and tolerability and to define the maximum tolerated cumulative 
activity (MTCA) of fractionated intravenous (i.v.) administration over two cycles of 
177Lu-OPS201 in previously treated subjects with locally advanced or metastatic cancers 
expressing sstr2 as identified by 68Ga-OPS202 Positron Emission Tomography/Computed 
Tomography (PET/CT) scans. 
Phase II 
To evaluate the objective response rate (ORR) of fractionated i.v. administration of 
177Lu-OPS201 in previously treated subjects with locally advanced or metastatic cancers 
expressing sstr2 as identified by 68Ga-OPS202 PET/CT scans. 
Secondary objectives 
Phase I 
• 
To determine the whole-body distribution and pharmacokinetics (PK) of 
177Lu-OPS201 after each administration. 
• 
To determine the radiation dosimetry of 177Lu-OPS201 (organ exposure to radiation) 
after each administration. 


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• 
To determine the PK of OPS201 in plasma and urine. 
• 
To describe the preliminary anti-tumour activity of 177Lu-OPS201. 
• 
To evaluate progression free survival (PFS) until Long-term Follow-up Visits up to 
2 years after the end of core trial (EOCT) Visit. 
• 
To determine the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 on 
PET/CT images and estimate its correlation with the uptake on 177Lu-OPS201 Single 
Photon Emission Computerised Tomography (SPECT)/CT. 
• 
To evaluate the association between uptake on 68Ga-OPS202 PET/CT and tumour 
response to 177Lu-OPS201. 
Phase II 
• 
To evaluate the efficacy of 177Lu-OPS201 using Response Evaluation Criteria In 
Solid Tumours (RECIST) v1.1 and/or Positron Emission Tomography Response 
Criteria In Solid Tumours (PERCIST) v1.0 criteria, volumetric CT and modified 
PERCIST using 68Ga-OPS202 PET scans and modified RECIST using the 
68Ga-OPS202 avid lesions.  
• 
To evaluate PFS until Long-term Follow-up Visits up to 2 years after the EOCT 
Visit. 
• 
To estimate the 1-year overall survival (OS) rate. 
• 
To further evaluate the safety profile of 177Lu-OPS201. 
• 
To evaluate the association between uptake on 68Ga-OPS202 PET/CT with tumour 
response to 177Lu-OPS201 therapy. 
• 
To determine the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 on 
PET/CT images and estimate its correlation with the uptake on 177Lu-OPS201 
SPECT/CT. 
• 
To evaluate the impact of 177Lu-OPS201 on the health-related quality of life of 
treated subjects. 
• 
To estimate the proportion of sstr2-positive tumour lesions by 68Ga-OPS202 
PET/CT scans as assessed by standardised uptake volume (SUV) in subjects 
screened for 177Lu-OPS201 treatment. 
• 
To further assess some PK and dosimetry parameters of 177Lu-OPS201 based on the 
phase I results. 
Exploratory objectives 
Phase I/II 
• 
To explore renal and haematological safety by measuring urinary specific 
biomarkers and deoxyribonucleic acid-double strand breaks (DNA-DSB) and DNA 
repair capacity in peripheral lymphocytes (at selected centres). 
• 
To evaluate the tumour microenvironment, transcriptomics, DNA repair, gene 
mutation in tumour as compared to germinal mutation and other markers of interest 
through assessment of tumour biopsies. 
• 
To collect biobank samples for future analysis of circulating markers (optional, 
additional informed consent required). 
• 
To evaluate the association between the tumour uptake of 68Ga-OPS202 and sstr2 
expression on tumours as determined by immunohistochemistry (IHC). 


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• 
To generate a model integrating PK, pharmacodynamics, dosimetry, anti-tumour 
activity and safety data if warranted by the data. 
Study hypothesis:  
Phase I  
177Lu-OPS201 will be sufficiently safe to permit clinical investigation in phase II when 
administered in previously treated subjects with limited disease (LD)- or extensive disease 
(ED)- small cell lung cancer (SCLC) and in previously treated metastatic hormone receptor 
positive (HR+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer 
(BC), expressing sstr2 as identified by 68Ga-OPS202 PET/CT scans (see eligibility 
criteria).  
Phase II 
Previously treated subjects with LD- or ED-SCLC, or metastatic HR+/HER2- BC 
expressing sstr2 as identified by 68Ga-OPS202 PET/CT scans and treated with 
177Lu-OPS201 will attain a clinically meaningful ORR, which is superior to the historical 
ORR obtained by current standard-of-care (SoC) treatment. 
Methodology:  
Study design: 
This is a phase I/II, multicentre, open-label single-arm study of 177Lu-OPS201 therapy with 
companion diagnostic imaging 68Ga-OPS202 PET/CT in previously treated subjects with 
locally advanced or metastatic solid tumour expressing sstr2 who progressed under or after, 
failed to respond to, or are intolerant or having a contraindication to available SoC 
treatment options and are deemed suitable for treatment with 177Lu-OPS201 as per the 
investigator’s clinical assessment and/or their individual disease state. More specifically: 
• 
Subjects who had ED-SCLC at presentation who have progressed on or after one 
line of standard chemotherapy. If a subject had LD-SCLC at presentation and 
received surgery and/or radiotherapy as first line treatment (with or without 
chemotherapy) and has localised relapse, further local treatment (such as surgery) 
should be considered in addition to the chemotherapy options. 
For subjects with either ED-SCLC or LD-SCLC, if subjects relapse more than 6 
months after first-line treatment, re-treatment with their initial regimen is 
recommended. Subjects may have received prior immunotherapy. 
• 
Subjects with HR+/HER2- metastatic BC after failure of prior SoC treatments and 
who have received, if indicated, at least one line of hormonal therapy, cyclin-
dependent kinase (CDK) 4/6 inhibitor for advanced or metastatic disease and at least 
one line of chemotherapy for metastatic disease; subjects with BRCA-mutated 
metastatic disease who may have received a poly adenosine diphosphate ribose 
polymerase (PARP) inhibitor, if available, are eligible; prior adjuvant hormonal 
treatment and prior adjuvant chemotherapy are allowed. 
Before any study-specific procedures with 177Lu-OPS201, subjects will be administered 
68Ga-OPS202 and PET/CT images will be acquired. Focal avid lesion will be interpreted 
as sstr2-positive if the uptake is 1.5-fold or greater than the non-tumour liver and lung 
tissue is noted and if subjects have at least two avid lesions of ≥20 mm in the longest 
diameter on 68Ga-OPS202 PET/CT scan. Furthermore, subjects will be considered eligible 
for treatment with 177Lu-OPS201 if the imaging core laboratory (ICL) confirms ≥50% 
matching 
between 
the 
lesions 
detected on 
68Ga-OPS202-PET/CT 
and 
on 


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18F-fluorodeoxyglucose (FDG)-PET/CT and if the subjects meet all the other protocol 
eligibility criteria. 
The study consists of two phases: phase I with 177Lu-OPS201 radioactivity escalation and 
peptide mass dose escalation, and phase II assessing the efficacy of 177Lu-OPS201 in 
subjects in selected indications, in a basket design. A clinical research Master Protocol will 
encompass this biomolecular target study protocol together with other study protocols 
targeting the same receptor (sstr2) and will describe the overall background, rationale, 
objectives, design, methodology and organisation of the overall sstr2-positive cancer 
research project for OPS201 and OPS202. 
Phase I:  
During phase I, it is planned to enrol subjects with tumours expressing sstr2 as identified 
by 68Ga-OPS202 PET/CT scans in a basket design initially including SCLC and 
HR+/HER2- BC. Further types of tumours may be added according to advances in the 
preclinical and clinical knowledge on 68Ga-OPS202 and 177Lu-OPS201 and emerging 
clinical and non-clinical published data. 
Core treatment (two first cycles) 
In the core treatment period of phase I, up to three radioactivity levels of 177Lu-OPS201 
are planned to be tested with the radioactivity delivered in two administrations: one loading 
dose followed by a lower maintenance dose, 6 weeks apart (+ up to additional 4 weeks in 
case of adverse events (AEs) that need to be adequately recovered). It is anticipated that 
three cohorts of three to five subjects in each cohort will be included in the radioactivity 
escalation of phase I.  
A treatment cycle is defined as the timeframe of 6 (up to 10) weeks between two 
administrations or the timeframe of 6 weeks following the last administration. In case of 
logistical issues, the cycle could be extended by up to additional 2 weeks. 
The size of the cohorts will be three to five subjects. Once five subjects are enrolled in a 
cohort, enrolment will be stopped in that cohort. A cohort will be considered as evaluable 
once three subjects of the cohort complete Cycle 2 or discontinue early during Cycle 2. 
Cohorts will be enrolled using the following escalation approach (Table S1): 
• 
starting cumulative radioactivity of 9 GBq of 177Lu-OPS201 fractionated into one 
administration of 6 GBq followed by a second administration of 3 GBq, 6 weeks 
apart (+ up to additional 4 weeks in case of AEs that need to be adequately 
recovered).  
• 
maximum cumulative radioactivity of 12.9 GBq of 177Lu-OPS201 fractionated into 
two administrations, 6 weeks apart (+ up to additional 4 weeks in case of AEs that 
need to be adequately recovered).  
• 
maximum radioactivity administrable in one cycle is 7.4 GBq of 177Lu-OPS201. 
• 
the inter-cohort radioactivity escalation will be performed by maximum increment 
of 2 GBq. 
Table S1 
Radioactivity Escalation Plan (Irrespective of Peptide Mass Dose)  
Planned radioactivity 
escalation 
Cohort 1 and 2 
Cohort 3 and 4 
Cohort 5 and 6 
Cumulative (GBq) 
9 
11 
12.9 
Schedule (GBq) 
6 + 3 
7 + 4 
7.4 + 5.5 
Abbreviation: GBq=Gigabecquerel. 


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Each subject will only participate in one cohort. 
Proceeding to the second administration 
Data review will take place before the second cycle of each subject in a cohort based on all 
available safety and dosimetry data from the subject. The decision to proceed to second 
administration will be done as follows: 
• 
subjects with dose limiting toxicities (DLTs) after first administration will be 
discontinued from 177Lu-OPS201 treatment. 
• 
subject will be eligible for second administration of 177Lu-OPS201 only if: 
- 
blood cell counts and renal function tests are in the range defined in the study 
inclusion criteria (#7), within the treatment cycle 
- 
subject's organ absorbed doses did not exceed 1.5 Gy in bone marrow (BM) 
and 23 Gy in kidney. 
The radioactivity dose of the second administration will be adjusted based on 
dosimetry results to prevent exceeding limiting organ absorbed doses limits (1.5 Gy 
for bone marrow; 23 Gy for kidney). 
Proceeding to radioactivity escalation 
Data review board (DRB) for radioactivity escalation will take place after the third subject 
of each cohort has received two cycles of 177Lu-OPS201 with DLT assessments performed. 
The DRB will review all available safety and dosimetry data from the study to decide the 
radioactivity level that will be administered in the next cohort. 
If no DLT is observed, the radioactivity will be escalated by 2 GBq in the next cohort of 
radioactivity escalation using the following guidance (Table S1): 
• 
if 6 GBq followed by a second administration of 3 GBq is well tolerated, escalate 
to 7 GBq followed by a second administration of 4 GBq, 6 weeks apart (+ up to 
additional 4 weeks in case of AEs that need to be adequately recovered). 
• 
if 7 GBq followed by a second administration of 4 GBq is well tolerated, escalate 
to 7.4 GBq followed by a second administration of 5.5 GBq, 6 weeks apart (+ up to 
additional 4 weeks in case of AEs that need to be adequately recovered). 
However, if DLTs are reported, a statistical Bayesian modelling approach will be 
implemented to produce a more precise dose-DLT and dose-organ radiations dose curve to 
guide the dose selection and predict a radioactivity level not exceeding the 
MTCA/maximum tolerated single activity (MTSA) that could be tested in the next cohort 
of radioactivity escalation.  
 
Proceeding to radioactivity de-escalation 
If the starting cumulative radioactivity of 9 GBq is not well tolerated, another cohort with 
a decreased cumulative radioactivity will start. In this case, the cumulative radioactivity 
could be 7.5 GBq (one administration of 4.5 GBq followed by an administration of 3 GBq, 
6 weeks apart (+ up to additional 4 weeks in case of AEs that need to be adequately 
recovered)). 
The MTCA is defined as the maximum cumulative radioactivity that may be administered 
following fractionated i.v. administrations of at least 6 weeks apart, so that: 
• 
no more than 33% of the subjects experience a DLT after first or second 
administration of 177Lu-OPS201 and/or 


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• 
no more than 10% of the subjects have cumulative absorbed dose in each target 
organ exceeding the acceptability limits (1.5 Gy in BM and 23 Gy in kidney) after 
second administration of 177Lu-OPS201. 
The MTSA is defined as the highest single radioactivity that can be given so that no more 
than 33% of the subjects experience a DLT during Cycle 1. The MTSA will be determined 
in case of unacceptable toxicity seen after first administration of 177Lu-OPS201. 
The radioactivity escalation will be stopped as soon as: 
• 
the MTCA and/or MTSA have been defined with good precision; or 
• 
the maximum planned radioactivity of 12.9 GBq, fractionated into two 
administrations separated by 6 weeks (+ up to additional 4 weeks in case of AEs 
that need to be adequately recovered), is administered without safety concerns and 
is thus defined as the maximum administrable cumulative activity (MACA). 
Once the radioactivity escalation has been completed, the MTCA level may be repeated in 
a last cohort of three to five subjects with the same peptide mass dose (300 μg ±15%) to 
confirm the safety profile. If the MTCA is not reached and if limiting organ dose levels are 
not exceeded at the highest planned radioactivity (12.9 GBq) and if no individual 
withdrawal criteria are met, an additional cohort with a higher cumulative radioactivity 
may be planned. 
Note: an application for a substantial amendment will be submitted for approval by the 
Competent Authorities (CAs) and/or Ethic Committees (ECs) (as applicable) before 
initiating changes to the study conduct.  
The DLTs are defined for any of the following investigational radiopharmaceutical product 
(IRPP)-related AEs according to National Cancer Institute - Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) scale version 5.0 that occur during the defined 
DLT assessment period (from the first administration of 177Lu-OPS201 to 6 weeks after 
the second administration): 
• 
Grade 4 neutropenia lasting for seven or more consecutive days. 
• 
Grade 3 and 4 febrile neutropenia. 
• 
Grade 4 thrombocytopenia for seven or more consecutive days. 
• 
Grade 3 thrombocytopenia complicated by a bleeding event. 
• 
Grade 4 anaemia. 
• 
Grade 3 anaemia requiring transfusion. 
• 
Grade 3 or higher laboratory abnormalities of aspartate amino transferase/alanine 
amino transferase (AST/ALT) and/or bilirubin, with the following exceptions: 
- 
for subjects with Grade 1 AST/ALT at baseline (>upper limit of normal 
(ULN) to 3xULN), a AST/ALT value of >7.5xULN will be considered a DLT. 
- 
for subjects with Grade 2 AST/ALT at baseline (>3xULN to 5xULN), a 
AST/ALT value >10xULN will be considered a DLT. 
• 
any Grade 3 or higher acute kidney injury (creatinine >3x baseline or >4.0 mg/dL). 
• 
Grade 3 or higher non-haematological toxicity excluding: 
- 
Grade 3 nausea, vomiting or diarrhoea for less than 72 hours with adequate 
supportive care 
- 
Grade 3 fatigue lasting less than a week 


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- 
Grade 3 or higher electrolyte abnormality that lasts for less than 72 hours, is 
not clinically complicated and resolves spontaneously or with conventional 
medical interventions 
- 
Grade 3 or higher amylase or lipase not associated with symptoms or clinical 
manifestations of pancreatitis 
• 
any toxicity related to 177Lu-OPS201 resulting in a treatment delay of more than 
4 weeks due to delayed recovery to baseline or resolution of any AE of Grade 2 or 
more (exception of alopecia and lymphopenia). 
• 
Grade 5 toxicity (death) 
The EOCT visit will be done 6 weeks after last 177Lu-OPS201 dose administration, and 
subjects will be followed-up until resolution of any AE of Grade >1. Subjects who 
discontinue study treatment for reasons other than disease progression (e.g. toxicity) should 
continue to undergo scheduled tumour assessments until the subject dies, withdraws 
consent, or until the study closes, whichever occurs first. 
Optional additional cycles 
If a subject tolerates well the treatment and shows clinical benefit (e.g. complete response 
(CR), partial response (PR), or stable disease), up to four additional cycles of 
177Lu-OPS201 administration every 6 weeks (+ up to additional 4 weeks in case of AEs 
that need to be adequately recovered) can be administered to this subject. Dosimetry will 
be performed after each additional cycle and the radioactivity dose administrated will be 
adjusted based on dosimetry results to prevent exceeding limiting organ absorbed doses 
limits (ie, 23 Gy in kidney, 2 Gy in bone marrow if no Grade 3 or more haematotoxicity 
have been observed in this subject, otherwise limit in bone marrow is set to 1.5 Gy). For 
these subjects, an end of additional cycles (EOAC) visit will be done 6 weeks after last 
177Lu-OPS201 dose administration. 
Of note, the decision to administer additional cycles or any other anti-tumoural treatment 
is left at the investigator’s and subject’s discretion and must be discussed with and 
confirmed by the sponsor. 
Peptide mass dose evaluation 
In parallel with the radioactivity escalation phase, once the first cycle of a radioactivity 
level is considered acceptably tolerated by the DRB, the same radioactivity level will be 
repeated with a higher peptide mass dose (700 μg (±15%)). Three additional cohorts of 
three to five subjects will thus be enrolled in the peptide mass dose evaluation (see 
Figure S1). The schedule of assessments and safety evaluation in these cohorts will be the 
same as in the radioactivity escalation cohorts. 
The DRB for peptide mass dose escalation will meet after the third subject of each previous 
radioactivity escalation cohort has received the first cycle of 177Lu-OPS201 with DLT 
assessments performed. The DRB will review all safety and dosimetry data and allow the 
peptide mass dose escalation. The cohort with the high peptide mass dose (700 μg) will 
thus only start when the first cycle of the corresponding radioactivity level tested with 
300 μg peptide mass dose has been evaluated by the DRB and has been considered 
acceptably tolerated, except for the cohort 6 where the radioactivity for the first cycle (7.4 
GBq) is slightly different from the previous cohort (7.0 GBq) (see Figure S1) The same 
subject cannot participate in the radioactivity escalation cohort and the peptide mass dose 
cohort. 
Long-term follow-up 


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A long-term follow-up period will start after EOCT or after EOAC visit until 24 months 
maximum in total. Subjects will be followed-up every 3 months until 24 months, disease 
progression, death or withdrawal of full consent, whichever occurs first. 
Figure S1 
Initial Phase I Study Design 
 
Abbreviations: EOCT=end of core trial, FPI=first patient in, GBq=Gigabecquerel. 
Phase II  
Upon termination of phase I radioactivity escalation, peptide mass dose evaluation and/or 
determination upon reaching MTCA and stated jointly by the DRB and the sponsor, and in 
consideration of the accumulated subject data, a phase II will be started enrolling cohorts 
of subjects with sstr2-positive tumours as identified by 68Ga-OPS202 PET/CT scans to 
evaluate the efficacy and to confirm the safety of 177Lu-OPS201. Phase II will be conducted 
with indication-specific cohorts using a Simon's optimal two-stage design. 
Two cohorts will be initially investigated with 68Ga-OPS202 and 177Lu-OPS201: 
previously treated subjects with LD- or ED-SCLC or metastatic HR+/HER2- BC. Pending 
the results generated during the ongoing studies, advances of scientific and clinical 
knowledge and emerging published data, other cohorts could be initiated in this study.  
Note: an application for a substantial amendment will be submitted for approval by the 
CAs and/or ECs (as applicable) before initiating changes to the study conduct. 
Before any study-specific procedures with 177Lu-OPS201, subjects will be administered 
68Ga-OPS202 and PET/CT images will be acquired. Focal avid lesion will be interpreted 
as sstr2-positive if the uptake is 1.5-fold or greater than the non-tumour liver and lung 
tissue is noted and if subjects have at least two avid lesions of ≥20 mm in the longest 
diameter on 68Ga-OPS202 PET/CT scan. Furthermore, subjects will be considered eligible 
for treatment with 177Lu-OPS201 if ICL confirms ≥50% matching between the lesions 


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detected on 68Ga-OPS202-PET/CT and on 18F-FDG-PET/CT and if the subjects meet all 
the other inclusion criteria and none of the exclusion criteria. 
Dosing of 68Ga-OPS202 and PET image acquisition time as well as the eligibility criteria 
for sstr2 positivity could be revised at the start of phase II should emerging data from phase 
I and ongoing studies support modifications specific to these sstr2 expressing tumours. 
Note: an application for a substantial amendment will be submitted for approval by the 
CAs and/or ECs (as applicable) before initiating changes to the study conduct. 
Each cohort will enrol a defined number of subjects with sstr2-positive 68Ga-OPS202 
PET/CT scans (see Statistical Methods section below) and will investigate if treatment with 
177Lu-OPS201 attains an objective response rate (ORR or equivalent efficacy parameter) 
superior to a clinically accepted historical threshold of current SoC treatment for subjects 
with locally advanced or metastatic disease previously treated. 
In each cohort, subjects will receive the recommended phase II treatment schedule 
supported by dose-response and exposure-response analyses of phase I data as well as data 
emerging from other ongoing studies in other populations, if applicable. The recommended 
phase II treatment schedule corresponds to a recommendation of the cumulative 
radioactivity, the fractionation of the radioactivity, the peptide mass dose and the dosing 
interval. In any case, the cumulative radioactivity administered during phase II will not 
exceed the MTCA/MACA determined during phase I. Additional cycles (every 6 weeks 
(+ up to additional 4 weeks in case of AEs that need to be adequately recovered)) can be 
administered to subjects at investigator’s and subject’s discretion, provided additional 
benefit could be expected and limiting organ dose levels have not been exceeded. 
The current protocol may be amended at the end of the phase I to define the phase II design. 
Subjects in each phase of the study will have 2-year follow-up after the end of the last 
177Lu-OPS201 Cycle, with a visit every 3 months until 24 months, disease progression, 
death or withdrawal of full consent, whichever occurs first. 
An independent safety assessment committee (ISAC) structured to assess safety in addition 
to efficacy will be established during phase II in order to make recommendations regarding 
protocol modifications to reduce risks to subjects enrolled in the trial.  
Number of subjects planned:  
During phase I, up to 30 subjects will be enrolled for treatment with 177Lu-OPS201. Based 
on the current knowledge on the proportion of subjects presenting with sstr2-positive 
tumours, it is anticipated that approximately 55 to 60 subjects will need to be administered 
68Ga-OPS202 for PET imaging screening. 
During phase II, approximately 172 subjects (76 subjects with SCLC and 96 with BC) are 
planned to be enrolled for the Simon's optimal two-stage design. In this study phase, it is 
anticipated that approximately 340 subjects will be screened and administered 68Ga-
OPS202 for PET imaging. However, recruitment will be stopped once the number of 
required sstr2-positive subjects is reached. 
Further cohorts of subjects with other types of tumours expressing sstr2 could be added in 
this protocol according to the advances in the preclinical and clinical knowledge on 
68Ga-OPS202 and 177Lu-OPS201 and emerging published data on the diseases. In this case, 
the additional number of subjects will be estimated based on standard of care historical 
response (e.g. ORR/best overall response (BOR)) of the corresponding disease. 
Note: an application for a substantial amendment will be submitted for approval by the 
CAs and/or ECs (as applicable) before initiating changes to the study conduct. 


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Diagnosis and criteria for inclusion for 68Ga-OPS202 imaging:  
Inclusion criteria: 
All subjects must fulfil all the following criteria to undergo the 68Ga-OPS202 imaging 
(phase I/II): 
(1) 
signed 
informed 
consent 
prior 
to 
initiation 
of 
any 
study-specific 
activities/procedures.  
(2) 
male (except for BC cohort) or female subject aged 18 years or older. 
(3a) histologically confirmed cancer, that is locally advanced or metastatic disease, 
which has progressed during or after, failed to respond to, or for which there is poor 
tolerability or a contraindication to available SoC treatment options as per the 
assessment of the investigator; initially, subjects with the disease below may be 
considered: 
(a) 
Subjects who had ED-SCLC at presentation who have progressed on or after 
one line of standard chemotherapy. If a subject had LD-SCLC at presentation 
and received surgery and/or radiotherapy as first line treatment (with or 
without chemotherapy) and has localised relapse, further local treatment (such 
as surgery) should be considered in addition to the chemotherapy options. 
For subjects with either ED-SCLC or LD-SCLC, if subjects relapse more than 
6 months after first-line treatment, re-treatment with their initial regimen is 
recommended. Subjects may have received prior immunotherapy. 
(b) 
Subjects with HR+/HER2- metastatic BC after failure of prior SoC treatments 
and who have received, if indicated, at least one line of hormonal therapy, 
CDK4/6 inhibitor and/or everolimus for advanced or metastatic disease and 
at least one line of chemotherapy for metastatic disease; subjects with 
BRCA-mutated metastatic disease who may have received a PARP inhibitor, 
if available, are eligible; prior adjuvant hormonal treatment and prior adjuvant 
chemotherapy are allowed. 
(4) 
disease must be unsuitable for curative surgical resection and must not be amenable 
to curative radiotherapy. 
(5a)  documented progressive disease (radiological, based on RECIST v1.1) within 3 
months prior to first study drug administration. Screening study-related images 
should be sent to the ICL. 
Note: All images of the two datasets documenting progression should be sent to ICL. 
(6) 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
(7a) adequate organ function determined within 28 days prior to 177Lu-OPS201 
administration, defined as follows:  
• 
Haematological:  
- 
white blood cells (WBC) ≥3000/μL, with absolute neutrophil count 
≥1000/μL, platelet ≥100,000/μL and haemoglobin ≥9 g/dL (without 
need for hematopoietic growth factor or transfusion support). 
• 
Renal:  
- 
estimated glomerular filtration rate (eGFR) ≥55 mL/minute/1.73m2 
• 
Hepatic:  
- 
total serum bilirubin ≤2×ULN 


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- 
aspartate aminotransferase/ alanine aminotransferase ≤2.5×ULN 
(≤5×ULN if subject has liver metastases). 
(8a) has a formalin fixed paraffin embedded tumour sample (archival tumour sample 
obtained within 1 month prior to consent) from the primary or metastatic lesion OR 
is willing to undergo newly obtained biopsy prior to first dose of study treatment. 
Subjects who are unable or do not consent to provide acceptable tissue may not be 
enrolled unless there has been prior agreement with the sponsor. 
Note: the subject will be enrolled (if he/she fulfills all inclusion criteria and has no 
exclusion criterion) irrespective of the biopsy result 
(9) 
estimated life expectancy >3 months. 
Eligibility Criteria for Therapy (Phase I/II) 
To receive 177Lu-OPS201 therapy, each subject must fulfil all the eligibility criteria 
including the below criteria: 
(10a) 68Ga-OPS202 uptake in target tissue (primary tumour, lymph nodes and/or 
metastases) showing at least two avid (uptake ≥1.5 non-tumour liver and lung 
uptake) lesions of ≥20 mm in the longest diameter on PET/CT as confirmed by 
central reader. 
(11) Radiologically, ≥50% matching between the lesions detected on 68Ga-OPS202-
PET/CT and on 18F-FDG-PET/CT as confirmed by central reader 
The inclusion criteria for phase II will be refined based on the results from phase I as well 
as type of possible additional tumours and indications to be investigated and will be 
documented as part of a protocol amendment. 
Exclusion criteria: 
Eligible subjects must not have any of the following conditions (phase I/II): 
(1) 
male subjects with BC.  
(2a) 
unstable central nervous system metastasis defined as (any of the following): 
(a) 
radiographic evidence of new or progressive brain metastases after prior 
radiation therapy with at least one brain metastasis measuring ≥1 cm in 
longest diameter on gadolinium-enhanced magnetic resonance imaging 
(MRI), and/or 
(b) 
imaging following prior radiation is not consistent with pseudo-progression 
in the judgment of treating clinician, and/or 
(c) 
evidence of diffuse leptomeningeal disease on brain MRI or by previously 
documented cerebrospinal fluid cytology. 
NOTE: discrete dural metastases are permitted. 
Subjects with previously treated brain metastases (with no lesion measuring ≥1 cm in 
longest diameter on gadolinium-enhanced MRI at the time of evaluation for the study) may 
participate provided they are neurologically stable as defined by (all the following need to 
be met): 
i. 
no evidence of progression by imaging and any neurologic symptoms have 
returned to baseline 
ii. 
no use of steroids and anti-convulsants for at least 7 days prior to IRPP 
administration. 


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iii. 
no clinically significant mass effect, haemorrhage, midline shift, or 
impending herniation on baseline brain imaging. 
iv. 
no significant focal neurologic signs and/or symptoms that would necessitate 
radiation therapy or surgical decompression in the judgment of the treating 
clinician. 
(3a) centrally located lung tumours that show radiological evidence (CT or MRI) of 
either:  
(i) cavitation or necrosis, or,  
(ii) focal invasion or major blood vessels. 
(4a) Subjects had received chemotherapy within the previous 4 weeks or had not 
recovered from adverse events due to chemotherapy. Additional exclusion criteria 
were previous hemibody external radiotherapy, systemic radiotherapy with 
radioisotopes within the previous 24 weeks. 
(5) 
previous chemotherapy within a cycle interval, curative radiotherapy within 4 weeks 
or palliative radiotherapy within 7 days prior to IRPP administration. 
(6) 
prior treatment with any other investigational medicinal product (IMP) within five 
half-lives of the previous IMP or within 2 weeks, if the previous compound is a 
mechanism-based 
molecularly 
targeted 
agent 
whose 
half-life 
is 
not 
well-characterised and toxicities have not resolved from Grade 2 or higher prior to 
IRPP administration.  
(7) 
any unresolved NCI-CTCAE Grade 2 or higher toxicity (except alopecia and Grade 
2 platinum-therapy related neuropathy) from previous antitumour treatment and/or 
medical/surgical procedures/interventions.  
(8) 
nephrectomy, renal transplant or concomitant nephrotoxic therapy putting the 
subject at high risk of renal toxicity during the study as assessed by the investigator. 
(9a) history of major thrombotic or clinically relevant major bleeding event in the past 
6 months putting the subject at high risk of bleeding during the study as assessed by 
the investigator (international normalisation ratio (INR) or prothrombin time 
≥1.5xULN, unless the subject is receiving anticoagulant therapy). 
(10) prior major surgery from which the subject has not sufficiently recovered. 
(11a) known allergy to contrast medium product or 177Lu, DOTA, OPS200, OPS301 or 
any of the excipients of 177Lu-OPS201, as well as to 68Ga-OPS202 or its excipient. 
(12a) any condition that precludes the proper performance of PET and/or SPECT scans, 
CT scans and/or MRI: 
(a) 
subjects who are not able to tolerate the CT contrast agent.  
(b) 
subjects with metal implants or joint prosthesis (depending on the location, if 
interferes with the PET and/or CT analysis). 
Notes: Subjects with metal implants cannot undergo MRI; Subjects with 
medical devices in situ, which do not overlap with the Volume of Interest in 
the opinion of the radiologist or dosimetrist or are not expected to interfere 
with the imaging or interpretation, can be included. The dosimetry team 
should be informed of the presence of a device in situ. 
(c) 
or any other objects that might interfere with the PET and/or CT analysis. 
(d) 
subjects unable to raise arms for prolonged imaging purposes.  
(e) 
subjects unable to lie still for the entire imaging time. 


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(f) 
subjects weighing greater than 130 kg (287 lb). 
(13a) subject with history of other malignancy within the past 3 years with the following 
exceptions: malignancy treated with curative intent and with no active disease and 
has not received chemotherapy for the last 3 years for these conditions; adequately 
treated non-melanoma skin cancer without evidence of disease; adequately treated 
cervical carcinoma in situ without evidence of disease; adequately treated breast 
ductal carcinoma in situ without evidence of disease; prostatic intraepithelial 
neoplasia without evidence of prostate cancer at the time of enrolment; adequately 
treated superficial or in situ carcinoma of the bladder without evidence of disease. 
(14) other investigational procedures while participating in this study. 
(15a) clinically significant abnormalities on electrocardiogram (ECG) at screening 
including QTcF >450 msec for males or >470 msec for females at screening or 
subjects who cannot tolereate high volume load. 
(16) pregnant or lactating female. Female subject of childbearing potential who is 
unwilling to use acceptable method(s) of effective contraception during study 
treatment and through 6 months after the last dose of 177Lu-OPS201.  
OR  
male subject who is unwilling to use acceptable method of effective contraception 
during treatment and through 6 months after the last dose of 177Lu-OPS201. 
(17) subject likely not to be available to complete all protocol-required study visits or 
procedures and/or to comply with all the required study procedures to the best of the 
subject and investigator’s knowledge. 
(18a) history or evidence of psychiatric, substance abuse (except for tobacco smoking), or 
any other clinically significant disorder, condition or disease (including active 
known infection with human immunodeficiency virus (HIV) requiring systemic 
treatment, or known acquired immunodeficiency syndrome (AIDS)-related illness, 
or known active hepatitis B or C infection) that, in the opinion of the investigator or 
sponsor medical, if consulted, would pose a risk to subject safety or interfere with 
the study evaluation, procedures or completion. 
Notes: Female subjects must be either postmenopausal (any female who is age ≥55 years 
with cessation of menses for 12 or more months or less than 55 years and no spontaneous 
menses for at least 2 years or less than 55 years and no spontaneous menses within the 
past 1 year with postmenopausal gonadotropin and oestradiol levels) or permanently 
sterile, can enter the trial without taking specific contraceptive measures. Female subjects 
of childbearing potential must have a negative pregnancy test upon entry into this study 
and agree to use a highly effective method of contraception from Screening until 6 months 
after the last dose of 177Lu-OPS201; 
Highly effective methods of contraception that result in a low failure rate (i.e., <1% per 
year) when used consistently and correctly include combined (oestrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, or transdermal), progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, or implantable), intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, vasectomised partner, or sexual 
abstinence;  
True abstinence, when in line with the preferred and usual lifestyle of the subject, is 
considered a highly effective method only if defined as refraining from heterosexual 


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intercourse during the entire period of study participation and for 6 months after the last 
dose of 177Lu-OPS201. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical study and the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g. calendar, ovulation, symptothermal, and post-ovulation method) 
and withdrawal are not acceptable methods of contraception; and 
Male subjects must be either surgically sterile or agree to use a double-barrier 
contraception method from Screening until 6 months after the last dose of 177Lu-OPS201. 
Egg cell and sperm donation are not permitted during the contraception period (up to 2 
years after the study). 
Test product, dose, mode of administration: 
Investigational Imaging Product (IIP), 68Ga-OPS202:  
The IIP is a solution for injection prepared prior to administration from a radiolabelling 
"cold" kit and a 68Ge/68Ga-generator. The radiolabelling kit consists of two vials; one 
containing lyophilised OPS202 and excipients and a second containing a solution for 
reconstitution. After QC sampling, QC testing and release, the volume to be administered 
to the subject is withdrawn from the IIP vial, containing up to 45 μg OPS202. This volume 
is determined to obtain the target radioactivity at the time of administration, considering 
the decay of 68Ga. All subjects will receive a single dose of IIP (one at screening and 
another at EOCT), with 68Ga radioactivity of 150 to 200 MBq, injected intravenously. 
Screening administrations: 
To determine tumour uptake at Screening visit, subjects will receive a single i.v. injection 
of IIP (68Ga-OPS202) administered over 1 minute prior to a PET/CT scan. 
EOCT administrations: 
To monitor tumour uptake at EOCT visit, subjects will receive a single i.v. injection of IIP 
(68Ga-OPS202) administered over 1 minute prior to a PET/CT scan. 
Investigational Radiopharmaceutical Product (IRPP), 177Lu-OPS201:  
The IRPP is a 20-mL solution for infusion with OPS201 dose of either 300 μg (±15%) or 
700 μg (±15%) and radioactivity of 3 to 7.4 GBq 177Lu-OPS201. All subject will receive a 
loading dose ranging from 4.5 to 7.4 GBq (±10%) and a maintenance dose ranging from 3 
to 5.5 GBq (±10%), injected intravenously. 
Therapeutic administrations: 
The IRPP will be administered once per cycle by an i.v. infusion at a rate of 10 mL/h over 
120 minutes for 177Lu OPS-201. 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. For renal protection purpose, the IRPP will be co-infused with amino acid 
solution. The amino acid solution must be administered intravenously over 4 hours (or up 
to 6 hours in exceptional cases). The infusion of the amino acid solution should start 30 
minutes prior to start of IRPP. Premedication with antiemetics should be administered 30 
minutes before the start of the amino acid solution. 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. 
Note: The rate of infusion can be adjusted based on recommendations from DRB. 


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Duration of treatment: 177Lu-OPS201 will be administered once per cycle over a period 
of two cycles. A treatment cycle is defined as the timeframe of 6 (up to 10) weeks between 
two administrations or the timeframe of 6 weeks following the last administration. In case 
of logistical issues, the cycle could be extended by up to additional 2 weeks. 
Dosing period can be extended up to 36 weeks in case subjects receive up to four additional 
cycles. 
Reference therapy, dose and mode of administration:  
Not applicable. 
Criteria for evaluation and Endpoints: 
Criteria for evaluation 
See Schedule of Assessment in the protocol. 
Endpoints 
Primary endpoint 
Phase I: 
The primary endpoint is the MTCA or the MACA if the MTCA is not identified during the 
phase I. The primary variables determining the MTCA will be the incidence of DLTs and 
the cumulative organ absorbed doses (Gy) during two cycles of treatment. The DLT 
assessment period for the determination of the primary endpoint starts from the first 
administration of 177Lu-OPS201 and ends 6 weeks after the second administration. 
Phase II: 
The primary endpoint is ORR over the two treatment cycles of the core study measured by 
the ICL. Objective response is defined as the sum of PR and CR measured by CT or MRI 
using RECIST version 1.1. Tumour response assessments are performed 6 weeks after each 
administration of 177Lu-OPS201 during the core study or at the time of occurrence of first 
clinical signs of disease progression as determined by the investigator. All images will be 
sent to an ICL for evaluation and confirmation of response. 
Secondary endpoints 
Phase I: 
Pharmacokinetics, biodistribution and dosimetry 
For PK, biodistribution and dosimetry of 177Lu-OPS201, the endpoints are:  
• 
Maximum observed concentration (Cmax), time to maximum observed concentration 
(tmax), maximal uptake (%), area under the curve (AUC) at the target lesions, 
discernible organs and blood and elimination half-life (t½) of radioactivity 
concentrations in blood. 
• 
Highest absorbed dose, Specific absorbed dose to the target lesions (Gy/GBq), 
Specific absorbed dose per organ (Gy/GBq) and Cumulative absorbed organ doses 
(Gy). 
For PK of OPS201, the endpoints are: 
• 
Pharmacokinetic parameters including, but not limited to, Cmax, AUC, t1/2, total 
plasma clearance (CL), apparent volume of distribution (Vd), cumulative amount (of 
unchanged drug) excreted into the urine (Ae), renal clearance, as measured in plasma 
and urine at defined timepoints. 


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Pharmacodynamic/efficacy 
• 
Mean change (%) in tumour volume at 6 weeks after each 177Lu-OPS201 
administration compared to Screening as assessed by CT or MRI: 
- 
RECIST version 1.1 (tumour size is defined as the sum of the diameters of the 
target lesion in subjects who received 177Lu-OPS201) 
- 
volumetric CT 
• 
PFS as determined from start of study treatment until occurrence of tumour 
progression or death.  
• 
BOR defined as the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest 
measurements recorded since the treatment started). 
• 
OS at 1-year and 2-year follow-up as determined from start of study treatment until 
occurrence of death of any cause. 
• 
Quantitative changes (SUV normalised by lean body mass (SUL)max and SULmean) 
in tumour-to-background 18F-FDG-PET uptake using PERCIST version 1.0, from 
Screening to 6 weeks after second 177Lu-OPS201 administration (second cycle). 
• 
Correlation between tumour uptake on 68Ga-OPS202 PET/CT (assessed based on 
SUVmax and SUVmean) at screening with tumour response to 177Lu-OPS201 therapy 
from Screening to 6 weeks after second 177Lu-OPS201 administration (second 
cycle). 
• 
Correlation between the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 
on PET/CT images and the uptake on 177Lu-OPS201 SPECT/CT 
• 
Changes in tumour uptake (assessed based on SUVmax and SUVmean) on 
68Ga-OPS202 PET/CT from Screening to 6 weeks after second 177Lu-OPS201 
administration (second cycle) as compared to clinical response and BOR.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging using RECIST by subject-based 
analysis.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging using mGa-RECIST by subject-
based analysis.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by subject-based, organ-based and 
lesion-based analysis compared to standard-of-truth (SOT) of ceCT (or ceMRI).  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by both organ-based and lesion-
based analysis compared to SOT of 177Lu-OPS201 SPECT/CT. 
Phase II: 
Efficacy 
All the below endpoints will be calculated per cohorts. All imaging endpoints will be 
assessed by blinded independent readers managed by the ICL. 
• 
Durable response rate (DRR: CR or PR lasting ≥6 months)  
• 
PFS as determined from start of study treatment until occurrence of tumour 
progression or death. 
• 
Other response endpoints (same timepoints as for PFS): 
- 
disease control rate (DCR) 
- 
time to progression (TTP)  


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- 
time to response (TTR) 
- 
duration of response (DoR) 
• 
Mean change (%) in tumour volume at 6 weeks after each 177Lu-OPS201 
administration (each cycle) compared to baseline, as assessed by volumetric 
CT/MRI. 
• 
OS at 1-year and 2-year follow-up as determined from start of study treatment until 
occurrence of death of any cause. 
• 
Quantitative changes (SUV normalised by lean body mass (SUL)max and SULmean) 
in tumour-to-background 18F-FDG-PET uptake using PERCIST version 1.0, from 
Screening to 6 weeks after second 177Lu-OPS201 administration (second cycle). 
• 
Correlation between tumour uptake on 68Ga-OPS202 PET/CT (assessed based on 
SUVmax and SUVmean) at screening with tumour response to 177Lu-OPS201 therapy 
from Screening to 6 weeks after second 177Lu-OPS201 administration (second 
cycle). 
• 
Correlation between the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 
on PET/CT images and the uptake on 177Lu-OPS201 SPECT/CT 
• 
Change in 68Ga-OPS202 uptake on PET scan after the second 177Lu-OPS201 
administration (second cycle) as assessed by SUVmax and SUVmean in subjects 
screened for 177Lu-OPS201 treatment as compared to clinical response and ORR. 
• 
Proportion of subjects with sstr2-positive tumour lesions by 68Ga-OPS202 PET/CT 
scans as assessed by the identification of avid lesions in subjects screened for 
177Lu-OPS201 treatment at baseline.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging using RECIST by subject-based 
analysis.  
• 
Diagnostic sensitivity of 
68Ga-OPS202 imaging using mGa-RECIST by 
subject-based analysis.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by subject-based, organ-based and 
lesion-based analysis compared to SOT of ceCT (or ceMRI).  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by both organ-based and 
lesion-based analysis compared to SOT of 177Lu-OPS201 SPECT/CT. 
Subject Reported Outcomes 
• 
Changes in health-related quality of life scores from baseline to EOCT measured by 
EuroQoL 5-dimension 5-level (EQ-5D-5L) and The European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC 
QLQ-C30). 
Safety Endpoints and Evaluations 
• 
Safety and tolerability measured by the type, nature, severity, expectedness and 
frequency of AEs overall and per grade according to the current version of the 
NCI-CTCAE (version 5.0) and significant laboratory abnormalities. 
Pharmacokinetics, biodistribution and dosimetry endpoints and measurement timepoints 
for phase II will be defined according to the phase I results. 


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Exploratory endpoints  
Phase I/II: 
Biomarkers 
• 
Association between the uptake on 68Ga-OPS202 PET/CT with sstr2 expression on 
tumours as determined by IHC. 
• 
Change in renal safety biomarkers compared to baseline. 
• 
Change from baseline in tumour microenvironment, transcriptomics, DNA repair, 
gene mutations and other disease markers of interest. 
• 
Change from baseline in DNA repair capacity in blood. 
Biobanking 
The exploratory endpoint comprises biobanking of samples for future analysis, among 
subjects who consent. Analysis of additional biomarkers from the biobank samples will be 
performed outside the scope of the main study and reported separately. 
Serum, cfDNA and whole blood ribonucleic acid (RNA) samples will be collected on 
Day 1 (or Day -1) of Cycle 1, on Day 1 of Cycle 2 and at EOCT or early withdrawal (EW) 
visit.   
Statistical Methods: 
Data from phase I and phase II will be analysed and reported separately.  
Statistical methodology in phase I 
All safety, PK and pharmacodynamics data will be tabulated.  
Safety 
Continued monitoring of DLTs and toxicities will be performed. At the time of each DRB, 
the available safety data, including DLTs, toxicities, physiological parameters, ECG, 
laboratory test results and selected organ absorbed radiation doses (kidney and BM) will 
be tabulated to guide the radioactivity selection during the dose escalation. 
Biodistribution, dosimetry, pharmacokinetics of 177Lu-OPS201 
Descriptive summaries of pharmacokinetic parameters, absorbed organ/lesion dose will be 
presented for each cohort over the treatment period. 
Pharmacokinetics of OPS201 
If OPS201 levels are measurable in plasma and urine, PK parameters of OPS201 will be 
derived using a non-compartmental approach. An attempt to build an integrated model 
taking into account PK, dosimetry, anti-tumour activity and safety data will be made. 
Pharmacodynamics of 177Lu-OPS201 
Preliminary anti-tumour activity and BOR will be tabulated. Tumour response will be 
evaluated by the site investigator. Independent review of tumour assessment may be 
requested at the discretion of the sponsor. In both cases, response and progression will be 
evaluated using the revised RECIST guidelines and volumetric CT measurement guidance. 
Only subjects with measurable disease at baseline, who have received at least two 
administrations of 177Lu-OPS201 and reached the end of Cycle 2 or EOCT visit will be 
considered evaluable for response. 
Tumour response is assessed locally in the phase I and standardised ceCT/MRI images are 
collected for the purpose of central reading in case it is requested by health authorities. 


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Similar analyses to the cohorts with 300 μg (±15%) peptide mass dose will be conducted 
for the cohorts with the higher peptide mass dose (700 μg (±15%)). 
Monitoring of PFS for 2 years after the EOCT Visit (based on RECIST v1.1 status). 
Statistical methodology in phase II 
Efficacy / Futility analysis 
For phase II cohorts, tumour response will be assessed in imaging modalities of CT or MRI 
scans after 6 weeks of 177Lu-OPS201 administration of Cycles 1 and 2 of the core treatment 
period and during the 24-month follow-up period every 12 weeks. Images will be reviewed 
by an independent central review core laboratory. Objective Response Rates and other 
efficacy parameters will be tabulated. Objective response rate over the two treatment cycles 
of the core study will be calculated combining the number of subjects with a BOR of 
confirmed CR or PR per RECIST version 1.1. A similar analysis will be conducted using 
volumetric CT data. 
For the Simon's optimal two-stage design, the hypotheses that will be tested for each cohort 
are: H0: ORR≤ORR0 versus the alternative H1: ORR>ORR0 where ORR is the true 
objective response rate following 177Lu-OPS201 treatment that warrants further clinical 
development, and ORR0 is the minimum objective response rate to be excluded from 
further clinical development. The thresholds for ORR and ORR0 may be updated based on 
results from phase I and the advances in scientific knowledge. 
ORR will be analysed at the end of Stage 1 (6 weeks after the second 177Lu-OPS201 
administration (Cycle 2) of the core treatment period of the last evaluable subject of the 
Stage 1 cohort for each type of cancer). If the observed number of responders is below a 
predefined threshold, the respective study cohort will be stopped for futility. Otherwise, 
additional subjects will be treated to complete the planned enrolment. At the end of Stage 2, 
the null hypothesis will be rejected depending on the total observed number of responders 
based on a predefined threshold. 
At the end of phase II, descriptive summaries will be provided for all primary and 
secondary efficacy endpoints. For the primary endpoint, final analysis will take into 
account the sequential sampling procedure of the design and the underlying binomial 
distribution assumed by the Simon's optimal two-stage design. 
Sample size justification (treatment with 177Lu-OPS201) 
The sample size in phase II is calculated using Simon's optimal two-stage design based on 
the ORR rate (CR + PR) following 177Lu-OPS201 treatment.  
For the SCLC cohort, with 69 response evaluable subjects, there will be 90% power to test 
a null hypothesis ORR rate of 23% and an alternative hypothesis ORR rate of 40% at 
one-sided significance level of α=0.05. The first stage consists of 29 subjects. If seven 
responses or less are seen in the first 29 subjects then the trial is stopped. Otherwise accrual 
continues to a total of 69 response evaluable subjects.  
For the BC cohort, with 87 response evaluable subjects, there will be 90% power to test a 
null hypothesis ORR rate of 12% and an alternative hypothesis ORR rate of 25% at 
one-sided significance level of α=0.05. The first stage consists of 33 subjects. If four 
responses or less are seen in the first 33 subjects then the trial is stopped. Otherwise accrual 
continues to a total of 87 response evaluable subjects. 
Safety 
Descriptive statistics will be calculated for the safety parameters. No formal statistical 
analyses of safety data are planned. 


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Biodistribution, radiation dosimetry, PK of 177Lu-OPS201 and OPS201 
Analysis will be performed as for phase I and adjusted according to the phase I results. 
 


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TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...................................................................................... 3 
COORDINATING INVESTIGATOR’S AGREEMENT..................................................... 4 
SYNOPSIS ................................................................................................................................ 7 
TABLE OF CONTENTS ....................................................................................................... 27 
LIST OF ABBREVIATIONS ................................................................................................ 34 
1 
BACKGROUND INFORMATION ............................................................................ 40 
1.1 
Introduction ................................................................................................................... 40 
1.2 
Name and Description of Investigational Imaging/Medicinal Products .................. 40 
1.3 
Auxiliary Medicinal Product ....................................................................................... 41 
1.4 
Findings from Nonclinical Studies .............................................................................. 41 
1.4.1 
In Vitro Pharmacology ............................................................................... 41 
1.4.1.1 
68Ga-OPS202 ............................................................................................... 41 
1.4.1.2 
177Lu-OPS201 ............................................................................................... 42 
1.4.2 
In Vivo Pharmacology ................................................................................ 42 
1.4.3 
Toxicology ................................................................................................... 42 
1.4.3.1 
68Ga-OPS202 ............................................................................................... 42 
1.4.3.2 
177Lu-OPS201 ............................................................................................... 43 
1.4.4 
Pharmacokinetic Properties of Unlabelled OPS201 .................................. 43 
1.4.5 
Biodistribution and Dosimetry of Radiolabelled 177Lu-OPS201 ............... 43 
1.5 
Findings from Clinical Studies .................................................................................... 44 
1.5.1 
68Ga-OPS202 ............................................................................................... 44 
1.5.1.1 
Compassionate Use in NET Subjects ........................................................... 44 
1.5.1.2 
Study OPS-B-001 in GEP-NET Subjects ..................................................... 44 
1.5.2 
177Lu-OPS201 .............................................................................................. 45 
1.5.2.1 
Investigator Sponsored Pilot Study in NET Subjects ................................... 45 
1.5.2.2 
Investigator Sponsored Study in NET Subjects ............................................ 46 
1.5.2.3 
Ipsen Sponsored Study in NET Subjects ...................................................... 47 
1.6 
Known and Potential Risks and Benefits to Human Subjects .................................. 48 
1.7 
Selection of Investigational Radiopharmaceutical Products and Dosages .............. 50 
1.7.1 
68Ga-OPS202 ............................................................................................... 50 
1.7.2 
177Lu-OPS201 .............................................................................................. 51 
1.7.2.1 
Treatment Schedule ...................................................................................... 51 
1.7.2.2 
Dosing Interval of 177Lu-OPS201 ................................................................ 51 
1.7.2.3 
Starting Cumulative Radioactivity of 177Lu-OPS201 ................................... 52 
1.7.2.4 
Maximum Cumulative Radioactivity of 177Lu-OPS201 ................................ 53 
1.7.2.5 
Peptide Mass Dose of 177Lu-OPS201 ........................................................... 53 
1.8 
Compliance Statement .................................................................................................. 54 


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1.9 
Population to Be Studied .............................................................................................. 54 
1.9.1 
Disease ......................................................................................................... 55 
1.9.2 
Sstr2 Expression in Cancer ........................................................................ 56 
2 
PURPOSES OF THE STUDY AND STUDY OBJECTIVES .................................. 58 
2.1 
Rationale and Purpose of the Study ............................................................................ 58 
2.2 
Study Hypotheses .......................................................................................................... 59 
2.3 
Study Objectives ........................................................................................................... 59 
2.3.1 
Primary Objectives ...................................................................................... 59 
2.3.2 
Secondary Objectives .................................................................................. 59 
2.3.3 
Exploratory Objectives ................................................................................ 60 
3 
STUDY DESIGN ........................................................................................................... 61 
3.1 
General Design and Study Schema ............................................................................. 61 
3.1.1 
Study Sites ................................................................................................... 61 
3.1.2 
Number of Subjects ..................................................................................... 61 
3.1.3 
Pre-treatment Period ................................................................................... 62 
3.1.4 
Treatment Period - Phase I ......................................................................... 62 
3.1.4.1 
Radioactivity Escalation .............................................................................. 62 
3.1.4.2 
Peptide Mass Dose Evaluation .................................................................... 66 
3.1.5 
Treatment Period - Phase II ....................................................................... 67 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 68 
3.2.1 
Primary Endpoints and Evaluations .......................................................... 68 
3.2.1.1 
Phase I ......................................................................................................... 68 
3.2.1.2 
Phase II ........................................................................................................ 68 
3.2.2 
Secondary Endpoints and Evaluations ...................................................... 68 
3.2.2.1 
Phase I ......................................................................................................... 68 
3.2.2.2 
Phase II ........................................................................................................ 69 
Safety Endpoints and Evaluations ................................................................................ 70 
3.3 
Exploratory Endpoints (Phase I/II) ............................................................................. 70 
3.3.1 
Biomarkers .................................................................................................. 70 
3.3.2 
Biobanking .................................................................................................. 70 
3.4 
Randomisation and Blinding ....................................................................................... 71 
3.5 
Maintenance of Randomisation and Blinding ............................................................ 71 
3.6 
Study Treatments and Dosage ..................................................................................... 71 
3.6.1 
Investigational Imaging Product (IIP): 68Ga-OPS202 .............................. 71 
3.6.2 
Investigational Radio-Pharmaceutical Product (IRPP): 177Lu-OPS201 .. 72 
3.7 
Study Duration .............................................................................................................. 72 
3.8 
Stopping Rules and Discontinuation Criteria ............................................................ 73 
3.8.1 
Individual Discontinuation Rules .............................................................. 73 
3.8.1.1 
Definition of Dose Limiting Toxicity (Dose Escalation) .............................. 74 
3.8.1.2 
Procedures for Subject Discontinuation ...................................................... 75 


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3.8.1.3 
Replacement Rules ....................................................................................... 75 
3.8.2 
Discontinuation of a Cohort or a Site or Study Termination .................... 75 
3.8.3 
Study Stopping Rules .................................................................................. 75 
3.9 
Source Data Recorded on the Case Report Form ...................................................... 76 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 77 
4.1 
Eligibility Criteria for 68Ga-OPS202 Imaging ............................................................ 77 
4.1.1 
Inclusion Criteria ........................................................................................ 77 
4.1.2 
Exclusion Criteria ....................................................................................... 78 
4.2 
Rationale for Inclusion/Exclusion Criteria ................................................................. 81 
4.3 
Subject Withdrawal Criteria and Procedures ........................................................... 81 
5 
STUDY PROCEDURES .............................................................................................. 83 
5.1 
Study Schedule .............................................................................................................. 83 
5.2 
Study Visits .................................................................................................................... 90 
5.2.1 
Procedures for Screening and Enrolment ................................................. 90 
5.2.2 
Procedures Before Study Treatment (Day 1 of Each Treatment Cycle, 
Pre-Dose) ..................................................................................................... 90 
5.2.3 
Procedures During Study Treatment (Day 1 Post Dose of Each 
Treatment Cycle) ......................................................................................... 90 
5.2.4 
Procedures After Study Treatment ............................................................. 91 
5.2.4.1 
End of Study Visit (EOCT, EOAC or Early Withdrawal Visit) .................... 91 
5.2.4.2 
Follow up Visits ........................................................................................... 91 
5.2.5 
Unscheduled Visits ...................................................................................... 91 
5.3 
Tumour Imaging and Dosimetry ................................................................................. 91 
5.4 
Laboratory Assessments ............................................................................................... 92 
6 
IMAGING AND TREATMENT OF SUBJECTS ..................................................... 94 
6.1 
Investigational 
Imaging/Medicinal 
Product 
Preparation 
Storage 
and 
Accountability ............................................................................................................... 94 
6.1.1 
Investigational Imaging/Radiopharmaceutical Product Storage and 
Security ........................................................................................................ 94 
6.1.1.1 
68Ga-OPS202 ............................................................................................... 94 
6.1.1.2 
177Lu-OPS201 ............................................................................................... 94 
6.1.1.3 
Spillage ........................................................................................................ 94 
6.1.2 
Investigational Imaging/Radiopharmaceutical Product Preparation ...... 94 
6.1.2.1 
68Ga-OPS202 ............................................................................................... 94 
6.1.2.2 
177Lu-OPS201 ............................................................................................... 95 
6.1.3 
Investigational Imaging/Radiopharmaceutical Product Accountability .. 95 
6.2 
Investigational Imaging/Radiopharmaceutical Product Administered ................... 95 
6.2.1 
68Ga-OPS202 ............................................................................................... 96 
6.2.2 
177Lu-OPS201 .............................................................................................. 96 
6.3 
Concomitant Medication/Therapy .............................................................................. 97 
6.3.1 
Amino acid infusion: renal protection ....................................................... 98 


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6.3.2 
Antiemetic .................................................................................................... 99 
6.3.3 
Optional: Loop Diuretic .............................................................................. 99 
6.4 
Lifestyle Restrictions/Recommendations .................................................................... 99 
6.5 
Procedures for Monitoring Subject Compliance ....................................................... 99 
7 
ASSESSMENT OF PHARMACODYNAMICS/EFFICACY ................................. 100 
7.1 
Phase I .......................................................................................................................... 100 
7.1.1 
Secondary Tumour Activity Endpoints and Evaluations ........................ 100 
7.1.2 
Methods and Timing of Assessing, Recording and Analysing Anti-
Tumour Activity Data ................................................................................ 101 
7.1.2.1 
Imaging Assessments and Evaluations ...................................................... 101 
7.2 
Phase II ........................................................................................................................ 103 
7.2.1 
Primary Efficacy Endpoint and Evaluations ........................................... 103 
7.2.2 
Secondary Efficacy Endpoints and Evaluations ...................................... 103 
7.2.3 
Methods and Timing of Assessing, Recording and Analysing Efficacy 
Data ............................................................................................................ 105 
7.2.3.1 
Patient Reported Outcomes ....................................................................... 105 
8 
ASSESSMENT OF SAFETY ..................................................................................... 106 
8.1 
Adverse Events ............................................................................................................ 106 
8.1.1 
Definition of an Adverse Event ................................................................ 106 
8.1.2 
Categorisation of Adverse Events ............................................................. 106 
8.1.2.1 
Intensity Classification ............................................................................... 106 
8.1.2.2 
Causality Classification ............................................................................. 107 
8.1.2.3 
Assessment of Expectedness ....................................................................... 107 
8.1.2.4 
Laboratory Test Abnormalities .................................................................. 107 
8.1.2.5 
Abnormal Physical Examination Findings ................................................ 107 
8.1.2.6 
Other Investigation Abnormal Findings .................................................... 107 
8.1.3 
Adverse Events of Special Interest ........................................................... 107 
8.1.4 
Recording and Follow up of Adverse Events ........................................... 108 
8.1.4.1 
Reporting of Adverse Events ...................................................................... 108 
8.1.5 
Reporting of Serious Adverse Events ....................................................... 109 
8.1.6 
Suspected Unexpected Serious Adverse Reactions .................................. 110 
8.1.7 
Pregnancy .................................................................................................. 110 
8.1.8 
Deaths ........................................................................................................ 111 
8.1.9 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events ........................................................................................................ 111 
8.1.10 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ..... 111 
8.2 
Clinical Laboratory Tests .......................................................................................... 111 
8.2.1 
Haematology .............................................................................................. 111 
8.2.2 
Blood Biochemistry ................................................................................... 111 
8.2.3 
Urinalysis ................................................................................................... 112 


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8.2.4 
Pregnancy Test .......................................................................................... 112 
8.2.5 
Other Clinical Laboratory Tests ............................................................... 112 
8.2.6 
Hypothalamic-Pituitary-Adrenal Axis Biomarkers ................................. 112 
8.2.7 
Specific Renal Safety Biomarkers ............................................................ 112 
8.2.8 
Specific Pancreatic Function Biomarker ................................................. 113 
8.2.9 
Testicular Function Biomarkers .............................................................. 113 
8.3 
Physical Examination ................................................................................................. 113 
8.4 
Vital Signs .................................................................................................................... 113 
8.5 
Electrocardiography ................................................................................................... 113 
9 
ASSESSMENTS OF PHARMACOKINETICS ....................................................... 114 
9.1 
Pharmacokinetics of 177Lu-OPS201 .......................................................................... 114 
9.1.1 
Blood Sample Collection ........................................................................... 114 
9.1.2 
Urine Sample Collection ........................................................................... 114 
9.2 
Nuclear Medicine Imaging for Dosimetry ................................................................ 114 
9.3 
Pharmacokinetics of OPS201 ..................................................................................... 115 
9.3.1 
Blood Sample Collection ........................................................................... 115 
9.3.2 
Urine Sample Collection ........................................................................... 116 
10 
EXPLORATORY BIOMARKERS AND BIOBANKING ..................................... 117 
10.1 DNA-DSB in Peripheral Lymphocytes ..................................................................... 117 
10.2 DNA Repair Capacity in Peripheral Lymphocytes ................................................. 117 
10.3 Germinal Mutation in Blood ...................................................................................... 117 
10.4 Tumour Biopsy ............................................................................................................ 117 
10.4.1 
Tumour Micro-environment and Other Markers of Interest .................. 118 
10.4.2 
DNA Repair Capacity in Tumour Tissue ................................................. 118 
10.5 Biobanking ................................................................................................................... 118 
11 
STATISTICS ............................................................................................................... 120 
11.1 Analyses Populations .................................................................................................. 120 
11.1.1 
Populations Analysed ................................................................................ 121 
11.1.2 
Reasons for Exclusion from the Analyses ............................................... 121 
11.2 Statistical Methodology for Phase I .......................................................................... 121 
11.2.1 
Sample Size Determination ....................................................................... 121 
11.2.2 
Significance Testing and Estimations ...................................................... 121 
11.2.3 
Statistical Methods .................................................................................... 121 
11.2.3.1 
Demographic and Other Baseline Characteristics .................................... 122 
11.2.3.2 
Pharmacokinetic Data ............................................................................... 122 
11.2.3.3 
Radiation Dosimetry of 177Lu-OPS201: ..................................................... 122 
11.2.3.4 
Pharmacodynamics and Efficacy Evaluation ............................................ 123 
11.2.3.5 
Safety Evaluation ....................................................................................... 123 
11.2.3.6 
Maximum Tolerated Single and Cumulative Activity ................................ 124 
11.2.3.7 
Interim Analyses ......................................................................................... 124 


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11.3 Statistical Methodology for Phase II ......................................................................... 125 
11.3.1 
Sample Size Determination ....................................................................... 125 
11.3.2 
Significance Testing and Estimations ...................................................... 125 
11.3.3 
Statistical/Analytical Methods .................................................................. 125 
11.3.3.1 
Demographic and Other Baseline Characteristics .................................... 126 
11.3.3.2 
Subject Disposition and Withdrawals ........................................................ 126 
11.3.3.3 
Pharmacokinetic Data ............................................................................... 126 
11.3.3.4 
Efficacy Evaluation .................................................................................... 126 
11.3.3.5 
Adjustment for Country/Centre Effect ....................................................... 127 
11.3.3.6 
Safety Evaluation ....................................................................................... 127 
11.3.4 
Subgroup Analyses .................................................................................... 128 
11.3.5 
Interim / Futility Analyses and ISAC Safety Review Committees .......... 128 
12 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................. 130 
13 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 131 
13.1 Protocol Amendments and Protocol Deviations ...................................................... 131 
13.1.1 
Protocol Amendments ............................................................................... 131 
13.1.2 
Protocol Deviations and Exceptions......................................................... 131 
13.2 Information to Study Personnel ................................................................................ 132 
13.3 Study Monitoring ........................................................................................................ 132 
13.4 Investigator’s Regulatory Obligations ...................................................................... 133 
13.5 Audit and Inspection .................................................................................................. 133 
13.6 Data Quality Assurance .............................................................................................. 133 
14 
ETHICS ....................................................................................................................... 134 
14.1 Compliance with Good Clinical Practice and Ethical Considerations .................. 134 
14.2 Informed Consent for Participation in the Study .................................................... 134 
14.2.1 
Optional Informed Consent for Biobanking ............................................ 134 
14.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards .......................................................................................................................... 135 
14.4 Confidentiality Regarding Study Subjects ............................................................... 135 
15 
DATA HANDLING AND RECORD KEEPING ..................................................... 136 
15.1 Data Recording of Study Data ................................................................................... 136 
15.2 Data Management ....................................................................................................... 136 
15.3 Record Archiving and Retention ............................................................................... 137 
16 
FINANCING AND INSURANCE ............................................................................. 138 
16.1 Contractual and Financial Details ............................................................................. 138 
16.2 Insurance, Indemnity and Compensation ................................................................ 138 
17 
REPORTING AND PUBLICATIONS OF RESULTS ........................................... 139 
17.1 Publication Policy ....................................................................................................... 139 
17.2 Clinical Study Report ................................................................................................. 139 
18 
REFERENCES ............................................................................................................ 140 


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19 
LIST OF APPENDICES ............................................................................................ 144 
LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 6 
Table 2 
Number of 177Lu-OPS201 treatment cycles, cumulative radioactivity and 
safety data per subject ........................................................................................ 46 
Table 3 
Toxicology Studies with natLu-OPS201 and OPS201: Estimated Safety 
Margin Study/Species based on Human Equivalent Dose based on Body 
Surface Area ........................................................................................................ 54 
Table 4 
Cohorts and Radioactivity Escalation Plan ...................................................... 64 
Table 5 
Schedule of Assessments – Phase I (Core Treatment Phase) .......................... 84 
Table 6 
Schedule of Assessments – Phase I (Additional Cycles) ................................... 88 
Table 7 
Total Effective Dose (in mSv) per Subject for a Two Cycles Treatment 
Period .................................................................................................................... 92 
Table 8 
Blood Samples Collected at Screening and over First Two Cycles ................. 93 
Table 9 
Secondary Tumour Activity Endpoints and Evaluations in Phase I (Core 
Treatment) ......................................................................................................... 100 
Table 10 
Secondary Efficacy Endpoints and Evaluations in Phase II ......................... 104 
Table 11 
Prior Probability Distribution of MTSA ......................................................... 148 
Table 12 
Prior Probability Distribution of MTCA ........................................................ 148 
Table 13 
Simulated Radioactivity-DLT Probabilities ................................................... 151 
Table 14 
Main Operational Characteristics for the Five Trial Simulation Scenarios 153 
 
LIST OF FIGURES 
Figure 1 
Chemical structure of the radiopharmaceutical product 177Lu-OPS201 ....... 41 
Figure 2 
Individual Bone Marrow Absorbed Doses in Subjects Who Received Two 
Therapeutic Cycles (n=7; image-based method) .............................................. 47 
Figure 3 
Phase I Study Design Scheme (Without Additional Cycles) ............................ 63 
Figure 4 
Phase I Study Design Scheme (With Additional Cycles) ................................. 66 
Figure 5 
Initial Phase I Study Design Including Activity Escalation (in Blue) and 
Peptide Mass Dose Evaluation (in Green) ......................................................... 67 
Figure 6 
Forty Random Observations (Curves) from the Prior Distribution ............ 147 
Figure 7 
Radioactivity versus DLT Rates after Cycle 1 and Cycle 2 Simulation 
Scenarios ............................................................................................................. 151 
Figure 8 
Mean (SD) Sample Size per Single or Cumulative Radioactivity Level for 
the Five Simulation Scenarios .......................................................................... 153 
Figure 9 
Boxplot of Total Number of Subjects During Cycle 1 for the Five Simulation 
Scenarios ............................................................................................................. 154 
Figure 10 Boxplot of Total Number of Subjects During Cycle 2 for the Five Simulation 
Scenarios ............................................................................................................. 154 
Figure 11 Boxplot of Total Number of Cohorts for the Five Simulation Scenarios ..... 155 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
Wording Definition  
Ae 
Cumulative amount (of unchanged drug) excreted into the 
urine 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIDS 
Immunodeficiency syndrome 
ALT 
Alanine aminotransferase 
AMP 
Auxiliary medicinal product 
AST 
Aspartate amino transferase 
AUC 
Area under the curve 
BC 
Breast cancer 
BM 
Bone marrow 
BOR 
Best overall response 
Bq 
Becquerel, SI unit of radioactivity 
CA 
Competent authority 
CDK 
Cyclin-dependent kinase 
ceCT 
Contrast enhanced CT 
ceMRI 
Contrast enhanced MRI 
CI 
Confidence interval  
CFR 
Code of Federal Regulations (United States of America) 
CL 
Total plasma clearance 
Cmax 
Maximum observed concentration 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organisation 
CRP 
C-reactive protein 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria Adverse Event 
CV 
Coefficient of variation 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DNA-DSB 
Deoxyribonucleic acid-double strand breaks 
DOM 
Dosimetry operational manual 


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ABBREVIATION 
Wording Definition  
DoR 
Duration of response 
DOTA 
Tetraxetan (INN), a chemical chelator group 
DRB 
Data review board 
DRR 
Durable response rate 
EANM 
European Association of Nuclear Medicine  
EC 
Ethic committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ED 
Extensive disease 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOAC 
End of additional cycles 
EOCT 
End of core trial 
EORTC QLQ-C30 
The European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30 
EOS 
End of Study 
EQ-5D-5L 
EuroQoL 5-dimension 5-level 
EU 
European Union 
EW 
Early withdrawal 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
GCP 
Good Clinical Practice 
GEP-NET 
Gastroentero-pancreatic neuroendocrine tumours 
GMP 
Good Manufacturing Practice 
GST 
Alpha-glutathione S-transferase 
GSTP1 
Glutathione S transferase P1 
Gy 
Gray, SI unit of absorbed radiation dose 
HCG 
Human chorionic gonadotropin 
HEK cells 
Human embryonic kidney cells 
HER2- 
Human epidermal growth factor receptor 2 negative 
HIV 
Human immunodeficiency virus 
HPLC 
High-performance liquid chromatography 


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ABBREVIATION 
Wording Definition  
HR+ 
Hormone receptor positive 
IAEA 
International Atomic Energy Agency 
IB 
Investigator’s brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form  
ICH 
International Conference on Harmonisation 
ICL 
Imaging core laboratory 
IEC 
Independent ethics committee 
IHC 
Immunohistochemistry 
IIP 
Investigational Imaging Product 
IMP 
Investigational Medicinal Product 
INR 
international normalisation ratio 
IRB 
Institutional review board 
IRC 
Imaging Review Charter 
IRPP 
Investigational radiopharmaceutical product 
IRR 
Infusion related reactions 
ISAC 
Independent safety assessment committee 
ITT 
Intent to treat 
i.v. 
Intravenous 
JR11 
Somatostatin analogue peptide part (see OPS200) 
KIM-1 
Kidney injury molecule-1 
LD 
Limited disease 
MACA 
Maximum administrable cumulative activity 
MCV 
Mean corpuscular volume 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
mL 
Millilitre 
mGa-PERCIST 
Modified gallium PERCIST 
mGA-RECIST 
Modified gallium RECIST 
MRI 
Magnetic resonance imaging 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MTCA 
Maximum administered cumulative activity 


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ABBREVIATION 
Wording Definition  
MTSA 
Maximum tolerated single activity 
MTD 
Maximum Tolerated Dose 
natGa 
 
natLu 
Naturally occurring gallium, composed of the two stable 
isotopes 69Ga and 71Ga 
Naturally occurring lutetium, composed of one stable 
isotope 175Lu (97.4% natural abundance) and one long-lived 
radioisotope 176Lu 
NCI 
National Cancer Institute 
NET 
Neuroendocrine tumours 
NOAEL 
No observed adverse events level 
NOS 
Not otherwise specified 
NSAID 
Non-steroidal anti-inflammatory drug 
OPS200 
Somatostatin analogue peptide part or satoreotide (formally 
known as JR11) 
OPS201 
Somatostatin analogue OPS200 coupled to DOTA 
OPS202 
Somatostatin analogue OPS200 coupled to NODAGA 
OPS301 
Ipsen’s amino acid solution 
ORR 
Objective response rate 
OS 
Overall survival 
PARP 
Poly adenosine diphosphate ribose polymerase 
PERCIST 
Positron emission tomography response criteria in solid 
tumours 
PET 
Positron emission tomography 
PFS 
Progression free survival  
PP 
Per protocol 
PR 
Partial response 
PRO 
Patient reported outcome 
PRRT 
Peptide receptor radionuclide therapy 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred term 
QC 
Quality control 
QoL 
Quality of life 
RBC 
Red blood cell(s) 


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ABBREVIATION 
Wording Definition  
RECIST 
Response evaluation criteria in solid tumours  
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS® 
Statistical Analysis System® 
SD 
Standard deviation 
SCLC 
Small cell lung cancer 
SNMMI 
Society of Nuclear Medicine and Molecular Imaging 
SoC 
Standard-of-care 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
SOT 
Standard-of-truth 
SPECT 
Single Photon Emission CT 
sstr2 
Somatostatin receptors subtype 2 
SUL 
SUV normalised by lean body mass 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUV 
Standardised uptake volume 
t½ 
Elimination half life 
TEAE 
Treatment emergent adverse event 
tmax 
Time to maximum observed concentration 
TSH 
Thyroid stimulating hormone 
TTP 
Time to progression 
TTR 
Time to response 
ULN 
Upper limit of normal 
USA 
United States of America 
Vd 
Apparent volume of distribution 
WBC 
White blood cell(s) 
WHO-DD 
World Health Organisation-Drug Dictionary 
μg 
Microgram 
68Ga 
Gallium-68, positron-emitting isotope of gallium 
68Ga-OPS202 
Study medication; 68Ga-radiolabelled somatostatin 
analogue for diagnostic imaging 
111In 
Indium-111, gamma-emitting isotope of indium 


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ABBREVIATION 
Wording Definition  
177Lu 
 
Lutetium-177, beta- and gamma-emitting isotope of 
lutetium 
177Lu-OPS201 
Study medication; 177Lu-radiolabelled somatostatin 
analogue for PRRT 
 
 
 




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177Lu-OPS201 (satoreotide tetraxetan) is a drug substance consisting of three main components, 
namely the same OPS200, linked to the macrocyclic chelator DOTA (1,4,7,10 
tetraazacyclododecane-1,4,7,10-tetraacetic acid) which chelates the beta emitter lutetium-177 
(177Lu) radioisotope (see Figure 1). It is used for therapeutic application. 
Figure 1 Chemical structure of the radiopharmaceutical product 177Lu-OPS201 
 
A more detailed description of the product is given in Section 3.6. 
1.3 
Auxiliary Medicinal Product 
An amino acid solution, consisting of arginine and lysine, will be co-infused as an auxiliary 
medicinal product (AMP) with 177Lu-OPS201. Its role is to prevent nephrotoxicity during 
PRRT by blocking 177Lu-OPS201 reabsorption. The joint International Atomic Energy Agency 
(IAEA), the European Association of Nuclear Medicine (EANM) and the Society of Nuclear 
Medicine and Molecular Imaging (SNMMI) practical guidance on PRRT in NETs (Bodei 2013) 
recommends for renal protection to infuse a solution containing a 50-g cocktail of lysine and 
arginine (25 g of lysine and 25 g of arginine) diluted in 2 L. The solution should be infused over 
4 hours, starting 30 to 60 minutes before 177Lu-OPS201 administration (see more details in 
Section 6.3.1).  
Sites experienced in PRRT treatment can use Ipsen’s amino acid solution (OPS301, which will 
be provided during the study) or their established amino acid solution, preferably from 
commercial source, if it is covered by the recommendations of the joint IAEA, EANM and 
SNMMI practical guidance on PRRT in NETs (Zaknun 2013). The exact formulation and 
source must be documented in the eCRF. 
1.4 
Findings from Nonclinical Studies 
1.4.1 
In Vitro Pharmacology 
1.4.1.1 
68Ga-OPS202 
Receptor binding affinities of OPS202 and natGa-OPS202 were analysed in sstr2 overexpressing 
human embryonic kidney (HEK) cells. The metal ion in the chelator cage positively influenced 
the receptor binding affinity of the peptide (Fani 2012). The peptide antagonist natGa OPS202 
showed slightly weaker affinity to the sstr2 (half maximal inhibitory concentration (IC50) 
1.2±0.2 nM) compared to the peptide agonist natGa-DOTATATE (IC50 0.2±0.04 nM). In 
saturation experiments, 67Ga-OPS202 demonstrated ability to bind 4- to 6-fold more sites using 




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1.4.3.2 
177Lu-OPS201 
OPS201 and natLu-OPS201 showed high specificity to the targeted sstr2 in a binding profile in 
vitro assay, indicating low risk for off-target effects [Study no. 
. To investigate the 
safety profile of the clinical formulation intended for patients, natLu-OPS201 in OPS201 was 
tested in a single dose minipig study [Study no. 
 and repeated dose rat [Studies no. 
 and 
] studies using intravenous administration. No adverse effect has 
been observed in all investigated parameters of the treated animals. Transient clinical signs in 
minipigs (redness, decreased activity and vomiting immediately after administration) and renal 
findings in rats, both considered as non-adverse, were noted at high safety margins (at least 255 
times the human equivalent dose of 300 μg in human and approximately 106 times the human 
equivalent dose of 700 μg in human). Safety pharmacology investigations and genotoxicity 
studies [Studies no. 
, 
 and 
 did not show any potential safety effect. 
1.4.4 
Pharmacokinetic Properties of Unlabelled OPS201 
Pharmacokinetic and toxicokinetic studies have been performed in Sprague Dawley rats after 
single and repeated intravenous administration of natLu-OPS201 in OPS201. Pharmacokinetic 
profiles were similar between natLu-OPS201 and OPS201, with short elimination half-life (1 to 
3 hours), low plasma clearance and low volume of distribution. Linearity across the tested dose 
range and lack of apparent accumulation of OPS201 and natLu-OPS201 were observed after 
repeated administrations [IPSEN Report no. 
 
and 
]. Similar pharmacokinetic profile was observed in Gottingen Pig after single 
intravenous administration of natLu-OPS201 in OPS201 [IPSEN Report no. 
, 
]. 
1.4.5 
Biodistribution and Dosimetry of Radiolabelled 177Lu-OPS201 
A biodistribution study of 177Lu-OPS201 was investigated in mice bearing sstr2 expressing 
tumours (HEK human sstr2) at different injected doses of peptide mass (10, 200 and 2000 pmol) 
(Nicolas 2017). 177Lu-OPS201 accumulated predominantly in sstr2 expressing tumours and in 
the receptor positive organs such as pancreas, stomach and adrenals. A relatively high 
accumulation was found in the kidneys, as a consequence of urinary excretion. 177Lu-OPS201 
exhibits a higher tumour uptake and a longer tumour residence time compared with 
177Lu-DOTATATE. The mean tumour residence time was 15.6 hours for 177Lu-OPS201 and 
6.4 hours for 177Lu-DOTATATE, based on non–decay-corrected biodistribution data and 
normalised per gram of tumour. The different injected doses of peptide mass (10, 200 and 
2000 pmol, respectively) did not affect significantly the tumour uptake and the 
tumour-to-kidney ratio. On the other hand, the injected peptide dose had a major effect on the 
uptake of the other organs (i.e. tumour-to-liver from 16 to 80 and tumour to bone marrow (BM) 
from 25 to 150, from 10 to 2000 pmol, at 4 hours post-injection). The increased mass dose 
improved the tumour-to-bone marrow uptake ratio suggesting a favourable dosimetry profile at 
higher mass dose.  
Tissue distribution of 177Lu-OPS201 was also evaluated in sstr2 expressing tumour bearing 
mice (human small cell lung cancer H69) at peptide doses of 0.5 μg (300 pmol), 1 μg (600 pmol) 
and 2 μg (1200 pmol) (Dalm 2016a). Injection of 0.5 μg and 1 μg 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 absorbed dose of 1.8±0.7 Gy/MBq after 
injection of 0.5 μg 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 μg of 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI




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study protocol) for the diagnostic imaging of sstr2-positive GEP-NET using PET/CT (Nicolas 
2017). 
Six out of 12 subjects (50.0%) experienced 11 adverse events (AEs), all of which were assessed 
by the investigator as being non-serious. Most of the AEs were mild in intensity and were 
considered by the investigator as unlikely or not related to the Investigational Imaging Product 
(IIP). Three AEs (all Grade 1) in two subjects were assessed as possibly related to 
68Ga-OPS202: eosinophilia, rash and diarrhoea. At the end of the study, rash and diarrhoea were 
reported as resolved. 
The study also showed promising preliminary efficacy results, with the most frequently 
identified lesions being malignant lesions in the liver. In all scans (somatostatin receptor 1-hour 
scan performed within 6 months before start of the study [pre-baseline] and the two 
68Ga-OPS202 dose 1-hour scans), malignant liver lesions were detected in nine subjects. 
Malignant lymph node lesions were identified in seven subjects in the pre-baseline somatostatin 
receptor 1-hour scan and eight subjects in the 68Ga-OPS202 1-hour scans. 
The detection rate of malignant lesions considering all organs/tissues (total) was significantly 
higher in the 68Ga-OPS202 1-hour scans than in the pre-baseline somatostatin receptor 1-hour 
scan (p≤0.016). No significant difference was seen between the pre-baseline somatostatin 
receptor 1-hour scan and the 68Ga-OPS202 1-hour scans with regards to the detection rate of 
malignant lymph node lesions. 
1.5.2 
177Lu-OPS201 
1.5.2.1 
Investigator Sponsored Pilot Study in NET Subjects 
The investigational radiopharmaceutical product (IRPP), 177Lu-OPS201, has already been used 
in a pilot therapeutic study at the University Hospital in Freiburg (Wild 2014). 
This study included four subjects with histologically proven, progressively metastasised 
inoperable NETs and limited treatment options due to chronic Grade 2 or 3 kidney disease. 
These subjects received test injections of 177Lu-OPS201 (150±20 μg, 975±115 MBq) and 
177Lu-DOTATATE (175±15 μg, 1060±75 MBq) and then two to three therapeutic cycles of 
177Lu-OPS201 (105±35 μg, 4.12±1.26 GBq per cycle) with dosing interval of 8 weeks. The 
IRPP (177Lu-OPS201) showed significantly longer intratumoural residence time and higher 
tumour uptake than 177Lu-DOTATATE in all four subjects (between 1.3 and 2.8 times longer 
residence time and between 1.1 and 2.6 times higher tumour uptake), resulting in a 1.7 to 10.6 
times higher tumour dose. The median tumour dose was 7.0 Gy/GBq with 177Lu-OPS201 versus 
2.0 Gy/GBq with 177Lu-DOTATATE. Tumour-to-kidney and tumour-to-bone marrow dose 
ratios were up to 6.2 and 7.2 times higher for 177Lu-OPS201 than for 177Lu-DOTATATE. 
Reversible minor adverse effects of 177Lu-OPS201 were observed. All subjects developed 
reversible Grade 1/2 of leukopenia and/or anaemia and one subject Grade 3 thrombocytopenia, 
which completely recovered within 8 weeks after injection of 177Lu-OPS201 (Table 1). Despite 
the unfavourable initial tumour stage of the subjects, the treatment resulted in partial response 
in two subjects, stable disease in one subject and mixed response in the fourth subject after a 
12 to 15-month follow-up.  


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Table 2 
Number of 177Lu-OPS201 treatment cycles, cumulative radioactivity and safety data per subject  
Subject  
number 
Treatment 
cycle 
number 
Interval 
between cycles 
(weeks) 
Cumulative 
injected 
radioactivity 
(GBq) 
Haematotoxicity 
Grade (highest) 
BM cum 
dose 
(Gy)[a]  
Kidney  
cum dose 
(Gy) 
WBC 
Platelets 
1 
2 
8 
6.1 
2 
0 
0.79 
13.66 
2 
3 
8 
15.2 
1 
3 
1.50 
22.34 
3 
2 
8 
5.9 
2 
0 
0.55 
8.437 
4 
3 
8 
13.7 
0 
0 
1.12 
29.46 
Source: Wild 2014 
Abbreviations: GBq=gigabequerels; Gy=gray; WBC=white blood cell count.  
a BM cum dose: cumulative bone marrow dose (determined by blood-based red-marrow dose methodology). 
1.5.2.2 
Investigator Sponsored Study in NET Subjects 
An investigator study sponsored by Memorial Sloan Kettering Cancer Center (MSKCC), 
New York, United States of America (USA) was also initiated (Reidy 2017, NCT02609737). 
A total of 19 subjects (52% female) with heavily treated NETs and average age of 55 years (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 absorbed 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 contained up to 100 μg 
peptide (Data on file). 
Seven subjects received two therapeutic cycles of 177Lu-OPS201 with cumulative activities 
ranging from 13.28 to 16.65 GBq and the other 12 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 five subjects (26%) 
exhibited Grade 3 leukopenia that reversed to Grade 1 or Grade 0 before the second cycle. By 
contrast, 4/7 subjects were noted to have Grade 4 haematological toxicities (four 
thrombocytopenia and one leukopenia) starting 4 to 6 weeks after the administration of 
177Lu-OPS201 after the second cycle. These Grade 4 toxicities were long lasting and resolved 
to Grade 2 or lower in more than 8 weeks; none of these subjects demonstrated fever, infection, 
bleeding, or renal toxicity. The mean relative BM absorbed dose (image-based method) was 
0.077 Gy/GBq (range: 0.049 to 0.11) and the individual BM absorbed doses ranged from 1.3 to 
1.5 Gy in subjects who showed severe thrombocytopenia whereas it was below 1 Gy in the 
other subjects (Figure 2). 


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Figure 2 Individual Bone Marrow Absorbed Doses in Subjects Who Received Two Therapeutic Cycles 
(n=7; image-based method)  
 
Source: Data on file 
Following these safety events, the study was put on clinical hold and an amendment was 
prepared to reduce the limiting BM absorbed dose to 1 Gy and reduce the administered 
cumulative radioactivity so that the study has now restarted.  
The median tumour absorbed dose in the study was about 7.2 Gy/GBq. Preliminary efficacy 
results indicate that one subject had a complete response (5%), six a partial response (32%), 
nine stable disease (47%) and three disease progression (16%). Among the seven subjects 
having received the two therapeutic cycles (13.28-16.65 GBq), one subject had a complete 
response (14%), three a partial response (43%), two a stable disease (29%) and one disease 
progression (14%) (Reidy 2017 and Data on file). 
Further details may be found in the Investigator’s brochure (IB). 
1.5.2.3 
Ipsen Sponsored Study in NET Subjects 
A study sponsored by Ipsen (study OPS-C-001) has also been initiated. A total of 27 subjects 
with heavily treated NETs have been included in this study (27 February 2019). The study, 
currently ongoing in Europe, is split into two parts. For Part A, for each treatment cycle, subjects 
received approximately 4.5 GBq of 177Lu-OPS201 at a peptide mass of approximately 300 μg. 
Part B is a dose escalation cohort design evaluating both peptide mass and radioactivity dose. 
A safety review committee was held after the first six subjects completed their third 
administration. Only two serious adverse events were reported: one Grade 3 drug-related vaso-
vagal reaction and one Grade 3 unrelated fever. One Grade 2 and one Grade 3 thrombocytopenia 
events were both seen in one subject. In the other subjects, only mild reversible 
thrombocytopenia and anaemia events as well as non-clinically significant lymphopenia events 
were observed. Short-lived reversible infusion-related episodes of different severity were 
managed successfully with infusion rate modification in three subjects. One subject was unable 
to receive the full dose (30%). Regarding anti-tumour activity, three subjects had confirmed 
partial response, one subject had unconfirmed partial response and five subjects had stable 
disease. Please refer to the IB for further safety information. 


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1.6 
Known and Potential Risks and Benefits to Human Subjects 
The therapeutic antagonist compound itself (177Lu-OPS201) and related agonist compounds 
(177Lu-DOTATATE) have already demonstrated anti-tumour activity in Grade 1 and 2 
GEP-NET that are known to overexpress sstr2 (Reidy 2017, Strosberg 2017). Moreover, in a 
preclinical model (NCI-H69) with a level of sstr2 expression in the same range of some SCLC 
biopsy samples, 177Lu-OPS201 presented a potential competitive advantage due to its specific 
binding properties as compared to 177Lu-DOTATATE and demonstrated higher uptake and 
inhibition of tumour growth.  
Based on this clinical and non-clinical evidence and since the target tumour types of this study 
(extensive disease (ED)-SCLC and hormone receptor positive (HR+) human epidermal growth 
factor receptor 2 negative (HER2-) breast cancer (BC)) have also shown significant expression 
of sstr2, evaluating 177Lu-OPS201 in these populations is justified. 
Subjects whose tumour have adequate level of sstr2 expression and consequently would have 
potential benefit with 177Lu-OPS201 treatment will be first selected with the companion 
diagnostic imaging product. The compound 177Lu-OPS201 and its imaging companion may 
thus offer a treatment option beyond standard of care for cancers such as progressing or 
refractory advanced SCLC and metastatic HR+ HER2-BC for which the unmet clinical and 
therapeutic needs are high. 
68Ga-OPS202 will be administered at the micro dosing ranges and PET/CT images will be 
acquired at the time defined by the data generated in GEP-NET subjects. The novel PET sstr2 
ligand 68Ga-OPS202 performance in low sstr2 expressing tumours is currently explored and 
evaluated. It is possible that due to tumour heterogeneity, small lesion sizes and low receptor 
density, the avidity required on 68Ga-OPS202 PET/CT scans during the screening period would 
not be met, resulting in an important screening failure in the identification of subjects to be 
treated with 177Lu-OPS201. 
It is hypothesised that a significant sstr2 expression level in a tumour lesion will correspond to 
a positive 68Ga-OPS202 PET imaging according to the criteria requested for enrollment. 
Significant sstr2 expression corresponds to tumour lesion with at least moderate H score (≥50), 
as assessed by Immunohistochemistry (IHC). Internal IHC studies demonstrated a significant 
expression of sstr2 in 15% of HR+/HER2- BC and SCLC samples tested. Therefore, it is 
anticipated to assess positive PET imaging results with 68Ga-OPS202 for at least 15% of 
subjects. As there is uncertainty with regards to the in-vivo characterisation of the sstr2 
overexpression in the tumour types targeted in this study and in order avoid exposing an 
important number of subjects to 68Ga-OPS202, a futility criterion is defined. Should, at the start 
of the study, 20 consecutive subjects fail screening due to 68Ga-OPS202 PET/CT negative for 
sstr2 with less than one subject deemed sstr2-positive while all the other inclusion/exclusion 
criteria are met, the administration of 68Ga-OPS202 and subsequent PET imaging will be 
stopped. 
An additional eligibility criterion for 177Lu-OPS201 administration requires radiologically 
≥50% matching between the lesions detected on 
68Ga-OPS202-PET/CT and on 
18F-FDG-PET/CT as confirmed by central reading (inclusion criteria #11). Some of the 
malignant lesions might show low or no metabolism on 18F-FDG-PET/CT and low or no focal 
uptake of 68Ga-OPS202 on PET. However, sstr2 expression might also be heterogenous, 
thereby leading to high retention of FDG with no uptake for 68Ga-OPS202 for some of the 
malignant lesions. The rationale for ≥50% matching of the two PET radionuclides is to ensure 
there is sufficient tumour burden that is sstr2-positive to ensure the possibility of a good 
response with 177Lu-OPS201. 


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There were no major safety concerns reported during the previous and ongoing studies 
conducted with 68Ga-OPS202.  
The known and potential risk to human subjects with 
177Lu-OPS201 as for all 
radiopharmaceuticals is the occurrence of haematotoxicity, particularly high-grade 
thrombocytopenia according to the administered and cumulative radioactivity. This risk will be 
mitigated by setting specific inclusion criteria in terms of estimated haematological reserve (e.g. 
platelet count level at baseline greater than currently recommended level) and monitoring 
haematology once a week after each administration of 177Lu-OPS201. Moreover, dosimetry will 
be performed up to 168 hours after each treatment cycle to carefully evaluate the BM absorbed 
dose. A maximum absorbed dose of 2 Gy to the BM is generally accepted (ICRP Publication 
128) with a probability for developing leukaemia of approximately 2%. In this study, the 
maximum absorbed dose in BM has been decreased to 1.5 Gy considering the safety results of 
MSKCC study. In MSKCC study, subjects with BM absorbed dose greater than 1.3 to 1.4 Gy 
indeed showed Grade 4 thrombocytopenia. The limit was nevertheless set to 1.5 Gy since the 
limit in maximum absorbed dose to the BM is a precaution to minimise longer term risks, such 
as leukaemia rather than to prevent acute haematotoxicities and since a limit of 1 Gy would 
limit too much the administered cumulative radioactivity. Moreover, the precision of the 
absorbed dose evaluation will be optimised by using an imaged-based method for computation 
of BM absorbed dose (Hindorf 2010) as well as by using Single Photon Emission Computerised 
Tomography (SPECT)/CT rather than planar scintigraphy for dosimetry analysis. 
In addition, the peptide doses administered (300 μg or 700 μg (±15%)) will be at least 3-times 
higher than in the MSKCC-sponsored trial (<100 μg). Based on pre-clinical data (mouse model, 
see Section 1.4.5), the highest peptide dose (cold peptide) is thought to increase 
tumour-to-background ratio and thus to improve safety by saturating sstr2 receptors in 
non-target organs (like BM) but not in the tumour. The proportion of hot peptide is about 1 to 
3% of the total peptide mass and thus at least 97% of the administered peptide mass is cold. 
Therefore, with increasing peptide mass, receptor saturation mostly with cold peptide is 
expected in organs such as the BM, whereas in the tumour, where sstr2 is overexpressed, 
receptor saturation is unlikely, leading to a higher peptide concentration and hence more 
radioactivity. This should further improve the tumour-to-background ratio of hot to cold 
peptide. 
Another potential risk with such compound is nephrotoxicity. Proximal tubular reabsorption of 
the radiopeptide and subsequent retention in the interstitium result in excessive and sustained 
renal irradiation. This risk will be mitigated by specific renal function inclusion criterion 
(estimated glomerular filtration rate (eGFR)>55 mL/minute) and infusion of amino acid 
solution (as OPS301) concomitant to 177Lu-OPS201 administration. The amino acid solution, 
consisting of the positively charged amino acids L-lysine and L-arginine, reduces tubular 
reabsorption of 177Lu-OPS201 by saturating renal transporters.  
Subjects will be carefully selected using 68Ga-OPS202 (sstr2) imaging to avoid administration 
of 177Lu-OPS201 to subjects with tumours with inadequate levels of sstr2 expression who 
consequently would not have potential benefit. 
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 (ICRP Publication 128).  In the urinary bladder wall and liver, 
the estimated absorbed doses (4.8 and 4.3 Gy, respectively) at the anticipated highest 
cumulative administered activity (7.4+5.5=12.9 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) (ICRP 
Publication 41). 


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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 
blood cells and act as a major reservoir for red, white blood cells and platelets 
(Kaushansky 2009, Bakovic 2005, Spencer 1975). It is reported to be the organ that receives 
the highest mean absorbed dose of all organs during PRRT (Bodei 2011, Kwekkeboom 2001), 
partly because of the presence of somatostatin receptors on lymphocytes (Reubi 1990, 
Wehrmann 2007). A dose-dependent relationship may exist between the total absorbed dose to 
the spleen and the blood cell count (Sabet 2013). In the spleen, the estimated absorbed dose is 
38.7 Gy at the anticipated highest administered activity (7.4+5.5=12.9 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 
(Teunissen 2009, Zatelli 2004, Baou 2000). Therefore, it is not unlikely that subjects treated 
with PRRT 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 at end of 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 (Wild 2014). The exception is the ovaries, where the radiation dose limit 
is 2-3 Gy (over this limit, there is a risk of permanent sterilization). With a specific absorbed 
dose of 0.1 Gy/GBq, absorbed doses of about 1.3 Gy could be reached at the highest 
administered activity (12.9 GBq). 
Participating subjects will be carefully monitored up to Day 3 in the morning and then will 
come back every week for AEs, laboratory tests, etc. They may be hospitalised until Day 3. 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. 
Each additional administration will be based on individual safety and tolerability. No 
177Lu-OPS201 will be administered to subjects who did not tolerate previous administration or 
did exceed the maximum organ radiation absorbed dose. 
Additional information regarding risks and benefits to human subjects may be found in the IB. 
1.7 
Selection of Investigational Radiopharmaceutical Products and Dosages 
1.7.1 
68Ga-OPS202 
In the pre-treatment period, all subjects with the informed consent signed will receive a single 
iv dose of 68Ga-OPS202, consisting of a peptide mass up to 45 μg, with a radioactivity range of 
150-200 MBq radioactivity of 68Ga. 68Ga-OPS202 will be prepared up to 3 hours prior to 
administration by 68Ga-radiolabelling of an OPS202 radiolabelling kit containing 50 μg of 
peptide.  
The PET images will be acquired at 1-hour post injection and one contrast enhanced (ce) CT 
scan will be acquired. The peptide mass and radioactivity range are based on findings from 
preclinical and clinical data in subjects with GEP-NET sstr2-positive. All images will be sent 
to an imaging core laboratory (ICL) for blinded reading. 68Ga-OPS202 uptake in target tissue 
(primary tumour, lymph nodes and/or metastases) will have to show at least two avid lesions of 
≥20 mm on longest diameter with 1.5-fold or greater uptake than the non-tumour liver and lung 
tissue on PET/CT. Radiologically, ≥50% matching between the lesions detected on 


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68Ga-OPS202-PET/CT and on 18F-FDG-PET/CT as confirmed by central reading will be 
required for enrolment.  
Dosing of 68Ga-OPS202 and PET image acquisition time as well as the eligibility criteria for 
sstr2 positivity could be revised at the start of phase II should emerging data from phase I and 
ongoing studies support modifications specific to these sstr2 expressing tumours. 
Note: an application for a substantial amendment will be submitted for approval by the 
Competent Authorities (CAs) and/or Ethic Committees (ECs) (as applicable) before initiating 
changes to the study conduct. 
Should, at the start of the study, 20 consecutive subjects fail screening due to 68Ga-OPS202 
PET/CT negative for sstr2 with less than one subject having at least two avid lesions of ≥20 mm 
on longest diameter with 1.5-fold or greater uptake than the non-tumour liver and lung tissue 
on PET/CT while the other inclusion/exclusion criteria met, the administration of 68Ga-OPS202 
and subsequent PET imaging will be stopped. Selection of sstr2-positive tumours for the 
treatment with 177Lu-OPS201 will be revised in a protocol amendment. 
1.7.2 
177Lu-OPS201 
The cumulative radioactivity range (9 to 12.9 GBq) applied in this study is derived mainly from 
previous experiences with 177Lu-OPS201 in subjects with NET (See Section 1.5.2). A statistical 
model correlating radioactivity and dose limiting toxicities (DLTs) as well as radioactivity and 
thrombocytopenia incidence from NET data also supported the choice of the maximum 
tolerated cumulative radioactivity and the possible starting radioactivity. 
1.7.2.1 
Treatment Schedule 
In this phase I radioactivity escalation, the radioactivity will be administered fractionated into 
one loading dose and one lower maintenance dose (e.g. 6 GBq followed by 3 GBq). The 
treatment schedule differs from the flat-dosing proposed for NET subjects in which sstr2 
expression reaches almost 100% and for whom the natural disease course is longer. With the 
aim to obtain a sufficient tumour absorbed dose in low expressing sstr2 tumours to translate 
into initial shrinkage of the lesions, the principle of intensive chemotherapy has been proposed 
in the current study. The schedule with a loading radioactivity is supported by the need for 
prompt effect on tumour bulk (decrease or stabilization), due to tumour doubling time and short 
life expectancy/fast clinical deterioration of the subject. The maintenance radioactivity should 
aim to prevent that doubling time growth take over again while ensuring a balanced benefit-risk 
ratio. As achieved tumour doses play an important role in treatment efficacy (Strigari 2014), 
the dosing regimen may need to be adapted to the tumour type and stage of the disease. 
Dose-intensity is equally important, the rhythm and dosage of cures are also calculated 
according to the recovery time and, in this case, in order to avoid dose-limiting haematological 
toxicity. In this context, we hypothesise that this dose-intensified regimen, with a loading dose 
with the highest single tolerated radioactivity followed by maintenance dose(s) (optimal lower 
radioactivity) would yield better benefit risk ratio comparing to a flat-dosing regimen and thus 
provide a therapeutic opportunity to these patients.  
1.7.2.2 
Dosing Interval of 177Lu-OPS201 
In radiotherapy, fractionation of the cumulative radioactivity is done for safety and tolerability 
reasons. However, the number of administrations (two cycles for DLT assessment) and the 
interval between two administrations (6 weeks) in this study have been reduced compared to 
NET subjects who receive three cycles separated by 8 weeks. Indeed, in this new target patient 
populations (e.g. ED-SCLC, pre-treated HR+ HER2- metastatic BC), tumour progression is 
rapid and may not allow to keep an 8-week interval between two administrations. The choice 


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of the dosing interval was driven by safety data rather than pharmacokinetic data, as the 
elimination of 177Lu-OPS201 is quick. Indeed, based on whole body scans acquired over 144 to 
168 hours after the start of the 177Lu-OPS201 administration, the mean remaining activity in the 
whole body is below 15% after 144 hours. Regarding safety data, the nadir of the blood cell 
counts decrease (any grade) occurred between 4 and 6 weeks after 177Lu-OPS201 
administration, as shown in MSKCC study (Reidy 2017, NCT02609737). These findings seem 
to be confirmed by the results of the ongoing Ipsen sponsored OPS-C-001 study in NET. The 
mean time to nadir of the platelet count (any grade) in this study was indeed 29 days after Cycle 
1 (n=10), 32 days after Cycle 2 (n=5) and up to 46 days after Cycle 3 (n=5). The interval of 
6 weeks was thus chosen since it allows to both reduce the risk of progression before the second 
administration and leave enough time to detect any potential haematotoxicity arising after each 
administration of 177Lu-OPS201. Moreover, the protocol offers the possibility to extend the 
dosing interval by up to 4 weeks if a subject has not recovered from a >Grade 1 
thrombocytopenia, anaemia or neutropenia. In any case, only subjects with adequate 
haematological reserve (defined as: white blood cells (WBC) ≥3000/μL, with absolute 
neutrophil count ≥1000/μL, platelet ≥100,000/μL and red blood cell (RBC) ≥3x106/μL) can be 
considered to receive an administration of 177Lu-OPS201. 
1.7.2.3 
Starting Cumulative Radioactivity of 177Lu-OPS201 
In this study, 9 GBq fractionated in two administrations (6 GBq followed by 3 GBq) will be 
used as the starting cumulative radioactivity. Indeed, the previous studies in NET showed good 
tolerance in this range of radioactivity. In the first in human pilot study performed in four 
subjects with advanced NET (Wild 2014), two cycles of 4.12 ± 1.26 GBq were well tolerated 
and three cycles showed encouraging preliminary anti-tumour activity. This treatment led to 
organ absorbed doses of 0.10 ± 0.021 Gy/GBq in BM (i.e. about 0.9 Gy for a cumulative 
radioactivity of 9 GBq) and 1.8 ± 0.44 Gy/GBq in kidney (i.e. about 15 Gy for a cumulative 
radioactivity of 9 GBq). These predicted mean organ doses are thus below the limiting organ 
absorbed doses fixed to 1.5 Gy in BM and 23 Gy in kidney.  
In the MSKCC study (Reidy 2017, NCT02609737), the tolerability after the first therapeutic 
cycle (mean cumulative radioactivity: 8.55 GBq; range: 6.94 - 9.43 GBq) was good with 17/19 
subjects experiencing mild to moderate haematotoxicity and only 2/19 subjects experiencing 
reversible Grade 3 leukopenia. This treatment led to organ absorbed doses of 0.077 Gy/GBq in 
BM (i.e. about 0.7 Gy for a cumulative radioactivity of 9 GBq). The predicted BM absorbed 
dose is thus below the limiting organ absorbed dose fixed to 1.5 Gy. 
The present study will include a different population with different sstr2 expression profile. 
However, the good tolerability in NET patients gives a reasonable safety margin. Moreover, the 
predicted organ absorbed doses are below the commonly defined thresholds (1.5 Gy in BM and 
23 Gy in kidney) with a cumulative radioactivity of 9 GBq. From a safety point of view, all 
these factors taken together allow to start with a cumulative radioactivity of 9 GBq in this 
different population.  
In both Wild 2014 and Reidy 2017 studies, consistent tumour absorbed doses were observed in 
NET subjects with median tumour absorbed doses of 7.0 and 7.2 Gy/GBq, respectively. Thus, 
in NET subjects administered with a cumulative radioactivity of 9 GBq, median tumour 
absorbed doses of 63 to 65 Gy that are in the range of ablative doses (Kalemkerian 2011) could 
be reached. Sstr2-positive non-NET tumours are known to express less sstr2 at tumoural cells 
surface but it is anticipated that significant tumour doses could be reached with the starting 
cumulative radioactivity of 9 GBq. Moreover, all subjects have the possibility to receive 
additional cycles of 177Lu-OPS201 if they tolerate the treatment show clinical benefit and have 


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not exceeded the limiting organ absorbed doses. During additional cycles, the BM dose limit is 
increased to 2 Gy for subjects who did not experience Grade 3 or more haematotoxicity during 
the two first cycles. Indeed, 2 Gy is a generally accepted safety limit (Verburg 2013, Rolleman 
2010, ICRP Publication 128) that allows more therapeutics options for those subjects who 
demonstrated good tolerance during the core trial. The choice of the activities and the possibility 
to administer additional cycles thus prevent underdosing subjects who may benefit from the 
treatment with 177Lu-OPS201. 
1.7.2.4 
Maximum Cumulative Radioactivity of 177Lu-OPS201 
During radioactivity escalation, it is planned not to exceed the cumulative radioactivity of 
12.9 GBq (7.4 GBq followed by 5.5 GBq). This value is indeed lower than the cumulative 
radioactivity of 15 GBq (two cycles of 7.5 GBq) that was not tolerated by NET subjects in 
Reidy 2017 study when given in two cycles of 7.5 GBq each (See Section 1.5.2). The statistical 
modelling performed based on this data showed that a dose-thrombocytopenia curve did predict 
a maximum tolerated cumulative activity (MTCA) around 13.7 GBq in subjects with NET. 
Moreover, to minimize the number of subjects who could be exposed to radioactivity exceeding 
the MTCA, a statistical Bayesian modelling approach will be implemented during the study to 
estimate a more precise radioactivity-DLT and organ radiation absorbed dose curve in order to 
guide further radioactivity selection and predict the radioactivity that could be tested in the next 
cohort of radioactivity escalation. 
1.7.2.5 
Peptide Mass Dose of 177Lu-OPS201 
As described in Section 1.4.5, the increase of peptide mass dose has been shown to improve 
tumour-to-background ratio and thus it is hypothesised that higher dose of peptide may improve 
the safety by reducing the radiation exposure in organs like BM or liver. Thus, a fixed peptide 
mass dose of 300 μg (±15%), that is higher than the dose of ≤100 μg used in both Wild 2014 
and Reidy 2017 studies, has been chosen for the escalation cohorts. This choice is also 
substantiated by the work of Dalm (Dalm 2016a) showing that the optimal peptide dose in a 
mouse model of SCLC (H69) was 1 μg (equivalent to a dose of 250 μg in human).  
In the phase I of this study, in addition to the 300 μg (±15%) peptide mass dose, safety and 
dosimetry with a higher peptide mass dose of 700 μg (±15%) will be evaluated. Therefore, once 
the first cycle of a radioactivity (e.g. 6 GBq followed by 3 GBq) has been shown to have 
acceptable tolerability with the lower peptide mass dose (300 μg (±15%)), the cohort will be 
repeated with the same radioactivity but with the higher peptide mass dose (700 μg (±15%)). 
The 700 μg peptide mass dose has been chosen since it allows the testing of a significant range 
of peptide mass doses and to clearly differentiate from the lower peptide mass dose. Moreover, 
this peptide mass dose is still well below the doses tested in the toxicology species (see 
calculations in Table 3). 
Table 3 summarises the safety margins for each species used in toxicology studies based on the 
Human Equivalent Dose calculated from body surface area (Food and Drug Administration 
(FDA) Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical 
Trials for Therapeutics in Adult Healthy Volunteers) (FDA Guidance). 


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Table 3 
Toxicology Studies with natLu-OPS201 and OPS201: Estimated Safety Margin Study/Species 
based on Human Equivalent Dose based on Body Surface Area 
Study 
Dose 
Estimated safety 
margin[a] 
Study D-FR-01072-002   
0.012 mg/kg of OPS201 (700 μg) 
- 
Single dose minipig 
Study I
 
NOAEL = 1.56 mg/kg of 175Lu-OPS201 in 
OPS201 (10:90 mol/mol) 
1.40 mg/kg of OPS201 
OPS201: 106 
14-day repeated dose rat 
Study I
 
NOAEL = 20 mg/kg/day of 175Lu-OPS201 in 
OPS201 (10:90 mol/mol) 
18 mg/kg of OPS201 
OPS201: 242 
 
NOAEL=no observed adverse events level 
a based on Human Equivalent Dose based on body surface area (divided by 1.1 for minipig and 6.2 for rats) 
For a 60-kg subject, a human dose of 700 μg of OPS201 (12.5 μg/kg) results in safety margin 
for OPS201 of about 106 times the human equivalent dose for minipigs and 242 times the 
human equivalent dose for rats. 
The 2.3-fold increase in peptide mass dose between 300 and 700 μg (±15%) is justified since 
both doses are well below the doses tested in animals and since no pharmacological activity is 
expected. 
A more detailed description of administration procedures is given in Section 6.1.  
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 Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. 
Any episode of noncompliance will be documented. 
FDA, 21 Code of Federal Regulations (CFR) Part 11, Electronic Records, Electronic Signatures 
and FDA, Guidance for Industry: Computerised Systems Used in Clinical Trials. 
In addition, the 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. 
1.9 
Population to Be Studied 
Tumours with significant sstr2 expression other than NET will constitute the target tumour 
types in the present study. In this phase I/II study, the subject population enrolled to receive 
177Lu-OPS201 will be limited first to pre-treated subjects with limited disease (LD)- or 
ED-SCLC and pretreated subjects with metastatic HR+/HER- BC (see full definition in Section 
3.1), which are expressing sstr2 and displaying higher tracer uptake than non-tumoural liver 
parenchyma on 68Ga-OPS202 PET/CT scans. Due to the late metastatic or advanced stage of 
the disease and progression or failure of response to standard-of-care (SoC) treatments, this 
population has in general a limited life expectancy. The line of therapy chosen for each cancer 
is the line for which the subject has exhausted validated treatments considered by the medical 
community and regulatory agencies as the SoC. 
CCI
CCI


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Note: Subjects with active known infection with human immunodeficiency virus (HIV) requiring 
systemic treatment or known acquired immunodeficiency syndrome (AIDS)-related illness, or 
known active hepatitis B or C infection that would pose a risk to subject safety or interfere with 
the study evaluation, procedures or completion will not be permitted screening for this study. 
Preclinical and clinical observations indicate that the therapeutic effect of radiotherapy is 
partially immune mediated (Demaria 2004, Brody 2010; Golden 2015, Rodriguez-Ruiz 2016, 
Hiniker 2016, Tang 2017). Cell death induced by radiations is thought to be immunogenic and 
results in modulation of lymphocyte effector function in the tumour microenvironment 
promoting local control (Walle 2018). Several synergistic mechanisms exist that relate to 
radiation and the subsequent immune response. These include tumour antigen release and 
increased priming, tumour adjuvant release, the deletion of anergic and regulatory T cells, as 
well as T cell activation, antigen processing machinery, death receptor upregulation, induction 
of cytokines and chemokines and increased immune-cell trafficking.  One synergistic 
interaction is the abscopal response, in which radiation acts as an in situ vaccine leading to 
increased control of distant disease sites. Another type of interaction is the immunogenic 
modulation, in which changes occur in the tumour microenvironment and any residual cancer 
cells leading to immune-mediated clearance of remaining local disease. Allowing inclusion of 
immunocompromised subjects in the study may render the interpretation of the study results 
difficult as would very likely interfer with these synergistic mechanisms. 
Active hepatitis causes inflammation of the liver (Suhail 2014), and tissue injuries may impact 
the quality of normal liver imaging. The uptake in the non-tumoural liver tissue is used to 
estimate the tumour-to-background uptake ratio to assess both safety and efficacy of 
177Lu-OPS201 and the performance of 68Ga-OPS202. In addition, changes in biological liver 
parameters may confound the assessment of safety parameters in terms of possible relationship 
to the investigational product. Hence, in the absence of a minimal product characterisation at 
this stage, it is reasonable that subjects with active hepatitis B or C be excluded from these 
studies. 
1.9.1 
Disease 
Progress in the management of patients with SCLC has been modest in the past 20 years, the 
main contribution to improving patient survival has been provided by concurrent radiotherapy 
and management prophylactic cranial irradiation. Chemotherapy with etoposide and platinum 
remains the standard treatment whereas irinotecan and cisplatin has been demonstrated to be 
superior in selected populations. Although patients usually have an excellent response to 
chemotherapy with or without initial radiotherapy, nearly all will relapse with local or distant 
disease and eventually die. Tumour cells at progression are less sensitive to treatment with 
cytotoxics, therefore, treatment selection will depend on the time of relapse or progression. 
However, despite strides in the management of SCLC, there has been little change in survival 
over the past 2 decades for limited- or extensive-stage disease. Indeed, very few new agents 
with activity in SCLC have been identified (rovalpituzumab tesirine for high expressing DLL3, 
anti -PDL1), even as identification of molecular targets and targeted therapies has proceeded at 
a brisk pace in non-SCLC. Clinical and basic research continues to identify better treatment 
strategies that help increase the duration and effectiveness of treatment of patients with SCLC 
refractory or relapsing after chemotherapy regimens. 
Patients with HR+ HER2- metastatic BC often respond to hormone therapy alone or in 
combination with targeted agents, which can reduce tumor burden and symptoms with generally 
fewer side effects and toxicities than chemotherapy. Furthermore, modern oestrogen therapy 
appears to prolong progression and possibly survival compared with older oestrogen treatments. 


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However, few if any patients with metastatic BC will be cured and the goal of therapy is, 
principally, palliation. All efforts are focusing on choosing the therapy that is most likely to 
stabilise or reduce the burden of disease with the fewest side effects and maintain that therapy 
until either unacceptable toxicity is evident or disease progression occurs. 
Over the last decade, several prospective randomised clinical trials have demonstrated that 
addition of agents that operate in different ways than through hormone receptor interference 
can enhance the benefit seen with oestrogen therapy alone. In particular, cyclin-dependent 
kinase (CDK) 4/6 inhibitors in combination with oestrogen therapy started to be used as a 
first-line therapy. Three separate agents, palbociclib, ribociclib and abemaciclib, which inhibit 
CDK 4/6, improve progression-free survival (PFS) when added to estrogen therapy as first-line 
or subsequent therapies. These trials have not yet demonstrated an overall survival (OS) benefit. 
However, the PFS benefit is considerable. Everolimus, an inhibitor of the mechanistic target of 
rapamycin (mTOR), has also demonstrated improved PFS when added to endocrine tharpy in 
the hormone-resistant setting. At this time, there are no randomised trials comparing the various 
CDK 4/6 inhibitors, everolimus, or their combination in patients receiving hormone therapy. 
However, there is a need in finding predictive biomarkers beyond the oestrogen receptor, 
determining whether to continue these agents beyond disease progression, creating novel 
combinations with other treatments or evaluating the sequence of treatment over different lines 
of metastatic disease.  
For the limited percentage of patients who have extensive visceral metastases with evidence of 
end-organ dysfunction, treatment starts with first-line chemotherapy. This approach aims to 
maximise the chances of an early, meaningful, and more rapid response.  
For patients with metastatic HER2-negative BC who have a germline BRCA mutation, the use 
of poly adenosine diphosphate ribose polymerase (PARP) inhibitors is discussed. 
The optimal sequence of single endocrine agents and combinations with targeted agents is 
currently unknown and is a research priority. Data beyond progression to better understand the 
efficacy of each class of agent when given after the other is awaited. In this context, it is 
important to evaluate new treatment modalities to address refractory disease, relapsed disease 
or intolerance to treatment with the newly approved agents.   
1.9.2 
Sstr2 Expression in Cancer 
The selection of the tumours of interest was performed by combining internal IHC data and 
literature review including IHC data but also in vivo uptake of radiolabeled somatostatin 
analogues, i.e. Octreoscan® or 68Ga-DOTATATE/TOC: 
• 
Small cell lung cancer (SCLC): Ipsen internal IHC data showed that 32.5% of the SCLC 
samples (tumour TMA) expressed sstr2. This proportion is even higher in the literature 
with 32 to 68% of positive SCLC samples (Papotti 2001, Righi 2010, Lapa 2016). Uptake 
of 68Ga-DOTATOC/TATE was also reported in 67% (16/24) of the primary tumours in 
subjects with metastatic SCLC with a high uptake in 50% of the subjects (12/24). 
Metastatic sites were correctly identified by PET/CT with 68Ga-DOTATOC/TATE in 
adrenals, lymph nodes and bone and in a lesser extent in brain and liver (Sollini 2013). 
In another study (Lapa 2016), 10/21 (48%) with ED-SCLC showed a significant uptake 
of 68Ga-DOTATATE. Four subjects (19%) showed positive uptake (greater than the 
liver) in all lesions. And 6/21 (29%) were rated intermediate since most of the lesions 
showed positive uptake. 
• 
Hormone receptor positive HER2 negative breast cancer (HR+/HER2- BC): two 
internal IHC studies showed positive sstr2 expression in the HR+ BC samples (24% of 
samples in a TMA study and 63% in sections). These results correlate with literature data 


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(Kumar 2005, Frati 2014). Moreover, several studies performed in small cohorts showed 
the feasibility of sstr-mediated nuclear imaging in BC subjects. In these studies, 
sensitivity for primary BC ranged from 36 to 100%. In a subset of the studies lymph 
nodes lesions were visualised, but sensitivity was lower compared to that for primary 
tumours. Most of these studies were performed with 111In-DTPA-octreotide or 
99T-octreotide (Dalm 2016b). 
Note: Male BC is a rare disease, representing 0.5% of all BCs (Nilsson 2011). Male BC 
shows some biological differences from female BC (Giordano 2004, Anderson 2004) and 
is contrasted in age at diagnosis, histological type, stage of disease, tumour grade, gene 
and ER expression (Shandiz 2015). Poorer survival outcomes were noted in male BC 
(Gnerlic 2011; Abreu 2016). Due to the very low frequency of male BC and major 
differences between male and female BCs, it is anticipated that in a study with limited 
sample size it is unlikely that a male subject with BC would be eligible and included in 
the study, and if any, the results generated may considerably increase data heterogeneity 
in the BC group. No IHC studies were performed in male BC samples, the sstr2 
expression in HR+ HER2- male BC is thus not characterised. 
To select the appropriate target population, tumours expressing sstr2 will be identified and 
documented through the lesion uptake of the companion diagnostic imaging product 
(68Ga-OPS202) during the screening period. Only subjects showing at least two avid lesions of 
≥20 mm on longest diameter with 1.5-fold or greater uptake than the non-tumour liver and lung 
tissue on PET/CT and with ≥50% matching between the lesions detected on 
68Ga-OPS202-PET/CT and on 18F-FDG-PET/CT as confirmed by the central reader will be 
enrolled for treatment with 177Lu-OPS201. 
Study population will thus be carefully selected to avoid administrating 177Lu-OPS201 to 
subjects whose tumours may have non-adequate level of sstr2 expression and for whom 
consequently a potential benefit is not expected. Including only subjects with sufficient tumour 
radioactivity uptake (greater than non-tumoural liver parenchyma) and an appropriate matching 
of lesions on molecular imaging (68Ga-OPS202 and 118F-FDG-PET) also offers the advantage 
to avoid having too much radioactivity available to accumulate in off-target and sstr2 
expressing organs like BM, pancreas or pituitary gland. 
 


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2 
PURPOSES OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Rationale and Purpose of the Study 
Several types of tumours other than NET 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 yields an 
important promise in a personalised treatment approach such as theranostic combining imaging 
and therapy. The somatostatin analogue peptide component (OPS200) is the targeting moiety 
of the compound with selective high affinity for sstr2 (OPS201 IC50=0.70 nM and 
177Lu-OPS201 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 beta minus emitting radionuclide, with a mean energy of 0.133 MeV and a mean 
penetration depth of 0.23 mm (Bodei 2013). In addition to beta-emission, 177Lu has gamma rays 
which allow performing SPECT images and consequently dosimetry.  
Non-NET tumours with significant sstr2 expression will constitute the target tumour types in 
this study. To identify the appropriate target population, an sstr2 molecular imaging 
radionuclide, 68Ga-OPS202, will be used in conjunction with PET scanning during the 
screening period as a companion diagnostic imaging product and only subjects showing avid 
lesion uptake of 68Ga-OPS202 in target tissue (primary tumour, lymph nodes and/or metastases) 
will be included in the study. 
The antagonist therapeutic compound itself (177Lu-OPS201) and related agonist compounds 
(177Lu-DOTATATE) have already demonstrated anti-tumour activity in Grade 1 and 2 
GEP-NET that are known to overexpress sstr2. Moreover, in a preclinical model (NCI-H69) 
with a level of sstr2 expression in the same range of some SCLC biopsy samples, 177Lu-OPS201 
presents a potential competitive advantage due to its specific binding properties as compared to 
177Lu-DOTATATE and demonstrated higher uptake and inhibition of tumour growth (Dalm 
2016a) and confirmed with internal study. Regarding breast cancer, a preclinical study with a 
ER+/HER2- PdX model with heterogenous level of sstr2 expression demonstrated a 2-fold 
higher uptake on the tumour for 177Lu-OPS201 versus 177Lu-DOTATATE (Dalm 2017). 
The compound 177Lu-OPS201 and its companion diagnostic imaging product 68Ga-OPS202 
may offer a treatment option beyond standard of care for cancers such as LD- or ED-SCLC or 
metastatic HR+/HER2- BC (refer to eligibility criteria Section 4.1.1, criterion #3) where there 
are still high unmet clinical and therapeutic needs. 
The purpose of the phase I of the study is to evaluate the safety and tolerability of the compound 
177Lu-OPS201 in this new population with a different benefit-risk ratio 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. The purpose of the phase II is to evaluate 
efficacy in selected sstr2-positive tumour types and further assess the safety of 177Lu-OPS201. 
Overall, the phase I/II study will evaluate a theranostic approach combining screening and 
assessment of subjects with the companion diagnostic imaging product (68Ga-OPS202) and 
therapy with 177Lu-OPS201. 


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2.2 
Study Hypotheses 
Phase I  
177Lu-OPS201 will be sufficiently safe to permit clinical investigation in phase II when 
administered in previously treated subjects with LD- or ED-SCLC and in previously treated 
metastatic HR+/HER2- BC, expressing sstr2 as identified by 68Ga-OPS202 PET/CT scans.  
Phase II  
Previously treated subjects with LD- or ED-SCLC, or metastatic HR+/HER2- BC expressing 
sstr2 as identified by 68Ga-OPS202 PET/CT scans and treated with 177Lu-OPS201 will attain a 
clinically meaningful objective response rate (ORR), which is superior to the historical ORR 
obtained by current SoC treatment. 
2.3 
Study Objectives 
2.3.1 
Primary Objectives  
Phase I  
To evaluate the safety and tolerability and to define the MTCA of fractionated intravenous (i.v.) 
administration over two cycles of 177Lu-OPS201 in previously treated subjects with locally 
advanced or metastatic cancers expressing sstr2 as identified by 68Ga-OPS202 PET/CT scans. 
Phase II 
To evaluate the ORR of fractionated i.v. administration of 177Lu-OPS201 in previously treated 
subjects with locally advanced or metastatic cancers expressing sstr2 as identified by 
68Ga-OPS202 PET/CT scans. 
2.3.2 
Secondary Objectives  
Phase I 
• 
To determine the whole-body distribution and pharmacokinetics (PK) of 177Lu-OPS201 
after each administration. 
• 
To determine the radiation dosimetry of 177Lu-OPS201 (organ exposure to radiation) 
after each administration. 
• 
To determine the PK of OPS201 in plasma and urine. 
• 
To describe the preliminary anti-tumour activity of 177Lu-OPS201. 
• 
To evaluate PFS until Long-term Follow-up Visits up to 2 years after the End of Core 
Trial (EOCT) Visit. 
• 
To determine the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 on PET/CT 
images and estimate its correlation with the uptake on 177Lu-OPS201 SPECT/CT. 
• 
To evaluate the association between uptake on 68Ga-OPS202 PET/CT and tumour 
response to 177Lu-OPS201. 
Phase II 
• 
To evaluate the efficacy of 177Lu-OPS201 using Response Evaluation Criteria In Solid 
Tumours (RECIST) v1.1 and/or Positron Emission Tomography Response Criteria In 
Solid (PERCIST) v1.0 criteria, volumetric CT and modified PERCIST using 
68Ga-OPS202 PET scans and modified RECIST using the 68Ga-OPS202 avid lesions.  
• 
To evaluate PFS until long-term follow-up visits up to 2 years after the EOCT Visit. 
• 
To estimate the 1-year OS rate. 
• 
To further evaluate the safety profile of 177Lu-OPS201. 


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• 
To evaluate the association between uptake on 68Ga-OPS202 PET/CT with tumour 
response to 177Lu-OPS201 therapy. 
• 
To determine the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 on PET/CT 
images and estimate its correlation with the uptake on 177Lu-OPS201 SPECT/CT. 
• 
To evaluate the impact of 177Lu-OPS201 on the health-related quality of life of treated 
subjects. 
• 
To estimate the proportion of sstr2-positive tumour lesions by 68Ga-OPS202 PET/CT 
scans as assessed by SUV in subjects screened for 177Lu-OPS201 treatment. 
• 
To further assess some PK and dosimetry parameters of 177Lu-OPS201 based on the 
phase I results. 
2.3.3 
Exploratory Objectives 
Phase I/II 
• 
To explore renal and haematological safety by measuring urinary specific biomarkers 
and deoxyribonucleic acid-double strand breaks (DNA-DSB) and DNA repair in 
peripheral lymphocytes (at selected centres). 
• 
To evaluate the tumour microenvironment, transcriptomics, DNA repair, gene mutation 
in tumour as compared to germinal mutation and other markers of interest through 
assessment of tumour biopsies. 
• 
To collect biobank samples for future analysis of circulating markers (optional, 
additional informed consent required). 
• 
To evaluate the association between the tumour uptake of 68Ga-OPS202 and sstr2 
expression on tumours as determined by IHC. 
• 
To generate a model integrating PK, pharmacodynamics, dosimetry, anti-tumour activity 
and safety data if warranted by the data. 


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3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
The proposed study is a phase I/II, multicentre, open-label study of 177Lu-OPS201 therapy with 
companion diagnostic imaging product 68Ga-OPS202 PET/CT in previously treated subjects 
with locally advanced or metastatic solid tumour expressing sstr2 who progressed under or 
after, failed to respond to, or are intolerant or having a contraindication to available SoC 
treatment options and are deemed suitable for treatment with 177Lu-OPS201 as per the 
investigator’s clinical assessment and/or their individual disease state. More specifically: 
• 
Subjects who had ED-SCLC at presentation who have progressed on or after one line of 
standard chemotherapy. If a subject had LD-SCLC at presentation and received surgery 
and/or radiotherapy as first line treatment (with or without chemotherapy) and has 
localised relapse, further local treatment (such as surgery) should be considered in 
addition to the chemotherapy options. 
For subjects with either ED-SCLC or LD-SCLC, if subjects relapse more than 6 months 
after first-line treatment, re-treatment with their initial regimen is recommended. 
Subjects may have received prior immunotherapy. 
• 
Subjects with HR+/HER2- metastatic BC after failure of prior SoC treatments and who 
have received, if indicated, at least one line of hormonal therapy, CDK4/6 inhibitor for 
advanced or metastatic disease and at least one line of chemotherapy for metastatic 
disease; subjects with BRCA-mutated metastatic disease who may have received a PARP 
inhibitor, if available, are eligible; prior adjuvant hormonal treatment and prior adjuvant 
chemotherapy are allowed. 
Once the maximum tolerated cumulative radioactivity is reached and the appropriate peptide 
mass determined, additional subjects may be treated at this radioactivity/peptide dose, per 
tumour type cohort. 
A clinical research Master Protocol in selected indications (basket design) will encompass this 
biomolecular target study protocol together with other study protocols targeting the same 
receptor (sstr2) and will describe the overall background, rationale, objectives, design, 
methodology and organisation of the overall sstr2-positive cancer research project for OPS201 
and OPS202. 
3.1.1 
Study Sites 
This study will be conducted at approximately 30 global clinical sites. Eight of these sites will 
participate in phase I and all sites in phase II. Participating regions are planned to be North 
America, Europe and Asia-Pacific. Additional sites may be added. 
3.1.2 
Number of Subjects 
During phase I, up to 30 subjects will be enrolled for treatment with 177Lu-OPS201. Based on 
the current knowledge on the proportion of subjects presenting with sstr2-positive tumours, it 
is anticipated that approximately 55 to 60 subjects will need to be administered 68Ga-OPS202. 
Should, at the start of the study, 20 consecutive subjects fail screening due to 68Ga-OPS202 
PET/CT negative for sstr2 with all the other inclusion/criteria met, the administration of 
68Ga-OPS202 and subsequent PET imaging will be stopped. Selection of sstr2-positive tumours 
for the treatment with 177Lu-OPS201 will be revised in a protocol amendment. 
During phase II, approximately 172 subjects (76 subjects with SCLC and 96 with BC) are 
planned to be enrolled for the Simon's optimal two-stage design. In this study phase, it is 
anticipated that approximately 340 subjects will need to be administered 68Ga-OPS202 for PET 


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imaging screening. However, recruitment will be stopped once the number of required 
evaluable subjects (i.e. 76 subjects with SCLC and 96 with BC) is reached. 
Further cohorts of subjects with other tumours expressing sstr2 could be added in this protocol 
according to the advances in the preclinical and clinical knowledge on 68Ga-OPS202 and 
177Lu-OPS201 and emerging published data on the diseases. In this case, the additional number 
of subjects will be estimated based on standard of care historical response (e.g. ORR/best 
overall response (BOR)) of the corresponding disease. 
3.1.3 
Pre-treatment Period 
A subject that qualifies will receive 68Ga-OPS202 and will be imaged on PET/CT. Subjects 
with at least two sstr2 avid lesions of ≥20 mm in the longest diameter on 68Ga-OPS202 PET/CT 
scan, confirmed by central read and having ≥50% matching between the lesions detected on 
68Ga-OPS202-PET/CT and on 18F-FDG-PET/CT as confirmed by central reader will then be 
treated with 177Lu-OPS201. 
Note: an application for a substantial amendment will be submitted for approval by the CAs 
and/or ECs (as applicable) before initiating changes to the study conduct. 
3.1.4 
Treatment Period - Phase I 
Phase I is a multicentre, open-label, single-arm study designed to primarily investigate the 
safety and tolerability of 177Lu-OPS201 following fractionated i.v. administrations in pretreated 
subjects with locally advanced or metastatic cancers expressing sstr2 as identified by 
68Ga-OPS202 PET/CT scans. This phase will encompass both radioactivity escalation and 
peptide mass dose evaluation. 
3.1.4.1 
Radioactivity Escalation 
The aim of the radioactivity escalation is to determine the MTCA and recommended phase II 
regimen.  
In the core treatment period of phase I, up to three radioactivity levels of 177Lu-OPS201 are 
planned to be tested with the radioactivity delivered in two administrations: one loading dose 
followed by a lower maintenance dose, 6 weeks apart (+ up to additional 4 weeks in case of 
AEs that need to be adequately recovered) (see Figure 3). 
The DLT assessment period is defined from the first administration of 177Lu-OPS201 to 6 weeks 
after the second administration. The DLT assessments will be performed over 6 weeks (up to 
10 weeks in case of AEs that need to be adequately recovered) between first and second 
administration and 6 weeks between second administration and EOCT visit. During this period, 
subjects will have repeated imaging for the calculation of individual dosimetry data and will be 
monitored for signs of toxicity. Tumour response will be assessed based on 
18F-Fluorodeoxyglucose (FDG) PET at screening and 6 weeks after the second administration 
of 177Lu-OPS201 and ceCT or contrast enhanced magnetic resonance imaging (ceMRI) scans 
at Screening and at 6 weeks after the first and second 177Lu-OPS201 administration. Tumour 
response will also be assessed based on 68Ga-OPS202 PET at screening and 6 weeks after the 
second administration of 177Lu-OPS201. A long-term follow-up period will start after EOCT 
visit. Subjects will be followed-up every 3 months thereafter, until 24 months, death or 
withdrawal of full consent, whichever occurs first. In case the subject receives optional 
additional cycles (see Section 3.1.4.1.6) the 24-month follow-up period will start at the end of 
the last cycle of 177Lu-OPS201. 


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Figure 3 Phase I Study Design Scheme (Without Additional Cycles) 
 
3.1.4.1.1 Definition of the MTSA and MTCA 
The purpose of the radioactivity escalation is to determine the MTCA. If not feasible, the 
maximum tolerated single activity (MTSA) or the maximum administered cumulative activity 
(MACA) will be determined as indicated below. 
The MTCA is defined as the maximum cumulative radioactivity that may be administered 
following fractionated i.v. administrations of at least 6 weeks apart, so that: 
• 
no more than 33% of the subjects experience a DLT after first or second administration 
of 177Lu-OPS201 (see DLT definition in Section 3.8.1.1) and/or 
• 
no more than 10% of the subjects have cumulative absorbed dose in each target organ 
exceeding the acceptability limits (1.5 Gy in BM and 23 Gy in kidney) after second 
administration of 177Lu-OPS201. 
The MTSA is defined as the highest single radioactivity that can be given so that no more than 
33% of the subjects experience a DLT during Cycle 1. The MTSA will be determined in case 
of unacceptable toxicity seen after first administration of 177Lu-OPS201. 
The MACA will be determined if the MTCA is not reached during the dose escalation. 
3.1.4.1.2 Cohorts Description 
The planned radioactivity escalation will be conducted over three cohorts from a starting 
cumulative radioactivity of 9 GBq up to a maximum cumulative radioactivity of 12.9 GBq (see 
Figure 5). 
The size of the cohorts will be three to five subjects. Once three subjects of the cohort complete 
Cycle 2 or discontinue early during Cycle 2, the cohort will be considered as complete. No more 
than five subjects should be enrolled per cohort. 
3.1.4.1.3 Dose Escalation Mode 
Cohorts will be enrolled using the following escalation approach: 
• 
starting cumulative radioactivity of 9 GBq of 177Lu-OPS201 fractionated into one 
administration of 6 GBq followed by a second administration of 3 GBq, 6 weeks apart 
(+ up to additional 4 weeks in case of AEs that need to be adequately recovered).  


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• 
maximum cumulative radioactivity of 12.9 GBq of 177Lu-OPS201 fractionated into two 
administrations, 6 weeks apart (+ up to additional 4 weeks in case of AEs that need to be 
adequately recovered).  
• 
maximum radioactivity administrable in one cycle is 7.4 GBq of 177Lu-OPS201. 
• 
the inter-cohort radioactivity escalation will be performed by maximum increment of 
2 GBq. 
The predefined escalation scheme is described in Table 4. However, if DLTs are reported in 
Cohort 1 from the first administration of 6 GBq, it may be decided to deescalate the 
administered cumulative activity and start a cohort receiving a cumulative activity of 7.5 GBq 
fractionated into an administration of 4.5 GBq followed by an administration of 3 GBq. Then, 
if this cumulative activity is well tolerated, another cohort receiving a cumulative activity of 
9 GBq fractionated into two administrations of 4.5 GBq may be started. During the escalation, 
in case DLTs are reported or if radiation absorbed dose is predicted to exceed the acceptability 
limits in at least one organ, the escalation scheme may be revised so that radioactivity not 
exceeding the MTCA/MTSA could be tested in the next cohort of radioactivity escalation. A 
statistical Bayesian modelling approach will be implemented to produce a more precise 
radioactivity-DLT curve and organ absorbed dose curve to guide the radioactivity selection (see 
details in Section 11 and Appendix 1) and predict the MTCA/MTSA. 
Table 4 
Cohorts and Radioactivity Escalation Plan 
Planned radioactivity 
escalation  
Cohort 1 
Cohort 3 
Cohort 5 
Cumulative (GBq) 
9 
11 
12.9 
Schedule (GBq) 
6 + 3 
7 + 4 
7.4 + 5.5 
Abbreviation: GBq=Gigabecquerel 
 
Once the radioactivity escalation has been completed, the MTCA level may be repeated in a 
last cohort (see Section 3.1.4.1.5 for stopping rule and MTCA definition). 
3.1.4.1.4 Data Review Board 
The DRB for radioactivity and peptide mass escalation, consisting of a team of “permanent” 
decision makers (the core team), including selected principal investigators and Ipsen personnel, 
will review the safety and dosimetry data and jointly decide with the sponsor whether to proceed 
with the enrolment of the next cohort. A DRB charter will be developed in a separate document 
to define attendees and roles and responsibilities, as well as the data reports to be reviewed by 
the DRB and the review timepoints.  
3.1.4.1.4.1 Proceeding to the Second Administration 
The investigator should follow the following rules before proceeding to the second 
administration: 
• 
subjects with DLTs after first administration will be discontinued from 177Lu-OPS201. 
• 
subject will be eligible for second administration of 177Lu-OPS201 only if: 
- 
subject’s blood cell counts and renal function are in the range defined in the study 
inclusion criteria (#7), within the treatment cycle 
- 
subject's organ absorbed doses did not exceed 1.5 Gy in BM and 23 Gy in kidney. 
The radioactivity dose of the second administration will be adjusted based on dosimetry results 
to prevent exceeding limiting organ absorbed doses limits (1.5 Gy for bone marrow; 23 Gy for 
kidney). The planned maintenance dose for Cycle 2 may be revised in any eligible subject, if 


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the cumulative radioactivity is anticipated to exceed the predicted MTCA. In that case the 
maintenance dose will not exceed the predicted MTCA minus the loading dose. In any case, the 
maintenance dose will be adjusted in a way not to exceed the limiting organ absorbed doses. 
3.1.4.1.4.2 Proceeding to the Next Cohort 
The DRB meeting for radioactivity escalation will take place after three subjects of the 
radioactivity escalation cohort have completed two cycles of 177Lu-OPS201. The DRB will 
review all available safety and dosimetry data from the study to decide if the escalation can 
proceed as planned (see Table 4).  
If DLTs are reported, a statistical Bayesian modelling approach will be implemented to produce 
more precise radioactivity-DLT and organ absorbed doses curves to guide the radioactivity 
selection and predict a radioactivity not exceeding the predicted MTCA/MTSA that could be 
tested in the next cohort of radioactivity escalation.  
If the starting cumulative radioactivity of 9 GBq is not well tolerated, another cohort with a 
decreased cumulative radioactivity will start. In this case, the cumulative radioactivity could be 
determined using the statistical Bayesian approach, for example, 7.5 GBq (one administration 
of 4.5 GBq followed by an administration of 3 GBq, 6 weeks apart (+ up to additional 4 weeks 
in case of AEs that need to be adequately recovered)).  
3.1.4.1.5 Stopping Rules for Dose Escalation 
The radioactivity escalation will be stopped as soon as: 
• 
the MTCA and/or MTSA have been defined with good precision; or 
• 
the maximum planned radioactivity of 12.9 GBq, fractionated into two administrations 
separated by 6 weeks, is administered without safety concerns and is thus defined as the 
MACA. 
Once the radioactivity escalation has been completed, the MTCA level may be repeated based 
on the results of the Bayesian model in a last cohort of three to five subjects with the same 
peptide mass dose to confirm the safety profile. If the MTCA is not reached and if limiting 
organ absorbed doses are not exceeded at the highest planned radioactivity (12.9 GBq) and if 
no individual withdrawal criteria are met, the inclusion of an additional cohort with a higher 
cumulative radioactivity will be evaluated. 
Note: an application for a substantial amendment will be submitted for approval by the CAs 
and/or ECs (as applicable) before initiating changes to the study conduct. 
3.1.4.1.6 Optional Additional Cycles 
If a subject tolerates well the treatment and shows clinical benefit (e.g. complete response (CR), 
partial response (PR), or stable disease) after the two first cycles, up to four additional cycles 
(177Lu-OPS201 administration, 6 weeks apart) at a radioactivity adjusted based on dosimetry 
results can be administered to this subject provided limiting organ absorbed doses have not been 
exceeded (see Figure 4). The decision to administer additional cycles or any other anti-tumoural 
treatment is left 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: 
• 
  subject will be eligible for an additional administration of 177Lu-OPS201 only if: 
- 
blood cell counts and renal function are in the range defined in the study inclusion 
criteria (#7), within the treatment cycle 
- 
organ absorbed doses did not exceed 1.5 or 2 Gy in BM (see details below) and 23 
Gy in kidney. 




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parallel of Cohort 5 (see Figure 5)). The same subject cannot participate in the radioactivity 
escalation cohort and the peptide mass dose cohort. 
Figure 5 Initial Phase I Study Design Including Activity Escalation (in Blue) and Peptide Mass Dose 
Evaluation (in Green) 
 
3.1.5 
Treatment Period - Phase II  
Phase II is a multicentre study with open-label multiple single arm cohorts using Simon's 
optimal two-stage design to evaluate the efficacy, as assessed by ORR, of treatment with 
177Lu-OPS201 in subjects with locally advanced or metastatic SCLC, or metastatic HR+/HER2- 
BC expressing sstr2, as identified by 68Ga-OPS202 PET/CT scans. 
Approximately 76 subjects with locally advanced or metastatic SCLC and approximately 96 
subjects with metastatic HR+/HER2- BC deemed sstr2-positive on 68Ga-OPS202 PET/CT 
scans will receive the 177Lu-OPS201 treatment regimen recommended based on the results of 
the phase I. It is expected that two cycles of 177Lu-OPS201 will be administered in subjects 
enrolled in phase II. Up to four additional cycles might be administered in subjects who tolerate 
the treatment well and show clinical benefit (CR, PR, or stable disease) after the first two cycles. 
These additional cycles will be administered at radioactivity adjusted based on dosimetry 
results, provided limiting organ radiation dose levels have not been exceeded.  
Additional cohorts could be added to the study according to evidence based on preclinical and 
clinical work and data on 68Ga-OPS202 and 177Lu-OPS201, sstr2 expression and candidate 
diseases. 
An independent safety assessment committee (ISAC) structured to assess safety in addition to 
efficacy will be established during phase II in order to make recommendations regarding 
protocol modifications to reduce risks to subjects enrolled in the trial.  


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Post-treatment Period 
Subjects in each phase of the study will have 2-year follow-up after the end of the last 
177Lu-OPS201 Cycle, with a visit every 3 months until 24 months, disease progression, death 
or withdrawal of full consent, whichever occurs first. 
3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Primary Endpoints and Evaluations 
3.2.1.1 
Phase I 
The primary endpoint is the MTCA or the MACA if the MTCA is not identified during the 
phase I. The primary variables determining the MTCA will be the incidence of DLTs and the 
cumulative organ absorbed doses (Gy) during two cycles of treatment. The DLT assessment 
period for the determination of the primary endpoint starts from the first administration of 
177Lu-OPS201 and ends 6 weeks after the second administration. 
3.2.1.2 
Phase II 
The primary endpoint is ORR over the two treatment cycles of the core study measured by the 
ICL. Objective response is defined as the sum of PR and CR measured by CT or MRI using 
RECIST version 1.1. Tumour response assessments are performed 6 weeks after each 
administration of 177Lu-OPS201 during the core study or at the time of occurrence of first 
clinical signs of disease progression as determined by the investigator. All images will be sent 
to an ICL for evaluation and confirmation of response (see Section 7). 
3.2.2 
Secondary Endpoints and Evaluations 
3.2.2.1 
Phase I 
Pharmacokinetics, Biodistribution and Dosimetry 
For PK, biodistribution and dosimetry of 177Lu-OPS201, the endpoints are:  
• 
Maximum observed concentration (Cmax), time to maximum observed concentration 
(tmax), maximal uptake (%), area under the curve (AUC) at the target lesions, discernible 
organs and blood and elimination half-life (t½) of radioactivity concentrations in blood. 
• 
Highest absorbed dose, Specific absorbed dose to the target lesions (Gy/GBq), Specific 
absorbed dose per organ (Gy/GBq) and Cumulative absorbed organ doses (Gy). 
For PK of OPS201, the endpoints are: 
• 
Pharmacokinetic parameters including, but not limited to, Cmax, AUC, t1/2, total plasma 
clearance (CL), apparent volume of distribution (Vd), cumulative amount (of unchanged 
drug) excreted into the urine (Ae), renal clearance, as measured in plasma and urine at 
defined timepoints. 
Pharmacodynamic/Efficacy 
• 
Mean change (%) in tumour volume at 6 weeks after each 177Lu-OPS201 administration 
compared to Screening as assessed by CT or MRI: 
- 
RECIST version 1.1 (tumour size is defined as the sum of the diameters of the 
target lesion in subjects who received 177Lu-OPS201) 
- 
volumetric CT 
• 
PFS as determined from start of study treatment until occurrence of tumour progression 
or death.  


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• 
BOR defined as the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). 
• 
OS at 1-year and 2-year follow-up as determined from start of study treatment until 
occurrence of death of any cause. 
• 
Quantitative changes (SUV normalised by lean body mass (SUL)max and SULmean) in 
tumour-to-background 18F-FDG-PET uptake using PERCIST version 1.0, from 
Screening to 6 weeks after second 177Lu-OPS201 administration (second cycle). 
• 
Correlation between tumour uptake on 68Ga-OPS202 PET/CT (assessed based on 
SUVmax and SUVmean) at screening with tumour response to 177Lu-OPS201 therapy from 
Screening to 6 weeks after second 177Lu-OPS201 administration (second cycle). 
• 
Correlation between the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 on 
PET/CT images and the uptake on 177Lu-OPS201 SPECT/CT 
• 
Changes in tumour uptake (assessed based on SUVmax and SUVmean) on 68Ga-OPS202 
PET/CT from Screening to 6 weeks after second 177Lu-OPS201 administration (second 
cycle) as compared to clinical response and BOR.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging using RECIST by subject-based 
analysis.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging using mGa-RECIST by subject-based 
analysis.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by subject-based, organ-based and 
lesion-based analysis compared to standard-of-truth (SOT) of ceCT (or ceMRI).  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by both organ-based and lesion-based 
analysis compared to SOT of 177Lu-OPS201 SPECT/CT. 
3.2.2.2 
Phase II 
Efficacy 
All the below endpoints will be calculated per cohorts. All imaging endpoints will be assessed 
by blinded independent readers managed by the ICL. 
• 
Durable response rate (DRR: CR or PR lasting ≥6 months)  
• 
PFS as determined from start of study treatment until occurrence of tumour progression 
or death. 
• 
Other response endpoints (same timepoints as for PFS): 
- 
disease control rate (DCR) 
- 
time to progression (TTP)  
- 
time to response (TTR) 
- 
duration of response (DoR) 
• 
Mean change (%) in tumour volume at 6 weeks after each 177Lu-OPS201 administration 
(each cycle) compared to baseline, as assessed by volumetric CT/MRI. 
• 
OS at 1-year and 2-year follow-up as determined from start of study treatment until 
occurrence of death of any cause. 
• 
Quantitative changes (SUV normalised by lean body mass (SUL)max and SULmean) in 
tumour-to-background 18F-FDG-PET uptake using PERCIST version 1.0, from 
Screening to 6 weeks after second 177Lu-OPS201 administration (second cycle). 


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• 
Correlation between tumour uptake on 68Ga-OPS202 PET/CT (assessed based on 
SUVmax and SUVmean) at screening with tumour response to 177Lu-OPS201 therapy from 
Screening to 6 weeks after second 177Lu-OPS201 administration (second cycle). 
• 
Correlation between the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 on 
PET/CT images and the uptake on 177Lu-OPS201 SPECT/CT 
• 
Change in 68Ga-OPS202 uptake on PET scan after the second 177Lu-OPS201 
administration (second cycle) as assessed by SUVmax and SUVmean in subjects screened 
for 177Lu-OPS201 treatment as compared to clinical response and ORR. 
• 
Proportion of subjects with sstr2-positive tumour lesions by 68Ga-OPS202 PET/CT scans 
as assessed by the identification of avid lesions in subjects screened for 177Lu-OPS201 
treatment at baseline.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging using RECIST by subject-based 
analysis.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging using mGa-RECIST by subject-based 
analysis.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by subject-based, organ-based and 
lesion-based analysis compared to SOT of ceCT (or ceMRI).  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by both organ-based and lesion-based 
analysis compared to SOT of 177Lu-OPS201 SPECT/CT. 
Subject Reported Outcomes 
• 
Changes in health-related quality of life scores from baseline to EOCT measured by 
EuroQoL 5-dimension 5-level (EQ-5D-5L) and The European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). 
Safety Endpoints and Evaluations 
• 
Safety and tolerability measured by the type, nature, severity, expectedness and 
frequency of AEs overall and per grade according to the current version of the National 
Cancer Institute Common Terminology Criteria Adverse Event (NCI-CTCAE) 
(version 5.0) and significant laboratory abnormalities. 
Pharmacokinetics, biodistribution and dosimetry endpoints and measurement timepoints for 
phase II will be defined according to the phase I results. 
3.3 
Exploratory Endpoints (Phase I/II) 
3.3.1 
Biomarkers 
• 
Association between the uptake on 68Ga-OPS202 PET/CT with sstr2 expression on 
tumours as determined by IHC. 
• 
Change in renal safety biomarkers compared to baseline. 
• 
Change from baseline in tumour microenvironment, transcriptomics, DNA repair, gene 
mutations and other disease markers of interest. 
• 
Change from baseline in DNA repair capacity in blood. 
3.3.2 
Biobanking 
The exploratory endpoint comprises biobanking of samples for future analysis, among subjects 
who consent. Analysis of additional biomarkers from the biobank samples will be performed 
outside the scope of the main study and reported separately. 


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Serum, cfDNA and whole blood ribonucleic acid (RNA) samples will be collected on Day 1 
(or Day -1) of Cycle 1 before infusion and at Day 1 of Cycle 2 before infusion and at 
EOCT/EOAC/early withdrawal (EW).  
3.4 
Randomisation and Blinding 
This is a nonrandomised, open-label study. 
Independent readers will evaluate 68Ga-OPS202 PET/CT and 18F-FDG-PET/CT images 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 exam findings.  
Independent readers are specialised radiologists and/or nuclear medicine physicians who are 
experienced in reading PET/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 (IRC). 
3.5 
Maintenance of Randomisation and Blinding 
This is a nonrandomised, open-label study. 
3.6 
Study Treatments and Dosage 
3.6.1 
Investigational Imaging Product (IIP): 68Ga-OPS202 
The treatment is provided as a sterile two-vial radiolabelling kit constituted of freeze-dried 
powder containing 50 μg non-radiolabelled precursor OPS202 and excipients (Vial A) and the 
solvent for reconstitution (Vial B) to be used prior to radiolabelling. 
The investigators will receive a certificate of conformity and a certificate of analysis for each 
batch of the radiolabelling kit. A Material Safety Data Sheet is also available.  
The radiolabelling kit will be packaged and delivered to the investigational sites. A sufficient 
quantity of radiolabelling kit will be supplied as well as an acknowledgement of receipt form. 
The investigator’s representative will receive: 
• 
A Certificate of Compliance/Analysis for each batch of kit for radiolabelling that will be 
used during the study which reflect the product release statement. 
• 
Material Data Safety Sheet. 
• 
Packaging order. 
The radiolabelling kit and all vials will be labelled. After preparation, the IIP will be placed in 
a shielding container and the container labelled. Each label will be designed in accordance with 
Appendix 13 of the European Union Good Manufacturing Practices (EU-GMP) and in 
accordance with specific local requirements if any. 
Radiolabelling yields the IIP 68Ga-OPS202 as a solution for injection. After quality control 
(QC) sampling, the volume to be injected into the subject is withdrawn from the IIP vial, 
containing up to 45 μg OPS202. This volume is determined to obtain the target radioactivity at 
the time of administration, taking into account the decay of 68Ga. All subjects will receive at 
Screening visit a single dose of 68Ga-OPS202 (IIP), with 68Ga radioactivity of 150-200 MBq, 
injected intravenously. A single dose of 68Ga-OPS202 will also be administered after two cycles 
at EOCT. 
The investigator or designee will only dispense IIP to subjects included in this study. Each 
subject will be given the IIP carrying his/her number. 
A more detailed description of preparation and administration procedures is given in 
Section 6.2.1. 


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3.6.2 
Investigational Radio-Pharmaceutical Product (IRPP): 177Lu-OPS201 
The IRPP is manufactured and supplied directly to the clinical site from a central contract 
manufacturing organisation. It is manufactured by Sofie Co. dba Sofie (110 Clyde road, 
Somerset, NJ 08873, USA). The IRPP will be supplied in a type 1 borosilicate glass vial sealed 
with a chlorobutyl stopper and aluminium seal with a flip off cap, within a secondary shielding 
container and is shipped inside a temperature-controlled and Type A package for transporting 
radioactive materials. 
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 EU-GMP and in accordance 
with specific local requirements if any. 
The IRPP is a 20-mL solution for injection with OPS201 dose of either 300 μg (±15%) or 
700 μg (±15%) and radioactivity of 3 to 7.4 GBq 177Lu-OPS201. All subjects will receive a 
loading dose ranging from 4.5 to 7.4 GBq (±10%) and a maintenance dose ranging from 3 to 
5.5 GBq (±10%), injected intravenously.  
The investigator or designee will only dispense IRPP to subjects included in this study. Each 
subject will be given the IRPP carrying his/her number. 
For renal protection purpose, an amino acid solution (Lysine and Arginine based) must be 
administered intravenously. 
A more detailed description of administration procedures is given in Section 6.2.2.  
3.7 
Study Duration 
In phase I, for subjects receiving only two treatment cycles of 177Lu-OPS201, this study will 
consist of up to 3-week screening period and a 12-week dosing period (+ up to additional 
4 weeks in case of AEs that need to be adequately recovered). A treatment cycle is defined as 
the timeframe of 6 (up to 10) weeks between two administrations or the timeframe of 6 weeks 
following the last administration. In case of logistical issues, the cycle could be extended by up 
to additional 2 weeks. Dosing period can be extended up to 36 weeks in case subjects receive 
up to four additional cycles (see Section 3.1.4.1.6). Subjects are thus expected to participate in 
this study for a minimum of 15 weeks and up to 39 weeks (+ up to additional 4 weeks in case 
of AEs that need to be adequately recovered). In all cases, a long-term follow-up lasting 
24 months will start after the end of the last 177Lu-OPS201 cycle. 
For phase II, it is anticipated that the duration of the study will be identical to the duration in 
phase I; however, pending the results of phase I on recommended treatment regimen (doses and 
intervals) the study duration will be refined.  
The subject’s participation in the treatment period of the study will be considered to have ended 
at the EOCT or EOAC visit. The subject’s participation in the 24-month follow-up period of 
the study will be considered to have ended when the subject dies, withdraws consent to the 
follow-up period, or ends the 24-month follow-up, whichever occurs first. 
The overall duration of the study will be approximately 5.5 years. The study will be considered 
to have started when the first site has been initiated.  
The study will be considered to have ended after the last subject has completed the last 
follow-up visit in the study. 


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3.8 
Stopping Rules and Discontinuation Criteria 
3.8.1 
Individual Discontinuation Rules 
A subject (or a legal representative) has the right to withdraw from the study at any time and 
for any reason without prejudice to their future medical care by the investigator at the 
institution.  
The investigator and/or sponsor can decide to withdraw a subject from investigational product 
and/or other protocol-required therapies, protocol procedures, or the study as a whole at any 
time prior to study completion for the following reasons: 
• 
Subject no longer experiences clinical benefit as determined by the investigator. If study 
treatment is withdrawn for this reason, the date this decision is to be recorded and every 
effort should be made to continue safety evaluations, tumour assessments, and collection 
of subsequent anticancer treatment information and follow-up information for survival. 
• 
Unacceptable side effects the investigator feels may be due to study treatment. 
• 
The investigator feels it is not in the best interest of the subject to continue on study. 
• 
Subject participation in another clinical study using an investigational agent or 
investigational medical device. 
• 
Necessity for treatment with other systemic anticancer therapy (non-protocol defined). 
• 
Necessity for withholding study drug for greater than 6 weeks for study-treatment related 
AEs. 
• 
Refusal of sexually active fertile subjects (excluding subjects who have been sterilised) 
to use medically accepted methods of contraception. 
• 
Female subjects who become pregnant. 
• 
Request by the sponsor. 
• 
Subject request to discontinue study treatment (with or without concurrent withdrawal of 
informed consent). 
• 
Significant noncompliance with the protocol schedule in the opinion of the investigator 
or the sponsor (see protocol violation or deviation as defined in Section 13.1.2). 
In addition, if any of the following occur, no further treatment will be administered: 
• 
Cumulative kidney absorbed dose exceeds 23 Gy. 
• 
Cumulative BM absorbed dose exceeds 1.5 Gy during core trial or up to 2 Gy during 
additional cycles, as determined by dosimetry of peripheral blood samples and imaging. 
• 
Subject has not sufficiently recovered from an adverse event despite extension of the 
dosing interval by 4 weeks (such as delayed grade 3-4 haematotoxicity) 
• 
Hypersensitivity to the active substance or to any of the excipients of the study drugs 
• 
Radiological disease progression 
Subjects who experience a significant toxicity (such as DLT or Grade 3 or 4 haematological 
toxicity) will be allowed to continue to receive study treatment at a lower activity level at the 
discretion of the investigator and will be closely monitored for safety. 
Temporary discontinuation of treatment with 177Lu-OPS201 could be decided upon occurrence 
of an intercurrent disease, which according to the investigator could increase the risks 
associated to the IRPP administration; major surgery, specific adverse reactions to 
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No radiation dose limits have been set for other organs than kidney and bone marrow either 
since the expected cumulative absorbed dose in these organs is well below the limits described 
in the ICRP guideline (e.g. liver) (ICRP Publication 41) or since no radiation dose limit is 
reported in the aforementioned guideline for this organ (e.g. spleen). 
All cases of discontinuation will be discussed between the investigator and the sponsor. 
A subject can also withdraw their consent to the treatment period but agree to take part in 
24-month follow-up period. This will be captured in the medical file and in the electronic case 
report form (eCRF).  
3.8.1.1 
Definition of Dose Limiting Toxicity (Dose Escalation) 
The DLTs are defined for any of the following IRPP-related AEs according to NCI-CTCAE 
scale version 5.0 that occur during the defined DLT assessment period (from the first 
administration of 177Lu-OPS201 to 6 weeks after the second administration): 
• 
Grade 4 neutropenia lasting for seven or more consecutive days. 
• 
Grade 3 and 4 febrile neutropenia. 
• 
Grade 4 thrombocytopenia for seven or more consecutive days. 
• 
Grade 3 thrombocytopenia complicated by a bleeding event. 
• 
Grade 4 anaemia. 
• 
Grade 3 anaemia requiring transfusion. 
• 
Grade 3 or higher laboratory abnormalities of aspartate amino transferase/alanine amino 
transferase (AST/ALT) and/or bilirubin, with the following exceptions: 
- 
for subjects with Grade 1 AST/ALT at baseline (>upper limit of normal (ULN) to 
3xULN), a AST/ALT level of >7.5xULN will be considered a DLT. 
- 
for subjects with Grade 2 AST/ALT at baseline (>3xULN to 5xULN), a AST/ALT 
level > 10xULN will be considered a DLT. 
• 
any Grade 3 or higher acute kidney injury (creatinine >3x baseline or >4.0 mg/dL). 
• 
Grade 3 or higher non-haematological toxicity excluding: 
- 
Grade 3 nausea, vomiting or diarrhoea for less than 72 hours with adequate 
supportive care 
- 
Grade 3 fatigue lasting less than a week 
- 
Grade 3 or higher electrolyte abnormality that lasts for less than 72 hours, is not 
clinically complicated and resolves spontaneously or with conventional medical 
interventions 
- 
Grade 3 or higher amylase or lipase not associated with symptoms or clinical 
manifestations of pancreatitis 
• 
any toxicity related to 177Lu-OPS201 resulting in a treatment delay of more than 4 weeks 
due to delayed recovery to baseline or resolution of any AE of Grade 2 or more 
(exception of alopecia and lymphopenia). 
• 
Grade 5 toxicity (death) 
DLT Assessment: During the DLT assessment period (from first administration of 
177Lu-OPS201 to 6 weeks after the second administration), two assessments over 6 weeks each 
will be performed. The first, between first and second administration and the second, between 
second administration and EOCT visit. 
DLT Population: Subject will be evaluable for DLT if received Cycle 1 and Cycle 2 
administrations and completed DLT assessment period (i.e. 6 weeks after second 


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administration) or stopped treatment because of a DLT during DLT assessment period. 
If a subject is considered Not Evaluable for DLT due to withdrawal during DLT assessment 
period, he/she will be replaced by another subject. 
3.8.1.2 
Procedures for Subject Discontinuation 
If a subject drops out or is discontinued from the treatment period of the study after IRPP 
administration and before planned study completion, an EW visit will take place within 6 weeks 
after the last IRPP administration. This visit will correspond to an EOCT visit (or EOAC visit 
if the subject dropout during additional cycles). Thereafter, follow-up visits will take place 
every 3 months. Subjects who discontinue study treatment for reasons other than disease 
progression (e.g. toxicity) should continue to undergo scheduled tumour assessments until the 
subject dies, experiences disease progression, withdraws consent to the follow-up period, or 
until the end of the two-year follow-up, whichever occurs first. 
The reason for and date of withdrawal from the study must be recorded in the eCRF.  
If the discontinuation is based on subject decision, every attempt will be made to determine the 
reason for discontinuation. The data collected on the subject to the point of withdrawal remains 
part of the study database and may not be removed. 
Subjects withdrawn from the study for unacceptable AE(s) will be followed by the investigator 
until resolution or stabilisation of the AEs.  
3.8.1.3 
Replacement Rules 
In phase I, a cohort will be considered as completed once three subjects of the cohort complete 
Cycle 2 or discontinue early during Cycle 2. If subjects discontinue for any reason other than a 
DLT (e.g. disease progression) before end of Cycle 2, they might be replaced. 
3.8.2 
Discontinuation of a Cohort or a Site or Study Termination 
The phase I will be terminated once the MTCA has been determined. The phase II is designed 
with early stopping criteria, allowing any cohort to be closed early in case of futility. 
A specific site or a given cohort can also be discontinued or the entire study may be terminated 
at any time if the sponsor judges it necessary for any reason. In that case, all scheduled 
procedures and assessments for subjects who are still in the study will be performed. Some 
possible reasons for the closure of a study site may include: 
• 
failure of the investigator staff to comply with the protocol or with the GCP guidelines. 
• 
safety concerns. 
• 
inadequate subject recruitment. 
Both safety and anti-tumour activity of 177Lu-OPS201 in subjects in phase II as well as of 
subjects from phase I receiving additional cycles of 177Lu-OPS201 will continue to be 
monitored by the DRB and by the ISAC on an ongoing basis. The decision to halt enrolment or 
to discontinue a subject or a cohort may be made by DRB and ISAC at any point if a safety 
signal or unacceptable toxicity are observed. 
In case of premature discontinuation of a site or the complete study, depending on the reason(s) 
for the discontinuation, the sponsor will notify the investigator(s) affected in writing as to 
whether the ongoing subjects should continue the remaining IRPP dose administration(s).  
3.8.3 
Study Stopping Rules 
Should, at the start of the study, 20 consecutive subjects fail screening due to 68Ga-OPS202 
PET/CT negative for sstr2 with all the other inclusion/criteria met, the administration of 


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68Ga-OPS202 and subsequent PET imaging will be stopped. Selection of sstr2-positive tumours 
for the treatment with 177Lu-OPS201 will be revised in a protocol amendment. 
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 (with subject status), 
IIP/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). 
The subject must have consented to their medical records being viewed by the sponsor’s 
authorised personnel and by local and possibly foreign, CAs. This information is included in 
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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Eligibility Criteria for 68Ga-OPS202 Imaging 
4.1.1 
Inclusion Criteria 
All subjects must fulfil all the following criteria to undergo the 68Ga-OPS202 imaging (phase 
I/II): 
(1) 
signed informed consent prior to initiation of any study-specific activities/procedures.  
(2) 
male (except for BC cohort) or female subject aged 18 years or older. 
(3a) histologically confirmed cancer, that is locally advanced or metastatic disease, which has 
progressed during or after, failed to respond to, or for which there is poor tolerability or 
a contraindication to available SoC treatment options as per the assessment of the 
investigator; initially, subjects with the disease below may be considered: 
(a) 
Subjects who had ED-SCLC at presentation who have progressed on or after one 
line of standard chemotherapy. If a subject had LD-SCLC at presentation and 
received surgery and/or radiotherapy as first line treatment (with or without 
chemotherapy) and has localised relapse, further local treatment (such as surgery) 
should be considered in addition to the chemotherapy options. 
For subjects with either ED-SCLC or LD-SCLC, if subjects relapse more than 
6 months after first-line treatment, re-treatment with their initial regimen is 
recommended.  Subjects may have received prior immunotherapy. 
(b) 
Subjects with HR+/HER2- metastatic BC after failure of prior SoC treatments and 
who have received, if indicated, at least one line of hormonal therapy, CDK4/6 
inhibitor and/or everolimus for advanced or metastatic disease and at least one line 
of chemotherapy for metastatic disease; subjects with BRCA-mutated metastatic 
disease who may have received a PARP inhibitor, if available, are eligible; prior 
adjuvant hormonal treatment and prior adjuvant chemotherapy are allowed. 
(4) 
disease must be unsuitable for curative surgical resection and must not be amenable to 
curative radiotherapy. 
(5a) documented progressive disease (radiological, based on RECIST v1.1) within 3 months 
prior to first study drug administration. Screening study-related images should be sent to 
the ICL. 
Note: All images of the two datasets documenting progression should be sent to ICL. 
(6) 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
(7a) 
adequate organ function determined within 28 days prior to 
177Lu-OPS201 
administration, defined as follows:  
• 
Haematological:  
- 
white blood cells (WBC) ≥3000/μL, with absolute neutrophil count 
≥1000/μL, platelet ≥100,000/μL and haemoglobin ≥9 g/dL (without need 
for hematopoietic growth factor or transfusion support). 
• 
Renal:  
- 
eGFR ≥55 mL/minute/1.73m2   
• 
Hepatic:  
- 
total serum bilirubin ≤2×ULN 
- 
-aspartate 
aminotransferase/ 
alanine 
aminotransferase 
≤2.5×ULN 
(≤5×ULN if subject has liver metastases). 


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(8a) has a formalin fixed paraffin embedded tumour sample (archival tumour sample obtained 
within 1 month prior to consent) from the primary or metastatic lesion OR is willing to 
undergo newly obtained biopsy prior to first dose of study treatment. Subjects who are 
unable or do not consent to provide acceptable tissue may not be enrolled unless there 
has been prior agreement with the sponsor. 
Note: the subject will be enrolled (if he/she fulfills all inclusion criteria and has no 
exclusion criterion) irrespective of the biopsy result 
(9) 
estimated life expectancy >3 months. 
Eligibility Criteria for Therapy (Phase I/II) 
To receive 177Lu-OPS201 therapy, each subject must fulfil all the eligibility criteria including 
the below criteria: 
(10a) 68Ga-OPS202 uptake in target tissue (primary tumour, lymph nodes and/or metastases) 
showing at least two avid (uptake ≥1.5 non-tumour liver and lung uptake) lesions of 
≥20 mm in the longest diameter on PET/CT as confirmed by central reader. 
(11) Radiologically, ≥50% matching between the lesions detected on 68Ga-OPS202-PET/CT 
and on 18F-FDG-PET/CT as confirmed by central reader 
The inclusion criteria for phase II will be refined based on the results from phase I as well as 
type of possible additional tumours and indications to be investigated and will be documented 
as part of a protocol amendment. 
4.1.2 
Exclusion Criteria 
Eligible subjects must not have any of the following conditions (phase I/II): 
(1) 
male subjects with BC.  
(2a) 
unstable central nervous system metastasis defined as (any of the following): 
(a) 
Radiographic evidence of new or progressive brain metastases after prior radiation 
therapy with at least one brain metastasis measuring ≥1 cm in longest diameter on 
gadolinium-enhanced magnetic resonance imaging (MRI), and/or 
(b) 
Imaging following prior radiation is not consistent with pseudo-progression in the 
judgment of treating clinician, and/or 
(c) 
Evidence of diffuse leptomeningeal disease on brain MRI or by previously 
documented cerebrospinal fluid cytology. 
NOTE: discrete dural metastases are permitted. 
Subjects with previously treated brain metastases (with no lesion measuring ≥1 cm in longest 
diameter on gadolinium-enhanced MRI at the time of evaluation for the study) may participate 
provided they are neurologically stable as defined by (all the following need to be met): 
i. 
no evidence of progression by imaging and any neurologic symptoms have 
returned to baseline 
ii. 
no use of steroids and anti-convulsants for at least 7 days prior to IRPP 
administration. 
iii. 
no clinically significant mass effect, haemorrhage, midline shift, or impending 
herniation on baseline brain imaging. 
iv. 
no significant focal neurologic signs and/or symptoms that would necessitate 
radiation therapy or surgical decompression in the judgment of the treating 
clinician. 


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(3a) 
centrally located lung tumours that show radiological evidence (CT or MRI) of either:  
(i) cavitation or necrosis, or,  
(ii) focal invasion or major blood vessels. 
(4a) Subjects had received chemotherapy within the previous 4 weeks or had not recovered 
from adverse events due to chemotherapy. Additional exclusion criteria were previous 
hemibody external radiotherapy, systemic radiotherapy with radioisotopes within the 
previous 24 weeks. 
(5) 
previous chemotherapy within a cycle interval, curative radiotherapy within 4 weeks or 
palliative radiotherapy within 7 days prior to IRPP administration. 
(6) 
prior treatment with any other investigational medicinal product (IMP) within five 
half-lives of the previous IMP or within 2 weeks, if the previous compound is a 
mechanism-based molecularly targeted agent whose half-life is not well-characterised 
and toxicities have not resolved from Grade 2 or higher prior to IRPP administration.  
(7) 
any unresolved NCI-CTCAE Grade 2 or higher toxicity (except alopecia and Grade 2 
platinum-therapy related neuropathy) from previous antitumour treatment and/or 
medical/surgical procedures/interventions.  
(8) 
nephrectomy, renal transplant or concomitant nephrotoxic therapy putting the subject at 
high risk of renal toxicity during the study as assessed by the investigator. 
(9a) history of major thrombotic or clinically relevant major bleeding event in the past 
6 months putting the subject at high risk of bleeding during the study as assessed by the 
investigator (international normalisation ratio (INR) or prothrombin time ≥1.5xULN, 
unless the subject is receiving anticoagulant therapy). 
(10) prior major surgery from which the subject has not sufficiently recovered. 
(11a) known allergy to contrast medium product or 177Lu, DOTA, OPS200, OPS301 or any of 
the excipients of 177Lu-OPS201, as well as to 68Ga-OPS202 or its excipient. 
(12a) any condition that precludes the proper performance of PET and/or SPECT scans, CT 
scans and/or MRI: 
(a) 
subjects who are not able to tolerate the CT contrast agent.  
(b) 
subjects with metal implants or joint prosthesis (depending on the location, if 
interferes with the PET and/or CT analysis). 
Notes: Subjects with metal implants cannot undergo MRI; Subjects with medical 
devices in situ, which do not overlap with the Volume of Interest in the opinion of 
the radiologist or dosimetrist or are not expected to interfere with the imaging or 
interpretation, can be included. The dosimetry team should be informed of the 
presence of a device in situ. 
(c) 
or any other objects that might interfere with the PET and/or CT analysis. 
(d) 
subjects unable to raise arms for prolonged imaging purposes.  
(e) 
subjects unable to lie still for the entire imaging time. 
(f) 
subjects weighing greater than 130 kg (287 lb). 
(13a) subject with history of other malignancy within the past 3 years with the following 
exceptions: malignancy treated with curative intent and with no active disease and has 
not received chemotherapy for the last 3 years for these conditions; adequately treated 
non-melanoma skin cancer without evidence of disease; adequately treated cervical 
carcinoma in situ without evidence of disease; adequately treated breast ductal carcinoma 
in situ without evidence of disease; prostatic intraepithelial neoplasia without evidence of 


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prostate cancer at the time of enrolment; adequately treated superficial or in situ 
carcinoma of the bladder without evidence of disease. 
(14) other investigational procedures while participating in this study. 
(15a) clinically significant abnormalities on electrocardiogram (ECG) at screening including 
QTcF >450 msec for males or >470 msec for females at screening or subjects who cannot 
tolereate high volume load. 
(16) pregnant or lactating female. Female subject of childbearing potential who is unwilling 
to use acceptable method(s) of effective contraception during study treatment and 
through 6 months after the last dose of 177Lu-OPS201.  
OR  
male subject who is unwilling to use acceptable method of effective contraception during 
treatment and through 6 months after the last dose of 177Lu-OPS201. 
(17) subject likely not to be available to complete all protocol-required study visits or 
procedures and/or to comply with all the required study procedures to the best of the 
subject and investigator’s knowledge. 
(18a) history or evidence of psychiatric, substance abuse (except for tobacco smoking), or any 
other clinically significant disorder, condition or disease (including active known 
infection with HIV requiring systemic treatment, or known AIDS-related illness, or 
known active hepatitis B or C infection) that, in the opinion of the investigator or sponsor 
medical, if consulted, would pose a risk to subject safety or interfere with the study 
evaluation, procedures or completion. 
Notes: Female subjects must be either postmenopausal (any female who is age ≥55 years with 
cessation of menses for 12 or more months or less than 55 years and no spontaneous menses 
for at least 2 years or less than 55 years and no spontaneous menses within the past 1 year with 
postmenopausal gonadotropin and oestradiol levels) or permanently sterile, can enter the trial 
without taking specific contraceptive measures. Female subjects of childbearing potential must 
have a negative pregnancy test upon entry into this study and agree to use a highly effective 
method of contraception from Screening until 6 months after the last dose of 177Lu-OPS201; 
Highly effective methods of contraception that result in a low failure rate (i.e., <1% per year) 
when used consistently and correctly include combined (oestrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, 
or transdermal), progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable), intrauterine device, intrauterine hormone-
releasing system, bilateral tubal occlusion, vasectomised partner, or sexual abstinence;  
True abstinence, when in line with the preferred and usual lifestyle of the subject, is considered 
a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of study participation and for 6 months after the last dose of 177Lu-OPS201. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, and post-ovulation method) and withdrawal are not acceptable 
methods of contraception; and Male subjects must be either surgically sterile or agree to use a 
double-barrier contraception method from Screening until 6 months after the last dose of 
177Lu-OPS201. 
Egg cell and sperm donation are not permitted during the contraception period (up to 2 years 
after the study). 


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4.2 
Rationale for Inclusion/Exclusion Criteria 
Eligibility criteria consists of two parts that define subjects eligible for sstr2 expression 
screening with 68Ga-OPS202 PET/CT scan first and then those eligible for 177Lu-OPS201 
therapy depending on 68Ga-OPS202 PET scan results and matching between the lesions 
detected on 68Ga-OPS202-PET/CT and on 11818F-FDG-PET/CT. The first eligibility check 
already includes all criteria that apply for 177Lu-OPS201 therapy, thereby excluding ineligible 
subjects for treatment early on even if their tumour express sstr2.  
These criteria define the overall sstr2-positive population and add some clarifications for 
specific anatomical sites when appropriate. It excludes subjects who have conditions that 
prevent having readable PET images and/or make the analysis and interpretation of the results 
difficult or biased. Importantly, some criteria are added to mitigate the risks known with PRRT 
treatment, especially haematological and renal side effects. 
4.3 
Subject Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each subject is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a subject from the study in the event of concurrent illness, AEs, or 
other reasons concerning the health or wellbeing of the subject, or in the case of lack of 
cooperation. In addition, a subject may be withdrawn from the study as described in 
Sections 3.8, 5.2.4.1, 6.3, 8.1.6 and 8.1.9.  
If a subject decides to withdraw from the study after administration of IIP/IRPP, or should the 
investigator decide to withdraw the subject, all efforts will be made to complete and report the 
observations up to the time of withdrawal as thoroughly as possible. A complete final evaluation 
at the time of the subject’s withdrawal should be made (see Sections 5.2.4.1 and 5.2.4.2) and 
an explanation given of why the subject is withdrawing or being withdrawn from the study.  
The reason for and date of withdrawal from the study must be recorded on the eCRF. If a subject 
withdraws consent, every attempt will be made to determine the reason. If the reason for 
withdrawal is an AE or a clinically significant laboratory test abnormality, monitoring will 
continue until the event has resolved or stabilised, until the subject is referred to the care of a 
local health care professional, or until a determination of a cause unrelated to the IIP/IRPP or 
study procedure is made. The specific AE or test result(s) must be recorded on the CRF. All 
evaluations should be performed, according to the protocol, on the last day the subject receives 
IIP/IRPP, or as soon as possible thereafter. 
Subjects who withdraw consent for the treatment period may still enter the follow-up period if 
they wish to. 
Subjects may withdraw from the study during the long-term follow-up. The reason for 
withdrawal will be collected, but this will not be reported as premature withdrawal. 
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 samples are kept). If a subject wish to withdraw 
their consent for biobanking and the samples are still at the investigator site or at Central 
Laboratory at the time, the investigator must inform the study monitor in writing of the subject’s 
decision and destroy the samples. If the samples are at the sponsor’s repository (biobanking 
vendor), the investigator must inform Ipsen directly using the e-mail address, 
, mentioning only the subject ID in this e-mail. Ipsen will ensure 
destruction of the samples and all corresponding aliquots and issue confirmation of the 
PPD


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destruction, which will be forwarded to the investigator. Analyses conducted before the 
withdrawal will not be affected. 


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5 
STUDY PROCEDURES 
5.1 
Study Schedule 
The phase I schedule of assessment during the study is summarised in Table 5 for the core 
treatment phase and in Table 6 for the additional cycles. The phase II schedule of assessment 
will be based on the phase I results and documented as part of a protocol amendment.  
 






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CONFIDENTIAL 
 
PROTOCOL: VERSION 2.0, 07 MARCH 2019 
PAGE 86/196 
 
Further antitumour 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Procedures and 
assessments 
Screening 
CORE TREATMENT PHASE 
EOCT 
or EW 
[a] 
Long-term FU [b] 
 
 
Cycle 1 
Cycle 2 
 
 
 
D-28 to  
D-1 
Week 1 
W3 
W4 
W5 
W6 
W7 
W9 W10 W11 W12 
W14 
 
 
D1 
D2 D3 D4 
D5 
D7 
D8 
D15 
D22 
D29 
D36 
D1 
D2 D3 D4 
D5 
D7 
D8 
D15 D22 D29 D36 
D50 
(EOCT) 
 
Visit window (days) 
 
 
 
 
 
±1 
±1 
±1 
±1 
+28 [c] 
 
 
 
 
±1 
±1 
±1 
±1 
+7 
±14 
ECG (12-lead) [q] 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
6-hour ECG (Holter) [r] 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
[a] 
The End of Core Treatment (EOCT) visit, planned at Day 50 of Cycle 2, will take place for all subjects, even if they can benefit from additional cycles. In such a case, EOCT visit and Day 
1 of first additional cycle can occur on the same day. The Early Withdrawal (EW) visit will take place within 14 days after the decision to withdraw a subject early. Afterwards, the subject 
will enter the follow-up period. 
[b]  Follow-up visits will take place every 3 months (±14 days) for 2 years. It starts after the cycle of the last IRPP (177Lu-OPS201) administration. Subjects will be monitored for survival. 
Tumour imaging will also take place for the subjects who discontinued study treatment before disease progression and who have not withdrawn consent for this long-term follow-up. 
[c] 
In case of toxicity management requiring a delay, the next 177Lu-OPS201 treatment administration will be delayed to up to 4 weeks. 
[d] Supine and standing systolic and diastolic blood pressure, heart rate, body temperature, respiratory rate. For the day of infusion: Prior to infusion and at infusion completion (0 minutes), 
30±5 minutes, 60±10 minutes, 4 hours ±10 minutes after the end of infusion. 
[e] 
At screening only: haematology should be repeated within 48h before first infusion. Blood haematology: RBC count, haemoglobin, haematocrit, mean corpuscular volume (MCV), mean 
corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils and basophils) 
and platelet count. See also Section 8.2. 
[f] 
At screening only: biochemistry should be repeated within 48h before first infusion. Blood biochemistry: urea, uric acid, creatinine, creatinine clearance, total bilirubin, conjugated 
bilirubin, chloride, bicarbonate, sodium, potassium, calcium, phosphate, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl 
transferase (GGT), albumin and total protein, total cholesterol, triglycerides, fasting glucose, C-reactive protein (CRP). eGFR will be calculated based on serum creatinine levels using 
MDRD formula. See also Section 8.2. 
[g] Urinalysis includes pH, protein, ketones, bilirubin, blood, urobilinogen, nitrites, leucocytes, glucose; proteinuria will be performed with dipsticks, in case of positivity, a proteinuria/24h 
will be performed. See also Section 8.2. 
[h] Serum pregnancy test will be performed at the screening visit and EOCT. A urine pregnancy test will be performed on Day 1 of each treatment cycle before IRPP infusion. 
[i] 
Predose DNA repair capacity in blood at Day 1 and specific renal safety biomarkers (alpha-glutathione S-transferase (GST), glutathione S transferase P1 (GSTP1), kidney injury molecule-
1 (KIM-1) antigen, clusterin, cystatin-C, calbindin, beta-2 microglobulin, creatinine) at Day 1 or at D-1 (before administration day). See also Section 8.2. 
[j] 
Activity measured on blood samples (n=10 per cycle) before the infusion (baseline), at the end of 177Lu-OPS201 infusion (0) and at 5±1 minutes, 30±5 minutes, 1 hour (±5 minutes) and 4 
hours (±30 minutes), 24±2 hours, 48±2 hours, 72 to 96 hours and 144 to 168 hours after the end of 177Lu-OPS201 infusion (Cycle 1 and 2). 
[k] OPS201 plasma levels in blood samples (n=10 samples) collected at Cycle 1 at the following time points: before the infusion (baseline), at the end of infusion (0) and at 5±1 minutes, 30±5 
minutes, 1 hour (±5 minutes) and 4 hours (±30 minutes), 6 hours (±30 minutes), 8 hours (±30 minutes), 24±2 hours and 48±2 hours post-infusion of 177Lu-OPS201 
[l] 
Activity measured on urine collected over the first 48 hours post-infusion at the following time intervals: 0 to 4, 4 to 8, 8 to 24 and 24 to 48 hours (0 to 4 and 4 to 8 hours only in US sites) 
post-infusion, with an initial void collection shortly before the infusion (0 hour) and a final collection 48 hours after administration of 177Lu-OPS201 (Cycle 1 only). 
[m] OPS201 urine levels in urine collected at Cycle 1 at the following time intervals: 0 to 4, 4 to 8, 8 to 24 and 24 to 48 hours (0 to 4 and 4 to 8 hours only in US sites) post-infusion, with an 
initial void collection shortly before the infusion (0 hour) and a final collection 48 hours after administration of 177Lu-OPS201 (Cycle 1 only).  


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D-FR-01072-002 
CONFIDENTIAL 
 
PROTOCOL: VERSION 2.0, 07 MARCH 2019 
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[n] Hypothalamic-pituitary-adrenal axis biomarkers sample for hormone analysis (sstr2 organ expressing) should be taken predose at the closest to 8.00 am and includes analysis of 
Pituitary/Adrenal axis (FT4, TSH, LH, FSH, cortisol, IGF-1) Pancreatic function (glucose, glycosylated haemoglobin (HbA1c)) and Testicular function (testosterone, Inhibin B; SHBG). 
Protocol allows the collection of those pre dose samples at D-1 before the administration day (D1). See also Section 8.2. 
[o] DNA-DSB measured in lymphocytes (n=6 per cycle) before the infusion (baseline), at 1 hour (±10 minutes),  4 hours (±30 minutes), 24 hours (±2 hours), 48 (±2 hours) and 72 to 96 hours 
after the end of 177Lu-OPS201 infusion (Cycle 1 and Cycle 2) 
[p] Biobanking samples (serum and whole blood) for exploratory biomarkers should be taken predose. It can only be obtained after signature of optional biobanking informed consent form. 
Protocol allows the collection of those pre-dose samples at D-1 before the administration day (D1). 
[q] Single 12-lead ECG to be recorded in the supine position after at least 5 minutes of rest at screening, at Day 1 before the infusion (baseline) and at EOCT visit. 
[r] 
Starting before study drug administration, a 6-hour 3-lead continuous Holter ECG will be recorded. 
[s] 
68Ga-OPS202 imaging will only be acquired once inclusion/exclusion criteria are confirmed (Biopsy can be done after 68Ga-OPS202 PET eligibility has been confirmed, provided the 
subject’s agreement to undergo biopsy was obtained before 68Ga-OPS202 PET). All images will be sent to the ICL. ceCT/MRI is to be performed with the 68Ga-OPS202 PET scan unless it 
was done with the 18F-FDG-PET or alone within 2 weeks. In this case low dose CT could be performed with 68Ga-OPS202 PET. 
[t] 
The ceCT/MRI imaging including brain will take place 6 weeks (± 3 days) after each administration of 177Lu-OPS201 using the same imaging method. 
[u] 
18F-FDG-PET whole-body including brain unless performed within 28 days prior to the first administration. All images must be sent to the central ICL. 
[v] In case archival tissue from a biopsy done in the 1 month prior to consent and after the end of previous treatment this can be used for sstr2 IHC, tumour biomarkers, tumour 
microenvironment analysis, transcriptomics. If not, a baseline biopsy has to be taken from the primary or metastatic lesion. If possible, the biopsy should be taken from an accesible lession 
which is positive for sstr2 with 68Ga-OPS202 scan following the eligibility criteria #10 (Section 5.2.1) and can be accomplished with reasonable safety. An optional post-treatment biopsy 
can also be performed during EOCT visit. In selected centres as for DNA repair capacity in blood, if tumour biopsy is >5 mm3, then 5 mm3 will be fixed for tumour microenvironment 
analysis, the rest will be frozen for DNA repair capacity assessment. 
[w] Tumour and organs uptake using Single Photon Emission CT (SPECT/CT) at Cycles 1 and 2 at 2 to 4 hours, 16 to 24 hours, 40 to 48 hours, at 72 to 96 and 144 to 168 hours after the end 
of 177Lu-OPS201 infusion. At the timepoint between 16 to 24 hours, SPECT/diagnostic CT will be performed (no contrast agent). For all other time points, SPECT/low dose CT will be 
performed. 
[x] Whole-body (planar scintigraphy) scan will be done at Cycles 1 and 2 at 2 to 4 hours, 16 to 24 hours, 40 to 48 hours, at 72 to 96 and 144 to 168 hours after the end of 177Lu-OPS201 
infusion. 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). 
[y] For the phase II only. Subjects will complete the EQ-5D-5L and EORTC QLQ-C30 questionnaires at the clinic prior to 177Lu-OPS201 infusion on Day 1 of Cycle 1 and at EOCT. 
[z] 
Subjects must be followed for AEs from the time they signed the informed consent form until the EOCT/EW or EOAC. All study treatment related toxicities will be followed by the 
investigator until they have resolved. 
[aa] Concomitant medications and treatments with doses and indications will be recorded from 60 days prior to the IRPP administration. Once the subject has withdrawn from the study, 
concomitant medications and treatments should be recorded until the EOCT/EW or EOAC or until all study treatment related toxicities have resolved, whichever is the later. 
[ab] Blood sample before infusion. 
[ac] Race and ethnicity will be recorded if allowed per local regulations. 
 




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[c] 
In case of toxicity management requiring a delay, the next treatment administration will be delayed to up to 4 weeks. 
[d]  
Supine and standing systolic and diastolic blood pressure, heart rate, body temperature, respiratory rate. For the day of infusion: Prior to infusion and at infusion completion (0 minutes), 
30±5 minutes, 60±10 minutes, 4 hours ± 10 minutes after the end of infusion. 
[e] 
Haematology: RBC count, haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration 
(MCHC), WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils and basophils) and platelet count. See also Section 8.2. 
[f] 
Blood biochemistry: urea, uric acid, creatinine, creatinine clearance, total bilirubin, conjugated bilirubin, chloride, bicarbonate, sodium, potassium, calcium, phosphate, alkaline 
phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), albumin and total protein, total cholesterol, triglycerides, fasting 
glucose, C-reactive protein (CRP). eGFR will be calculated based on serum creatinine levels using MDRD formula. See also Section 8.2 
[g] 
Urinalysis includes pH, protein, ketones, bilirubin, urobilinogen, blood, nitrites, leucocytes, glucose; proteinuria will be performed with dipsticks, in case of positivity, a proteinuria/24h 
will be performed. See also Section 8.2. 
[h] 
Activity measured on blood samples (n=10 per cycle) before the infusion (baseline), at the end of 177Lu-OPS201 infusion (0) and at 5±1 minutes, 30±5 minutes, 1 hour (±5 minutes) and 
4 hours (±30 minutes), 24±2 hours, 48±2 hours, 72 to 96 hours and 144 to 168 hours after the end of 177Lu-OPS201 infusion (for each additional cycle).  
[i] 
Single 12-lead ECG to be recorded in the supine position after at least 5 minutes of rest at screening, at Day 1 before the infusion (baseline) and at EOCT visit. 
[j] 
Imaging will take place 6 weeks (± 3 days) after each administration of 177Lu-OPS201 using the same imaging method. There will be also imaging done during the follow up period (see 
Section 5.2.4.2)  
[k] 
Tumour and organs uptake using Single Photon Emission CT (SPECT/CT) at each additional cycle at 2 to 4 hours, 16 to 24 hours, 40 to 48 hours, at 72 to 96 and 144 to 168 hours after 
the end of 177Lu-OPS201 infusion. At the timepoint between 16 to 24 hours, SPECT/diagnostic CT will be performed. For all other time points, SPECT/low dose CT will be performed. 
[l] 
Whole-body (planar scintigraphy) scan will be performed at 2 to 4 hours, 16 to 24 hours, 40 to 48 hours, at 72 to 96 and 144 to 168 hours after the end of 177Lu-OPS201 infusion. 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). 
[m] Subjects must be followed for AEs from the time they signed the informed consent form until the EOCT/EW or EOAC. All study treatment related toxicities will be followed by the 
investigator until they have resolved. 
[n] 
Concomitant medications and treatments with doses and indications will be recorded from 60 days prior to the IRPP administration. Once the subject has withdrawn from the study, 
concomitant medications and treatments should be recorded until the EOCT/EW or EOAC or until all study treatment related toxicities have resolved, whichever is the later. 
 


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D-FR-01072-002 
CONFIDENTIAL 
 
PROTOCOL: VERSION 2.0, 07 MARCH 2019 
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5.2 
Study Visits 
The study procedures and assessments for phase I are summarised in Table 5 and Table 6. 
A signed and dated informed consent form (ICF) will be obtained before screening procedures. 
5.2.1 
Procedures for Screening and Enrolment 
Eligibility should be checked before proceeding to the investigational Imaging with 
68Ga-OPS202 PET/CT.  
Avid lesions identified by 68Ga-OPS202 PET/CT scan will be interpreted as sstr2-positive if 
the uptake is 1.5-fold or greater than the non-tumour liver and lung tissue is noted and confirmed 
by central reading. Only subjects with at least two avid lesions of ≥ 20 mm on longest diameter 
on 68Ga-OPS202 PET/CT scan will be considered eligible for treatment with 177Lu-OPS201. 
Furthermore, it is required ≥50% matching between the lesions detected on 
68Ga-OPS202-PET/CT and on 18F-FDG-PET/CT as confirmed by central reader. 
If an 18F-FDG-PET or ceCT/ceMRI was done within 28 days prior to first administration of 
177Lu-OPS201, the procedure/s should only be repeated if the image/s are unreadable. If a 
tumour biopsy was obtained within 28 days prior to screening, the procedure/s should not be 
repeated. Evaluations obtained as part of routine medical care and performed during the 
screening period may also be used in place of the study specific evaluations. Subjects will 
acknowledge and agree to the possible use of this information for the study by giving informed 
consent. 
Subjects will be offered to participate to an optional research biobanking program. Subjects 
who agree to participate will be requested to sign a separate informed consent. 
After informed consent is obtained, subjects who are screened will be allocated a subject 
number. All screened subjects must be identifiable throughout the study. The investigator will 
maintain a list of subject numbers and names to enable records to be found at a later date if 
required. 
Subjects could be re-screened upon sponsor's approval (e.g. laboratory value back to allowed 
range within an acceptable timeframe). 
Following confirmation of eligibility for the treatment, subjects will be considered as enrolled 
and allocated to one of the cohorts specified in Figure 5. 
Each investigator will also maintain a record of all subjects screened into the study (i.e. who 
signed the informed consent form). In the event that the subject does not receive 68Ga-OPS202 
or 177Lu-OPS201, the primary reason will be recorded. 
5.2.2 
Procedures Before Study Treatment (Day 1 of Each Treatment Cycle, Pre-Dose) 
The following procedures may not be performed at Baseline on Day 1 of the study, prior to the 
administration of study treatments if an acceptable screening assessment was performed within 
7 days prior to the start of study treatment: 
• 
Haematology and biochemistry 
• 
Urinalysis 
• 
Pregnancy test 
• 
Body weight  
5.2.3 
Procedures During Study Treatment (Day 1 Post Dose of Each Treatment Cycle) 
Procedures during Cycle 1 and 2 and additional cycles are summarised in Table 5 and Table 6, 
respectively. 
Subject may be hospitalised from Day 1 to Day 3 at the discretion of the investigator.  


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The subjects must return to the study centre for further evaluations per the Schedule of 
assessment 
5.2.4 
Procedures After Study Treatment  
5.2.4.1 
End of Study Visit (EOCT, EOAC or Early Withdrawal Visit) 
Subjects who participate in the study in compliance with the protocol for at least two cycles of 
IRPP administration will be considered to have completed the study.  
Subjects may also withdraw from the study at any time if they meet any of the criteria described 
in Section 3.8. 
For subjects who complete the study, final evaluations will be performed within 6 weeks after 
the last IRPP administration; for those who withdraw prematurely from the study, final 
evaluations should be performed within 14 days. 
Subjects with ongoing AEs or clinically significant laboratory test abnormalities (as determined 
by the investigator) will be monitored by the investigator as described in Section 8.1.4 and 
Section 8.1.2.4, respectively. 
5.2.4.2 
Follow up Visits 
After the EOCT/EOAC or withdrawal visits, subjects will enter the follow-up period. 
Follow-up visits will take place every 3 months until 24 months, disease progression, death or 
withdrawal of full consent, whichever occurs first. It starts after the cycle of the last IRPP 
(177Lu-OPS201) administration. Subjects will be monitored for survival. Tumour imaging 
(ceCT/MRI) will also be performed every 3 months during the follow-up period.  
Subjects will be monitored for survival during 2 years after their withdrawal visit. Tumour 
imaging (ceCT/ceMRI) will also take place (every 3 months) for the subjects who discontinued 
study treatment before disease progression and who have not withdrawn consent.  
Antitumour treatment for the studied disease will be recorded during this follow-up period. 
5.2.5 
Unscheduled Visits 
Unscheduled visits or assessments may be necessary at any point during the treatment period 
to assess individual safety or tolerability. For example, laboratory assessments should be 
performed as clinically indicated during the study, tumour assessment could be performed 
whenever disease progression is suspected. Should an unscheduled visit or procedure listed in 
the schedule of assessment be performed during the study, the data will be recorded in the 
eCRF. 
5.3 
Tumour Imaging and Dosimetry 
The ICL will provide further technical instructions in separate image acquisition guidelines for 
the study. All the images will be sent to the central ICL for an independent review within 24 
hours (1 business day) of acquisition. 
• 
68Ga-OPS202 PET Imaging (Whole body): acquired at screening and 6 weeks after 
second administration of 177Lu-OPS201 (Cycle 2). The eligibility of the subjects will be 
assessed centrally on screening images. The central reading results will be used for the 
analysis of the imaging efficacy endpoints. CeCT/MRI for brain should be acquired with 
the 68Ga-OPS202 PET at screening. 
 
• 
ceCT/ceMRI: acquired at screening and 6 weeks after each administration of 
177Lu-OPS201 as well as every 3 months during the follow-up period. For each subject, 
the same imaging methods should be used throughout the study. The ceCT is acquired 


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either with 68Ga-OPS202 or 18F-FDG PET or separately, but should not be repeated for 
the same endpoint; a low dose CT could be done with each PET if not coupled with ceCT.  
 
• 
18F-FDG-PET (Whole body): acquired at screening and 6 weeks after second 
administration of 177Lu-OPS201 (Cycle 2). 
 
• 
SPECT/CT Scan: After the end of each 177Lu-OPS201 infusion: at 2 to 4 hours, 16 to 
24 hours, 40 to 48 hours, 72 to 96 and 144 to 168 hours.  
 
• 
Whole-body (planar scintigraphy) Scan: 2 to 4 hours, 16 to 24 hours, 40 to 48 hours, 
72 to 96 and 144 to 168 hours after the end of 177Lu-OPS201 infusion. 
The total radiation dose per subject for a two cycles treatment period is summarised in Table 7. 
Table 7 
Total Effective Dose (in mSv) per Subject for a Two Cycles Treatment Period  
Procedure 
Screening 
Cycle 1 
Cycle 2 
EW/EOCT 
Visit 
Total 
68Ga-OPS202 [a] 
4 
NA 
NA 
4 
8 
ceCT [b] 
15 - 30 
15 - 30 
15 - 30 
15 - 30 
60 - 120 
MRI [c] 
0 
0 
0 
0 
0 
18F-FDG-PET [d] 
6.3 
NA 
NA 
6.3 
12.6 
SPECT/CT low 
dose [e] 
 
4 (x4 scans) 
4 (x4 scans) 
 
32 
SPECT/diagnostic 
CT [e] 
 
6 (1 scan) 
6 (1 scan) 
 
12 
 
 
 
 
 
120 - 180 
Abbreviations: ceCT=contrast enhanced computed tomography; EOCT=end of core trial; EW=early withdrawal; 
FDG=fluorodeoxyglucose; MRI=magnetic resonance imaging; N=not applicabale ; PET=positron emitting tomography. 
a The phase I study 68Ga-OPS202, the calculated effective dose for an injection of 150 MBq (4 mCi) of 68Ga-OPS202 was 
3.6 mSv. The upper end of the activity is 200 MBq which equates to about 4 mSv. 
b Sources: Huang 2009, Christner 2010, Pearson 2014. 
c MRI has no radioactive dosing, only strong magnetic fields. 
d Source : Huang 2009. 
e Calculated from VirtualDose. There is no radiation from the SPECT, but just from the CT scan (the SPECT uses the 
radiation being emitted from the therapeutic 177Lu-OPS201). 
 
Confirmation of eligibility and details of the avid lesions to be further followed by SPECT and 
dosimetry conducted by the ICL will be provided to the site. The other results of the central 
imaging review or reads will not be provided to the subject nor to the investigational site 
personnel. Efficacy reads will be conducted by the central ICL and all subject management will 
be conducted by the principal investigator. 
5.4 
Laboratory Assessments 
The following samples will be analysed locally: 
• 
Standard haematology and biochemistry 
• 
Urinalysis 
• 
Pregnancy test (serum and urine) 
• 
Radiopharmaceutical PK urine (gamma-counting) 
• 
Radiopharmaceutical PK blood (gamma-counting) 
The following samples will be sent for central analysis: 
• 
Hypothalamic-pituitary-adrenal axis, testicular and pancreatic biomarkers 


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• 
OPS201 PK blood 
• 
OPS201 PK urine 
• 
DNA repair capacity in blood (in selected centres only) 
• 
DNA-DSB in peripheral lymphocytes 
• 
Specific renal safety biomarkers (alpha-glutathione S-transferase (GST), glutathione 
S-transferase P1 (GSTP1), kidney injury molecule-1 (KIM-1) antigen, clusterin, 
cystatin-C, calbindin, beta-2 microglobulin, creatinine) 
• 
Tumour microenvironment biomarkers  
• 
Biopsies  
• 
Biobanking (optional) 
 
The total volume of blood drawn for all evaluations throughout this study is approximately 
281.5 mL for each subject participating in the core trial (two first cycles). The detail of the 
blood samples collected at Screening and over the two first cycles of 177Lu-OPS201 is provided 
in Table 8. 
Table 8 
Blood Samples Collected at Screening and over First Two Cycles  
Test 
Number of Samples 
Volume per Sample 
PK 177Lu-OPS201 
20 
2 mL 
PK OPS201 
10 
2 mL 
DNA-DSB 
12 
4 mL 
DNA repair 
4 
8 mL 
Haematology 
16 
2 mL 
Biochemistry 
16 
5 mL 
Hypothalamic-pituitary-
adrenal-axis hormones and 
other biomarkers 
3 
 9 mL 
Germinal mutation in blood 
1 
2.5 mL 
Total volume 
 
281.5 mL 
 
An additional 19.5 mL of blood will be collected from subjects who have signed the optional 
biobanking informed consent for biobanking; this will be taken at Day 1 (or Day -1) of Cycle 1 
before infusion and at Day 1 of Cycle 2 before infusion and at EOCT/EOAC/EW for a total of 
58.5 mL. For subjects who have biobanking samples, a total of 340 mL blood will be collected. 


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6 
IMAGING AND TREATMENT OF SUBJECTS 
6.1 
Investigational 
Imaging/Medicinal 
Product 
Preparation 
Storage 
and 
Accountability 
6.1.1 
Investigational Imaging/Radiopharmaceutical Product Storage and Security 
6.1.1.1 
68Ga-OPS202 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all IIP and 
any other study related material is stored in a secured area, under recommended temperature 
monitored storage conditions, in accordance with applicable regulatory requirements. 
6.1.1.2 
177Lu-OPS201 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all IRPP and 
any other study related material is stored in a secured area, under recommended temperature 
monitored storage conditions, in accordance with applicable regulatory requirements. 
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. 
6.1.1.3 
Spillage 
All due precautions and site procedures should be implemented to prevent spillage or leakage 
of radiodiagnostics or radiotherapeutics. Infusion bags, intravenous 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 AE 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). 
See Section 9.2 for requirement of whole-body scan in case of spillage during infusion. 
6.1.2 
Investigational Imaging/Radiopharmaceutical Product Preparation 
6.1.2.1 
68Ga-OPS202 
The investigator, or an approved representative (e.g. pharmacist), will ensure that each 
radiolabelling kit is reconstituted, radiolabelled and dispensed by qualified staff members. 
The treatment is provided as a sterile two-vial radiolabelling kit (one kit per subject dose) 
constituted of:  
• 
freeze-dried powder containing 50 μg non-radiolabelled precursor OPS202 and 
excipients (Vial A) and  
• 
the solvent for reconstitution (Vial B) to be used prior to radiolabelling. 
The final radiolabelled IIP (68Ga-OPS202) will be prepared, up to 3 hours prior to 
administration, in the local radiopharmacy, in a two-step aseptic compounding process, 


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according to Good Radiopharmaceutical Practice (GRPP) per EANM guidelines and according 
to national regulations on radiopharmaceuticals preparation: 
• 
Reconstitution of the sterile Vial A containing the OPS202 precursor and excipients with 
1 mL of the solvent for reconstitution consisting of a solution of sterile sodium acetate 
from Vial B, 
• 
Radiolabelling of the precursor OPS202 achieved by the addition of a 5-mL sterile 
hydrochloric acid solution of 68Ga, eluted from a sterile pharmaceutical grade 68Ge/68Ga 
generator. 
68Ga-radiolabelling yields the IIP 68Ga-OPS202 as a solution for injection. After QC sampling, 
QC testing and release, the volume to be administered to the subject is withdrawn from the IIP 
vial, containing up to 45 μg OPS202. This volume is determined to obtain the target 
radioactivity at the time of administration, taking into account the decay of 68Ga. 
6.1.2.2 
177Lu-OPS201 
The IRPP is supplied as a 20-mL sterile solution for infusion. 
6.1.3 
Investigational Imaging/Radiopharmaceutical Product Accountability 
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 radiolabelling kit, treatment or any other study-related material are 
correctly received by a responsible person.  
• 
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. 
• 
The destruction of used and unused study treatment radiolabelling kit, IRPP, IIP and any 
other study related material should be carried out only after any discrepancies have been 
investigated and satisfactorily explained and the reconciliation has been accepted. The 
study treatment will be destroyed on site. 
• 
All radiolabelling kit, IIP, IRPP and any other study related material is to be accounted 
for on the IMP accountability log provided by the sponsor. 
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 
subject to whom the study treatment was dispensed, the quantity, the radioactivity and date of 
dispensing. This record is in addition to any drug accountability information recorded on the 
eCRF. Any discrepancies must be accounted for on the appropriate forms. 
6.2 
Investigational Imaging/Radiopharmaceutical Product Administered 
At screening, subjects will be allocated a subject number. Following confirmation of eligibility 
for the study, subjects will receive a single dose of 68Ga-OPS202 (IIP), of up to 45 μg peptide, 
with a radioactivity of between 150 to 200 MBq.  
Then, in phase I, subjects deemed eligible for treatment with 177Lu-OPS201 based on 
68Ga-OPS202 tumour uptake will receive: 
• 
In the radioactivity escalation: two cycles of 177Lu-OPS201 separated by 6 weeks 
(+4 week per cycle in case of AEs that need to be adequately recovered) of 300 μg 
(±15%) OPS201 with activities ranging from 4.5 to 7.4 GBq (±10%) for the loading dose 
and 3 to 5.5 GBq (±10%) for the maintenance dose. 


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• 
In the peptide mass dose evaluation phase: two cycles of 177Lu-OPS201 separated by 
6 weeks (+4 week per cycle in case of AEs that need to be adequately recovered) of 
700 μg (±15%) OPS201 with activities ranging from 4.5 to 7.4 GBq (±10%) for the 
loading dose and 3 to 5.5 GBq (±10%) for the maintenance dose. 
The radioactivity is measured before and after the administration of IIP and IRPP to the subject; 
the decay-corrected difference between these two measurements (in MBq and GBq, 
respectively) corresponds to the radioactivity administered to subject. 
The IIP 68Ga-OPS202 is administered as a slow bolus intravenous injection and the IRPP 
177Lu-OPS201 as an intravenous infusion over 120 minutes (at the investigator’s discretion - 
see details in Section 6.2.2). 
Radioactivity and peptide mass doses in phase II will depend on the results from phase I. 
6.2.1 
68Ga-OPS202 
68Ga-OPS202 is an imaging radiopharmaceutical with three main components, namely: 
• 
OPS200, an antagonist somatostatin analogue that binds to sst2  
• 
NODAGA, a chemical chelator moiety and 
• 
68Ga, a positron-emitting radionuclide with a half-life of 68 minutes.  
The radioactivity in the syringe is measured before and after the injection of 68Ga-OPS202 to 
the subject; the decay-corrected difference between these two measurements (in MBq) 
corresponds to the radioactivity injected to subject. 
There are no fasting conditions, nor food restrictions that should apply when administering 
68Ga-OPS202 to the subject. 
To determine tumour uptake at Screening visit, subjects will receive a single i.v. injection of 
IIP (68Ga-OPS202) administered over 1 minute prior to a PET/CT scan. 
6.2.2 
177Lu-OPS201 
177Lu-OPS201 is a therapeutic radiopharmaceutical with three main components, namely: 
• 
OPS200, an antagonist somatostatin analogue that binds to sstr2  
• 
DOTA, a chemical chelator moiety and 
• 
177Lu, a beta-emitting radionuclide with a half-life of 6.7 days  
The IRPP (20 mL of 177Lu-OPS201) will be administered once per cycle as 300 μg (±15%) or 
700 μg (±15%) of OPS201 by an i.v. infusion at a rate of 10 mL/h over 120 minutes for 
177Lu-OPS-201. 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: The rate of infusion can be adjusted based on recommendations from DRB. 
Activities will range from 4.5 to 7.4 GBq for the loading dose and 3 to 5.5 GBq for the 
maintenance dose. The IRPP will be co-infused with amino acid solution (see Section 6.3). 
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 6.3.2 and Section 6.3.3). 
Appropriate treatment should be administered should an infusion-related reaction occur 
including somatostatin analogues. 
There are no fasting conditions, nor food restrictions that should apply when administering 
177Lu-OPS201 to the subject. 
The same venous access for IRPP and amino acid solution administration will be used. Infusion 
should be done into the contra-lateral arm used for the PK sampling. Subjects with breast 


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surgery (and in particular lymphadenectomy) should not have any blood sampling in the 
corresponding arm. 
6.3 
Concomitant Medication/Therapy 
Any prior or concomitant therapy or medication given to a subject within 60 days before IIP 
administration or during IIP/IRPP administration will be indicated in the eCRF. Dose and 
generic name or tradename will be indicated. 
The following concomitant medications are not permitted during this study: 
• 
nephrotoxic compounds as assessed by the investigator  
• 
any tumour-targeted therapy (e.g. chemotherapy, radiotherapy) 
177Lu-OPS201 is investigated in the current study as monotherapy; thus, any tumour-targeted 
therapy (e.g. chemotherapy, radiotherapy) are not allowed during the study. The investigator 
may withdraw the subject in order to administer another tumour-targeted therapy if deemed 
necessary for the health of the subject. 
Subjects with brain metastasis who are receiving high doses of glucocorticosteroids must not 
be enrolled in the study (see Section 4.1). Likewise, investigator should consider withdrawing 
subjects from 177Lu-OPS201 treatment should the administration of high doses of 
glucocorticosteroids be needed for the management of any condition, as these drugs may induce 
down-regulation of sstr2. Glucocorticosteroids should be avoided as preventive anti-emetic 
treatment. In case prior treatment provided for nausea and vomiting is not efficient, a single 
dose of corticosteroids can be used. 
The potential of OPS201 to be associated with drug-drug interactions has not been established. 
It is anticipated that the major route of excretion will be via the kidneys and so medications 
which might affect renal function should be avoided or used with due caution as assessed by 
the investigator. These medications include but are not limited to the following. 
Drugs causing prerenal damage: 
• 
Drugs that cause excessive gastrointestinal losses, either through diarrhoea or vomiting, 
also cause volume depletion and may precipitate acute kidney injury (AKI). 
• 
Non-steroidal anti-inflammatory drugs (NSAIDs), even in short courses, can cause AKI 
as a result of renal underperfusion. 
• 
Angiotensin-converting enzyme (ACE) inhibitors can also cause a deterioration in renal 
function. However, this is a problem only in patients with compromised renal perfusion, 
particularly those with renal artery stenosis. 
• 
Care should be taken when an ACE inhibitor and NSAID are prescribed together, as this 
combination may precipitate an acute deterioration in renal function. 
Drugs causing intrarenal damage: 
• 
Intrarenal damage may result in a direct toxic effect on the kidneys or hypersensitivity 
reactions. 
• 
Most drugs that cause damage within the kidneys do so as a result of hypersensitivity 
reactions, which involve either glomerular or interstitial damage. 
• 
Drugs that have been reported to cause glomerulonephritis include penicillamine, gold, 
captopril, phenytoin and some antibiotics, including penicillins, sulfonamides and 
rifampicin. 
• 
Drugs that may cause interstitial nephritis include penicillins, cephalosporins, 
sulfonamides, thiazide diuretics, furosemide, NSAIDs and rifampicin. 


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• 
There are a number of drugs that cause direct toxicity to the renal tubules (acute tubular 
necrosis) - eg, aminoglycosides, amphotericin and ciclosporin. 
Drugs causing postrenal damage (urinary tract obstruction): 
• 
High-dose sulfonamides, acetazolamide or methotrexate may cause crystalluria and 
could therefore cause urinary tract obstruction. 
• 
Anticholinergics (eg, tricyclic antidepressants), and alcohol may cause urinary tract 
obstruction due to retention of urine in the bladder. 
Other nephrotoxic drugs: 
• 
Cephalosporins: cephaloridine, one of the first cephalosporins introduced, has been 
associated with direct renal toxicity and is no longer in clinical use. Other cephalosporins 
are much less likely to produce renal damage but third-generation cephalosporins (eg, 
cefixime) have (very rarely) been reported to cause nephrotoxicity. 
• 
Analgesics:  
- 
NSAIDs may cause AKI due to hypoperfusion and interstitial nephritis, as well as 
analgesic nephropathy (chronic interstitial nephritis and papillary necrosis). 
- 
Analgesic nephropathy has been most commonly seen with combination analgesic 
products that contain aspirin and/or paracetamol. 
- 
Analgesic nephropathy is one of the few preventable causes of chronic kidney 
disease. Discontinuation of the drugs often results in stabilisation or even 
improvement in renal function but continued use leads to further renal damage. 
• 
Lithium: serum levels of lithium consistently above the therapeutic range have been 
associated with development of a nephrogenic diabetes insipidus. 
The following concomitant medications are permitted during this study, but they must be 
monitored closely and every effort should be made to keep their dose and dose regimen constant 
throughout the course of the study.  
• 
Antiemetic premedication (oral or iv administration) should be administered 30 minutes 
before starting the amino acid solution. Despite the preventive treatment, a subject may 
suffer from nausea. The adverse event should be managed by hydrating the subject with 
normal saline and possibly by repeating antiemetic administrations of different 
pharmacological class. 
• 
Infusion related reactions (IRR) should be managed as per local guidelines or 
institutional protocols and according to their grading. If the time to symptom resolution 
does not allow to resume the IRPP infusion within the 60 minutes time span, the IRPP 
will be stopped. See also adverse events of special interest (Section 8.1.3). 
6.3.1 
Amino acid infusion: renal protection 
The role of amino acid solution is to protect subject’s kidneys during PRRT by blocking 
177Lu-OPS201 reabsorption and preventing nephrotoxicity of the radioactive element.  
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 (Bodei 2013) a 
solution of 25 g lysine and 25 g arginine in 2 L saline is recommended to be infused 
concomitantly with the PRRT administration over 4 hours (or up to 6 hours in exceptional 
cases), starting 30-60 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 
adverse events or subjects’ intolerance of the high-volume load in a short time. In case of severe 


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nausea or vomiting during amino acid solution infusion, an anti-emetic of a different 
pharmacological class can be administered. 
Sites experienced in PRRT treatment can use Ipsen’s amino acid solution (OPS301, which 
could be provided during the study) or their established amino acid solution, preferably 
commercialised product covered by the recommendations of the joint IAEA, EANM and 
SNMMI practical guidance on PRRT in NETs. The exact formulation must be documented in 
the eCRF. 
OPS301 is an amino acid solution made of arginine and lysine (1.25% w/v each). The solution 
is supplied as a 500-mL sterile solution for infusion. A maximum of four bottles are used per 
subject administration (equivalent to 2 L).  
6.3.2 
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). 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. 
6.3.3 
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. 
6.4 
Lifestyle Restrictions/Recommendations 
There are no alcohol, diet or smoking restrictions besides restrictions already presented in the 
exclusion criteria. Investigator will be advised to ensure appropriate hydration of subjects 
during urine collection periods.  
6.5 
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. 
Administration compliance will be assessed by the trained staff/nurse performing the injection 
in case of incomplete injection of the IIP or IRPP, the residual activity in the syringe should be 
recorded in the eCRF. 


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7 
ASSESSMENT OF PHARMACODYNAMICS/EFFICACY 
For the timing of assessments in this study, refer to the schedule in Table 5 and Table 6. 
7.1 
Phase I 
7.1.1 
Secondary Tumour Activity Endpoints and Evaluations 
Secondary tumour activity endpoints and evaluations planned in phase I are summarised in 
Table 9. All tumour endpoints will be evaluated by a central ICL. 
Table 9 
Secondary Tumour Activity Endpoints and Evaluations in Phase I (Core Treatment) 
Measure 
Timepoints 
Variable  
Endpoint 
Tumour size 
(longest 
diameter) 
Screening[a] and 
6 weeks after each 
177Lu-OPS201 
administration 
(each cycle) 
Tumour response 
according to RECIST v1.1 
ORR 
BOR 
DCR 
PFS 
Tumour size 
(longest 
diameter) 
Screening[a] and 
6 weeks after 
second 
177Lu-OPS201 
administration 
(second cycle) 
Tumour response 
according to 
mGa-RECIST; 
Metabolic tumour response 
by 18F-FDG-PET using 
PERCIST v1.0 and 
68Ga-OPS202 by 
mGa-PERCIST 
ORR 
BOR 
Tumour volume Screening[a] and 
6 weeks after each 
177Lu-OPS201 
administration 
(each cycle) 
Mean change (%) in 
tumour volume assessed by 
Volumetric CT (or MRI) 
% change from baseline in 
tumour volume 
Event of death 
1 and 2 years 
Death count 
OS 
SULmax and 
SULmean 
Screening[a] and 
6 weeks after 
second 
177Lu-OPS201 
administration 
(second cycle) 
Tumour-to-background 
ratio by 18F-FDG-PET 
using PERCIST v1.0 
Quantitative changes in tumour-
to-background 18F-FDG-PET 
uptake 
SUVmax and 
SUVmean  
 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration 
(second cycle) 
sstr2 targeted tumour 
uptake by 68Ga-OPS202 
PET/CT. 
 
Changes in tumour uptake on 
68Ga-OPS202 PET/CT  
 
SUVmax and 
SUVmean 
Screening[a] and 
6 weeks after 
second 
177Lu-OPS201 
administration 
(second cycle) 
68Ga-OPS202 uptake and 
177Lu-OPS201 therapy 
response 
Change in 68Ga-OPS202 uptake 
on PET scan in subjects 
screened for 177Lu-OPS201 
treatment as compared to 
clinical response and BOR 


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Measure 
Timepoints 
Variable  
Endpoint 
SUVmax and 
SUVmean 
Screening[a] for 
68Ga-OPS202 
PET/CT; 
Screening[a] and 
6 weeks after 
second 
177Lu-OPS201 
administration 
(second cycle) 
Uptake on 68Ga-OPS202-
PET/CT and 177Lu-OPS201 
therapy response (using 
ceCT/MRI – RECIST 
v1.1) 
Correlation between change 
(%) in tumour uptake on 
68Ga-OPS202 PET/CT at 
screening[a] with tumour 
response to 177Lu-OPS201 
therapy. 
Lesion count 
For 68Ga-OPS202 
at screening 
For 177Lu-OPS201 
at 24 hours after 
first administration 
(Cycle 1) 
Uptake on 68Ga-OPS202-
PET/CT and uptake on 
177Lu-OPS201 SPECT/CT 
Correlation between the uptake 
of 68Ga-OPS202 in tumour 
lesions expressing sstr2 on 
PET/CT images and the uptake 
on 177Lu-OPS201 SPECT/CT 
Abbreviations: BOR=Best overall response; ce= Contrast enhanced; CT=Computed tomography; DCR=Disease control 
rate; FDG=Fluorodeoxyglucose; mGa= Modified gallium; MRI=Magnetic resonance imaging; ORR=Objective response 
rate; OS=Overall survival; PERCIST=Positron emission tomography response criteria in solid tumours; PFS= Progression 
free survival; PET= Positron emission tomography; RECIST=Response evaluation criteria in solid tumours; SUL=SUV 
normalised by lean body mass; SUV=Standardised uptake volume. 
   a. Screening=Baseline scan 
 
7.1.2 
Methods and Timing of Assessing, Recording and Analysing Anti-Tumour Activity 
Data 
Methods for assessing efficacy data are described below. Timing of efficacy assessments are 
discussed in Section 5. Procedures for recording efficacy data are discussed in Section 15 and 
methods of analyses are discussed in Sections 11.2 and 11.3. 
7.1.2.1 
Imaging Assessments and Evaluations 
Expression of the target receptor (sstr2) will be determined using PET/CT imaging with the 
companion diagnostic imaging product 68Ga-OPS202. Radiographic response and disease 
progression will be determined using RECIST v1.1 (CT/MRI) and PERCIST v1.0 
(18F-FDG-PET), tumour volume (as assessed by volumetric analysis from CT/MRI), 
“mGa-RECIST” for sstr2-positive lesions (CT/MRI and OPS202 PET scan) and modified 
PERCIST evaluating PET 68Ga-OPS202 (see details in the IRC). 
For each subject, the same imaging methods should be used throughout the study (e.g. ceCT or 
ceMRI for RECIST v1.1 tumour response assessment). Imaging parameters and approach used 
at screening should remain consistent throughout the study.  
The same PET scanner for all the 68Ga-OPS202 and scans must be used for each subject and 
likewise for the 18F-FDG-PET (although it can be a different scanner to the 68Ga-OPS202 
scans). 
7.1.2.1.1 Timing of Imaging Assessments 
Screening 
Within 3 weeks before first 177Lu-OPS201 administration, each subject will undergo a 
68Ga-OPS202 PET/CT to evaluate eligibility for OPS201 treatment. As part of baseline 
assessments, a whole-body ceCT or ceMRI including brain will be performed unless a similar 
exam has already been performed within 28 days before first 177Lu-OPS201 administration. 
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In addition, 18F-FDG-PET will be performed as baseline assessment for PERCIST v1.0 
metabolic tumour response evaluation. (A second full diagnostic CT or MRI scan is not required 
since one will be obtained with the 68Ga-OPS202 scan, however a low dose CT will be acquired 
for anatomic localisation of the PET scan). 
Core Treatment Phase 
Imaging assessments will be performed as described in Section 5.3, the ICL and in the schedule 
of assessments (Table 5). Additionally, in the event of biological or clinical signs of disease 
progression further radiological assessments can be performed based upon the investigator’s 
judgment. 
Whole body including brain ceCT/MRI to assess tumour progression will be performed on Day 
1 of each cycle (except for Cycle 1 replaced by screening scan) as well as at EOCT/EOAC visit. 
The scans can be performed in three images if required; head, chest, abdomen and pelvis. 
18F-FDG-PET will be repeated after second cycle and 68Ga-OPS202 PET/CT will be repeated 
after second and last cycles (if different from second cycle). 
Long-term Follow-up 
After EOCT/EOAC visit, subjects will be followed up every 3 months to further evaluate, in 
addition to safety, the post-therapy efficacy (by CT or MRI) until 24 months, disease 
progression, administration of any other tumour-targeted therapy (e.g. chemotherapy or 
radiotherapy) or death, whichever occurs first (see Section 5.2.4.2). 
7.1.2.1.2 Methods of Imaging Assessments 
68Ga-OPS202 scans are anticipated to be identified on lesions that may or may not be seen by 
FDG-PET scans due to the different metabolic pathways. Therefore, PERCIST, which is based 
on evaluating the most avid lesion, is likely to be different than one selected by 68Ga-OPS202 
and hence the need for evaluation by the modification (mGa-PERCIST). Likewise, RECIST 
requires the identification of the five largest lesions, which are generally selected by ceCT and 
a fused PET image. 68Ga-OPS202 may provide an alternative radiological interpretation, which 
will be evaluated using the modification (mGa-RECIST). 
Tumour Response Using RECIST v1.1 
For phase I, tumour response will be evaluated using the revised RECIST guideline v1.1 (see 
IRC). Only subjects with measurable disease at baseline, who have received at least two 
administrations of 177Lu-OPS201 and reached the end of Cycle 2 or EOCT visit would 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. 
A modified version of RECIST (“mGa-RECIST”) will also be assessed. In this second 
evaluation, tumours will be assessed for reading based on 68Ga-OPS202 and CT. There will be 
a tumour mapping, so that RECIST can be determined on 68Ga-OPS202 positive lesions. Since 
there is a possibility for a different set of lesions to be identified by 68Ga-OPS202, this provides 
the direct response of 177Lu-OPS201 on these tumours to be evaluated. 
Tumour response of each subject will be graded as CR, PR, stable disease or progressive disease 
and unevaluable according to RECIST version 1.1. Based on this classification, the following 
endpoint will be calculated as defined by RECIST v1.1 and “mGa-RECIST”: 
• 
ORR: proportion of subjects with a BOR characterised as either CR or PR relative to the 
total number of evaluable subjects. 


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• 
DCR: proportion of subjects with a BOR characterised as CR, PR or stable disease 
relative to the total number of evaluable subjects. 
• 
PFS will be evaluated as defined per RECIST version 1.1. 
• 
Tumour response using volumetric CT/MRI assessment 
The same tumours identified as target lesions and assessed by “mGa-RECIST” will also be 
evaluated by the percentage change in volume. The criteria are defined in the RSNA QIBA 
working group on tumour volume. 
Tumour Response Using PERCIST v1.0 
For phase I, tumour response will be evaluated using the PERCIST guideline v1.0 (see IRC). 
Only subjects with measurable disease at baseline, who have received at least two 
administrations of 177Lu-OPS201 and reached EOCT visit will be considered evaluable for 
response. 
Key elements of PERCIST include performance of PET scans in a method consistent with the 
NCI recommendations (UPICT) and those of The Netherlands multicentre trial group on 
well-calibrated and well-maintained scanners. A baseline PET scan will be obtained at 
approximately 1 hour (50 to 70 minutes) after 18F-FDG injection. At EOCT, the PET scan will 
be obtained with the same interval (between 18F-FDG-injection and acquisition time) reported 
at baseline ±15 minutes, but never less than 50 minutes from the injection. All scans will be 
performed on the same PET scanner with the same injected dose ±20% of radioactivity.  
A PERCIST evaluation will also be performed using the 68Ga-OPS202 scans (mGa-PERCIST). 
This will provide a different set of analyses and support the possibility of using 68Ga-OPS202 
as a surrogate endpoint in future studies.  
Tumour metabolic response of each subject will be defined based on quantitative changes 
(SULmax and SULmean) in tumour-to-background after two cycles versus baseline and will be 
graded as complete metabolic response (CMR), partial metabolic response (PMR), stable 
metabolic disease (SMD) or progressive metabolic disease (PMD) or unevaluable according to 
PERCIST v1.0. The grading scale for “mGa-PERCIST” will be evaluated. 
Sstr2 Targeted Tumour Uptake 
Sstr2 targeted tumour uptake will be determined using PET/CT molecular imaging with the 
companion diagnostic imaging product 68Ga-OPS202.  
The change in 68Ga-OPS202 PET/CT tumour uptake will be computed as a change in SUVmax 
and SUVmean from baseline to EOCT/EOAC visit. These changes will also be compared to 
clinical outcome and ORR. 
7.2 
Phase II 
7.2.1 
Primary Efficacy Endpoint and Evaluations 
The primary endpoint is ORR over the two treatment cycles of the core study. Objective 
response is defined using RECIST v1.1 measured by CT or MRI. Tumour response assessments 
are performed 6 weeks after each administration of 177Lu-OPS201 during the core study or at 
the time of occurrence of first clinical signs of disease progression as determined by the 
investigator (see Section 7.1.2.1.2). Radiological interpretation for subject management will be 
performed at the site, whereas efficacy evaluation will be conducted by the ICL. 
7.2.2 
Secondary Efficacy Endpoints and Evaluations 
Secondary efficacy endpoints and evaluations are summarised in Table 10. 


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Table 10 Secondary Efficacy Endpoints and Evaluations in Phase II 
Measure 
Timepoint 
Variable 
Endpoint 
Tumour size (longest 
diameter) 
Screening[a] and 6 
weeks after each 
177Lu-OPS201 
administration (each 
cycle) 
Tumour response 
according to RECIST 
v1.1 
BOR 
PFS (complemented 
with events of death) 
DRR (CR or PR lasting 
≥6 months) 
DCR 
TTP 
TTR 
DoR 
Tumour size (longest 
diameter) 
Screening[a] and 
6 weeks after second 
177Lu-OPS201 
administration (second 
cycle) 
Tumour response 
according to 
mGa-RECIST; 
Metabolic tumour 
response by 18F-
FDG-PET – PERCIST 
v1.0 and 68Ga-OPS202 
by mGa-PERCIST 
BOR 
Tumour volume 
Screening[a] and 
6 weeks after each 
177Lu-OPS201 
administration (each 
cycle) 
Mean change (%) in 
tumour volume 
assessed by volumetric 
CT/MRI 
% change from baseline 
in tumour volume 
Event of death 
1 and 2 years 
Death count 
OS 
SULmax and SULmean 
Screening[a] and 
6 weeks after second 
177Lu-OPS201 
administration (second 
cycle) 
Tumour-to-background 
ratio by 18F-FDG-PET 
using PERCIST v1.0 
Quantitative changes in 
tumour-to-background 
18F-FDG-PET uptake 
SULmax and SULmean 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration (second 
cycle) 
sstr2 targeted tumour 
uptake by 
68Ga-OPS202-PET/CT 
Change in tumour 
uptake on 68Ga-OPS202 
PET/CT scan 
SULmax and SULmean 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration (second 
cycle) 
68Ga-OPS202 uptake 
and 177Lu-OPS201 
therapy response 
Change in 
68Ga-OPS202 uptake on 
PET scan in subjects 
screened for 
177Lu-OPS201 
treatment as compared 
to clinical response and 
ORR 
SULmax and SULmean 
Screening[a] for 68Ga-
OPS202 PET/CT; 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration (second 
cycle) 
Uptake on 
68Ga-OPS202 PET/CT 
and 177Lu-OPS201 
therapy response (using 
ceCT/MRI – RECIST 
v1.1) 
Correlation between the 
uptake on 68Ga-OPS202 
PET/CT at baseline[a] 
with tumour response to 
177Lu-OPS201 therapy 


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Measure 
Timepoint 
Variable 
Endpoint 
Lesion count 
For 68Ga-OPS202 at 
screening 
For 177Lu-OPS201 at 24 
hours after first 
administration 
(Cycle 1) 
Uptake on 
68Ga-OPS202-PET/CT 
and uptake on 
177Lu-OPS201 
SPECT/CT 
Correlation between the 
uptake of 68Ga-OPS202 
in tumour lesions 
expressing sstr2 on 
PET/CT images and the 
uptake on 
177Lu-OPS201 
SPECT/CT 
Identification of avid 
lesions 
Screening[a] 
Number of subjects 
with avid lesions 
Proportion of subjects 
with sstr2-positive 
tumour lesions by 
68Ga-OPS202 PET/CT 
Abbreviations: ce= Contrast enhanced; CR=Complete response; CT=Computed tomography; DCR=Disease control rate; 
DoR=Duration of response; DRR=Durable response rate; FDG=Fluorodeoxyglucose; MRI=Magnetic resonance imaging; 
OS=Overall survival; PERCIST=Positron emission tomography response criteria in solid tumours; PET=Positron emission 
tomography; PFS=Progression free survival; PR=Partial response; RECIST=Response evaluation criteria in solid tumours; 
SUL=SUV normalised by lean body mass; SUV=Standardised uptake volume; TTP=Time to progression; TTR=Time to 
response. 
[a] Screening=Baseline scan 
 
7.2.3 
Methods and Timing of Assessing, Recording and Analysing Efficacy Data 
Methods for assessing efficacy data in phase II are planned to be similar to those of the phase 
I. However, considering the phase I results these methods may be adjusted through a protocol 
amendment. 
7.2.3.1 
Patient Reported Outcomes 
Patient Reported Outcomes (PROs) will be assessed in phase II using the following 
questionnaires: the EQ-5D-5L and EORTC QLQ-C30. The two questionnaires are commonly 
used, uniformly accepted and validated instruments to evaluate health outcomes in subjects 
with cancer. PRO questionnaires will be administered to subjects where translations into local 
language are available at baseline and EOCT. 
7.2.3.1.1 EQ-5D-5L  
The EQ-5D-5L questionnaire is a 2-page, generic preference-based Quality of Life (QoL) 
measure comprised of a 5-item health status measure and a visual analogue scale and is used to 
generate two scores. The EQ-5D utility score is based on answers to five questions to evaluate 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D-5L 
visual analogue scale generates a single health status index, the analogue scale ranges from 0 
to 100 in which subjects are asked to rate their current health state by drawing a line from a box 
marked. 
7.2.3.1.2 EORTC QLQ-C30  
The EORTC QLQ-C30 is a 2-page, self-reporting 30-item generic instrument for use in cancer 
subjects across tumour types. It assesses 15 domains consisting of five functional domains 
(physical, role, emotional, cognitive, social), nine symptom domains (fatigue, nausea and 
vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, financial difficulties) 
and a global health status or QoL scale. 


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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 until at least 8 weeks after the last dose of study treatment. Information 
will be elicited by direct, nonleading questioning or by spontaneous reports. Further details for 
AE reporting can be found in Section 8.1.2. 
The investigator will be responsible for a clinical assessment of the study participants during 
the whole participation of the subjects in the study, from informed consent up to discharge from 
the study and for the setup of a discharge plan if needed.  
The sponsor medical monitor and the global patient safety physician will monitor safety data 
throughout the course of the study. 
8.1.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g. laboratory findings, electrocardiogram). In clinical 
studies an AE can include an undesirable medical condition occurring at any time, including 
run in or washout periods, even if no IIP/IRPP has been administered.  
This definition includes events occurring from the time of the subject giving informed consent 
until the end of the study (as defined in Section 3.7). 
Natural progression or deterioration of the 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 antitumour activity and will not 
be regarded as an SAE. 
Signs and symptoms should not be reported as AEs/SAEs if they are clearly related by the 
investigator to a relapse or an expected change or progression of the baseline malignancy. 
These signs and symptoms should only be reported as AEs/SAEs (depending on the 
investigator’s judgement) if they are: 
• 
Judged by the investigator to be unusually severe or accelerated malignancy, or 
• 
If the investigator considers the deterioration of malignancy signs and symptoms to be 
caused directly by the IIP/IRPP. 
If there is any uncertainty about an AE being due solely to the malignancy under study, it should 
be reported as an AE/SAE as appropriate. 
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
Adverse events will be recorded and graded according to the current version of the NCI-CTCAE 
version 5.0, 27 November, 2017. In view of meta-analyses and for conversion purposes, the 
following conversion mapping will apply if the NCI-CTCAE scale is not available for a given 
AE: 
• 
NCI-CTCAE Grade 1 corresponds to mild, 
• 
NCI-CTCAE Grade 2 corresponds to moderate, 
• 
NCI-CTCAE Grade 3 corresponds to severe, 


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• 
NCI-CTCAE Grade 4 corresponds to life threatening/disabling, 
• 
NCI-CTCAE Grade 5 corresponds to death (related to AE). 
Where:  
• 
Mild: symptoms do not alter the subject’s normal functioning 
• 
Moderate: symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the subject 
• 
Severe: symptoms definitely hazardous to wellbeing, significant impairment of function 
or incapacitation. 
• 
Life threatening: any event that places the subject at immediate risk of death from the 
event as it occurred, i.e. it does not include a reaction that, had it occurred in a more 
severe form, might have caused death (also see Section 8.1.5). 
8.1.2.2 
Causality Classification 
The relationship of an AE to IIP/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 IIP/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 IIP/IRPP administration. 
8.1.2.3 
Assessment of Expectedness 
The reference document for assessing expectedness of AEs/event in this study will be the 
current IB. 
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. 
8.1.2.5 
Abnormal Physical Examination Findings  
Abnormal findings from physical examination that, in the judgement of the investigator, meet 
the definition of an AE should be recorded as such. This includes AEs of any severity, including 
mild, non-serious examination findings, irrespective of relation to treatment.  
8.1.2.6 
Other Investigation Abnormal Findings 
Abnormal test findings (e.g. thyroid function disturbances) should be recorded as AEs. 
Abnormal test findings already recorded in the eCRF in specific pages (ie, abnormal ECGs) do 
not need to be recorded as AE unless they meet the definition of an AE (of any severity).  
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 


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investigator to the sponsor. An AESI may be serious or non-serious. The rapid 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 IRR, the 
investigator should promptly contact the sponsor’s clinical monitor or his/her designated 
representative. 
The signs and symptoms of IRR may include: 
• 
vaso-vagal reaction 
• 
hypotension 
• 
palpitations 
• 
tachycardia 
• 
sweating 
• 
gastrointestinal (nausea or vomiting, metallic taste in mouth, right upper quadrant pain, 
abdominal cramps or bloating / diarrhoea) 
• 
wheezing 
See also IRR (Section 6.3).  
8.1.4 
Recording and Follow up of Adverse Events 
At each visit, the subject should be asked a nonleading question such as: “How have you felt 
since last dose?” 
All observed or volunteered AEs, regardless of treatment group or suspected causal relationship 
to IIP/IRPP, will be recorded on the AE page(s) of the eCRF. Events involving drug reactions, 
accidents, illnesses with onset during the treatment phase of the study, or exacerbations of 
pre-existing illnesses should be recorded according to the NCI. 
Any AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
requiring immediate notification to the sponsor or its designated representative. For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE (i.e. IIP/IRPP or other illness). The investigator is required to assess causality and record 
that assessment on the eCRF. Follow up of the AE, after the date of IRPP discontinuation, 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. 
8.1.4.1 
Reporting of Adverse Events  
Any AE/SAE regardless of causality occurring during the study, from informed consent until 
5 weeks after last study drug administration must be reported to the sponsor.  
Any AE/SAE considered related by the Investigator to study treatment or study procedure that 
the investigator becomes aware of after completion of the End of Study (EOS)/EW visit must 
be reported to the sponsor and will be recorded in the clinical database and SAE form (if an 
SAE is reported). 


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8.1.5 
Reporting of Serious Adverse Events 
All SAEs (as defined below) regardless of treatment group or suspected relationship to IIP/IRPP 
must be reported immediately (within 24 hours of the investigator’s knowledge of the event) 
through preferably email address specified at the beginning of this protocol, filling the Ipsen 
SAE report form. For further details consult SAE reporting plan/clinical research organisation 
(CRO) agreement plan). 
A SAE is any AE that: 
(1) 
Results in death, 
(2) 
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, 
(3) 
Results in in-patient hospitalisation or prolongation of existing hospitalisation, excluding 
admission for social or administrative reasons (see further), 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a substantial 
disruption of a person's ability to conduct normal life functions, 
(5) 
Results in congenital anomaly/birth defect in the offspring of a subject who received the 
IIP/IRPP, 
(6) 
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 corporate SAEs 
database system. 
• 
Hospitalisation is defined as any in-patient admission (even if less than 24 hours). For 
chronic or long-term in-patients, in-patient admission also includes transfer within the 
hospital to an acute/intensive care in-patient unit. 
• 
Prolongation of hospitalisation is defined as any extension of an in-patient 
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 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 to the sponsor.  
• 
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. 
Any SAE must be reported immediately (within 24 hours), using the e-mail address specified 
at the beginning of this protocol, independent of the circumstances or suspected cause, if it 
occurs or comes to the attention of the investigator at any time during the study period. 


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Any AE/SAE with a suspected causal relationship to IIP/IRPP administration occurring at any 
other time after completion of the study must be promptly reported. 
The following information is the minimum that must be provided to the sponsor within 24 hours 
for each SAE: 
• 
Study number 
• 
Centre number 
• 
Subject number 
• 
Adverse event 
• 
Investigator's name and contact details 
The additional information included in the SAE form must be provided to the sponsor or 
representative as soon as it is available (within 24 hours of the investigator’s response). The 
investigator should always provide an assessment of causality for each event reported to the 
sponsor. Upon receipt of the initial report, the sponsor will ask for the investigator's causality 
assessment if it was not provided with the initial report. 
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. 
8.1.6 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the approved IB and that the investigator identifies as related to IIP/IRPP or procedure. 
8.1.7 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IIP/IRPP has 
interfered with a contraceptive method. If pregnancy occurs during the study, the outcome of 
the pregnancy will then need to be collected post study and it will be necessary to discontinue 
administration of the IIP/IRPP.  
Information regarding pregnancies must be collected on the AE page of the eCRF and reported 
to the sponsor as an expedited report according to SAE reporting plan/CRO agreement plan. 
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. Investigators must instruct female subjects to avoid 
pregnancy for at least 6 months after the end of the treatment. Due to a temporary impairment 
of fertility, related to a transient damage to Sertoli cells, male subjects should consider sperm 
banking before therapy. 
The investigator should counsel the subject, discuss the risks of continuing with the pregnancy 
and the possible effects on the foetus. Monitoring of the subject should continue until 
conclusion of the pregnancy, which may involve follow-up after the subject’s involvement in 
the study has ended. 
Pregnancies with a conception date before the completion of the study must also be reported to 
the investigator for onward reporting to the sponsor. 
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. 


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8.1.8 
Deaths 
For AEs leading to death, NCI CTCAE Grade 5 is the only appropriate grade (see Section 
9.1.1). 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 four 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 4.3). 
If the IRPP is discontinued due to a SAE, it must be reported immediately to the sponsor’s 
designated representative (see Section 8.1.5). 
In all cases, the investigator must ensure the subject receives appropriate medical follow-up 
(see Section 8.1.4). 
8.1.10 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The sponsor will ensure that processes are in place for submission of reports of SUSARs 
occurring during the study to the CA, IECs and other investigators concerned by the IIP/IRPP. 
Reporting will be done in accordance with the applicable regulatory requirements. 
The sponsor must report all SUSARs to European Medicines Agency’s (EMA) EudraVigilance 
database within 15 days. Fatal and life-threatening SUSARs should be reported immediately, 
with another 8 days for completion of the report. 
8.2 
Clinical Laboratory Tests 
Blood and urine samples will be collected described in the Schedule of Assessments provided 
in Table 5 and Table 6 for the evaluation of haematology, serum chemistry and urinalysis.  
The investigator will review the safety laboratory test results, document the review and record 
any clinically relevant changes occurring or observed during the study in the AE section of the 
eCRF (see Section 8.1.2.4 for abnormal laboratory tests that should be recorded as AEs). 
All clinically relevant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to Baseline or to a level deemed acceptable by the 
investigator and the sponsor’s clinical monitor (or his/her designated representative) or until 
the abnormality is explained by an appropriate diagnosis.  
8.2.1 
Haematology 
Blood samples will be collected to assess the following parameters: RBC count, haemoglobin, 
haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean 
corpuscular haemoglobin concentration (MCHC), WBC count with differential (neutrophils, 
lymphocytes, monocytes, eosinophils and basophils) and platelet count. 
8.2.2 
Blood Biochemistry 
Blood samples will be collected to assess the following parameters: 
• 
urea, uric acid, creatinine, creatinine clearance, total bilirubin, conjugated bilirubin 
• 
chloride, bicarbonate, sodium, potassium, calcium, phosphate 


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• 
alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma 
glutamyl transferase 
• 
albumin and total protein, total cholesterol, triglycerides, fasting glucose 
• 
C-reactive protein (CRP) 
eGFR will be calculated based on serum creatinine levels using MDRD formula. 
8.2.3 
Urinalysis 
Fresh urine samples (at least 10 mL) will be collected to assess the following parameters: pH, 
protein, ketones, bilirubin, blood, urobilinogen, nitrites, leukocytes, glucose. Proteinuria will 
be performed with dipsticks, in case of positivity, a proteinuria over 24 hours will be performed. 
Microscopy will be performed, if indicated, but results will not be collected in the eCRF. If in 
the opinion of the investigator there are any clinically significant abnormalities in microscopy, 
they will be recorded as an AE in the eCRF. 
8.2.4 
Pregnancy Test 
A β Human chorionic gonadotrophin (HCG) serum test will be performed for all female subjects 
of childbearing potential at Screening (visit 1) and if clinically indicated thereafter. Moreover, 
a HCG urine test will be performed at Day 1 of each cycle before each 177Lu-OPS201 
administration. Any subject becoming pregnant during the study will be withdrawn. All 
subject’s or subject’s partner pregnancies that occur during the study treatment phase and the 
2 years follow-up are to be reported as described in Section 8.1.6. 
8.2.5 
 Other Clinical Laboratory Tests 
Other clinical laboratory tests will be performed to ensure the safety of the subjects, but will 
not be an assessment of the safety of the study drug. 
8.2.6 
Hypothalamic-Pituitary-Adrenal Axis Biomarkers 
Sample for hormone analysis will be collected at predose Day 1 of each Cycle and at 
EOCT/EOAC visit. These samples should be taken at the closest to 8.00 am and includes 
analysis of cortisol, TSH, parathyroid hormone (PTH), luteinising hormone (LH), 
follicle-stimulating hormone (FSH), free thyroxine (FT4) and IGF-1. 
Hormone analyses will only be analysed in subjects who do not have substitution or therapy 
impacting one of the respective pituitary axis (e.g. no cortisol sampling in subjects who receive 
corticosteroids, no thyroid-stimulating hormone and free thyroxine sampling in subjects who 
have thyroxine substitution.  
TSH, cortisol and IGF-1 will be measured at baseline and at end of core trial. 
8.2.7 
Specific Renal Safety Biomarkers 
Specific exploratory renal safety biomarkers analysis will be performed on early morning 
midstream urine samples. The total volume of the collected urine should be documented in the 
eCRF. 
Renal safety biomarkers include markers specific of the different renal tubule regions toxicity: 
GST, GSTP1, KIM-1, clusterin, cystatin-C, calbindin, beta-2 microglobulin and creatinine.  
Urine samples will be collected (and frozen) at the following timepoints: 
• 
Cycle 1: 
- 
Day 1: early morning, before the infusion (baseline) 
- 
Day 3: early morning (48 hours after the end of 177Lu-OPS201 infusion at the 
latest) 


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• 
End of core trial Visit/Early Withdrawal Visit: early morning. 
Complete instructions on processing, handling and shipping will be provided by the dedicated 
analytical lab in charge of the different assessments. 
The results will not be communicated to the investigators. 
8.2.8 
Specific Pancreatic Function Biomarker 
Samples for specific pancreatic function biomarker will include glycosylated haemoglobin 
HbA1c and glucose. Blood will be collected at Day 1 of each visit before infusion and End of 
core trial visit / Early Withdrawal. 
8.2.9 
Testicular Function Biomarkers 
Samples for Testicular Function Biomarkers will include testosterone, Inhibin B and and sex 
hormone-binding globulin SHBG. Blood will be collected at Day 1 of each visit before infusion 
and End of core trial visit / Early Withdrawal. 
8.3 
Physical Examination 
Physical examinations, including body weight, will be conducted at the timepoints described in 
the Schedule of Assessments provided in Table 5 and Table 6 and height will be measured at 
Baseline. 
Any clinically significant physical examination findings (abnormalities) observed during the 
study will be reported as AEs. Any physical examination findings (abnormalities) persisting at 
the end of the study will be followed by the investigator until resolution or until reaching a 
clinically stable endpoint. 
8.4 
Vital Signs 
Blood pressure and heart rate will be assessed at timepoints described in the Schedule of 
Assessments (see Table 5 and Table 6) with an automated device so that measurements are 
independent of the observer. Blood pressure and heart rate will be recorded after five minutes’ 
rest in supine position. Absolute values and change from Baseline will be analysed. 
Respiratory rate and temperature will be recorded. 
8.5 
Electrocardiography 
An ECG analysis will be included as a safety evaluation/endpoint in this study. Twelve 
lead-ECG and 6-hour Holter ECG will be recorded at timepoints described in the Schedule of 
Assessments provided in Table 5 and Table 6. For the Holter ECG, radiotransparent electrodes 
must be used and the Holter cables must be removed when performing imaging procedures (eg, 
SPECT/CT at 2 to 4 hours after the end of 177Lu-OPS201 infusion). 
Twelve lead ECGs will be recorded so that the different ECG intervals (RR, PR, QRS, QT, 
QTcF) can be measured. The ECG will be recorded with the subject in supine position after 
5-minutes of rest until four regular consecutive complexes are available. Whenever possible, 
automated ECG interval estimates taken from the ECG recorder will be used in this study. 
Otherwise, ECG interval estimates will be measured manually in this study and a local ECG 
reader will be used.  
Any clinically significant abnormalities will be recorded as AEs. 
 


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9 
ASSESSMENTS OF PHARMACOKINETICS 
The PK of 177Lu-OPS201 and OPS201, as well as the dosimetry assessments and timepoints 
described below are related to the phase I of the study. PK and dosimetry assessments will also 
be included in phase II. However, the timepoints might be revised based on the phase I results 
and document as part of a protocol amendment. Time of samples collection must be accurately 
recorded in the eCRF. 
9.1 
Pharmacokinetics of 177Lu-OPS201 
9.1.1 
Blood Sample Collection 
Total radioactivity concentration in whole blood will be determined on site/locally using a 
gamma counter calibrated for 177Lu, according to the dosimetry operational manual (DOM). 
For each subject, total radioactivity concentration in whole blood will be measured. Each 
subject will have 20 blood samples (2 mL each) collected at Cycle 1 and Cycle 2 on the 
following timepoints after the end of 177Lu-OPS201 infusion: 
- 
Day 1: before the infusion (baseline), at the end of infusion (0), 5±1 minutes, 30±5 
minutes, 1 hour (±5 minutes) and 4 hours (±30 minutes) post infusion 
- 
Day 2: 24±2 hours 
- 
Day 3: 48±2 hours 
- 
Day 4 to Day 5: 72 to 96 hours 
- 
Day 7 to Day 8: 144 to 168 hours 
Blood samples should be collected from the contralateral arm used for the study drug infusion, 
or from another anatomical site. Subjects with breast surgery (and in particular 
lymphadenectomy) should not have any blood sampling in the corresponding arm. 
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. 
For subjects receiving additional administrations (up to four additional cycles), the same blood 
sample collection should be performed. 
Complete instructions for sample collection, processing and handling will be provided in a 
DOM. 
9.1.2 
Urine Sample Collection 
To determine the renal excretion of 177Lu, total radioactivity concentration in urine will be 
determined on site/locally using a gamma counter calibrated for 177Lu, according to the DOM. 
The samples for urine total radioactivity concentration analysis will be taken from urine 
collected during four different periods at Cycle 1 only: from 0 to 4, 4 to 8, 8 to 24 and 24 to 48 
hours (0 to 4 and 4 to 8 hours only in US sites) after the end of infusion, with an initial void 
collection shortly before the infusion (0) and a final collection, 48 hours after end of 
177Lu-OPS201 infusion. 
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 DOM. 
9.2 
Nuclear Medicine Imaging for Dosimetry 
Radioactive assessments in blood and urine are described in Section 9.1. 


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All images will be centralised and analysed by independent readers for dosimetry analysis of 
the dose limiting organs and tumour lesions. 
To determine the biokinetics and perform an absolute quantification, whole body scans (planar 
scintigraphy) and SPECT/CT will be performed at each cycle at the following timepoint ranges 
just after the end of 177Lu-OPS201 infusion: 
- 
Day 1: 2 to 4 hours 
- 
Day 2: 16 to 24 hours 
- 
Day 3: 40 to 48 hours 
- 
Day 4 to Day 5: 72 to 96 hours 
- 
Day 7 to Day 8: 144 to 168 hours. 
At the timepoint between 16 to 24 hours, SPECT/diagnostic CT will be performed. For all other 
time points, SPECT/low dose CT will be performed. 
For subjects receiving additional administrations (up to four additional cycles), dosimetry 
assessments will be performed after each additional administration with nuclear medicine 
imaging described above. 
Note that optimal schedule of the whole-body scans (planar scintigraphy) and SPECT/CT has 
not been established. Some adaptation of these timelines might be requiered during the study 
and will be decided by the dosimetry expert and the sponsor. In any case, the number of 
whole-body scans (planar scintigraphy) and SPECT/CT may be reduced but it will not be 
increased. 
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. 
9.3 
Pharmacokinetics of OPS201 
9.3.1 
Blood Sample Collection 
Blood will be sampled for the purpose of determining plasma levels of OPS201 using 
high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) 
detection, according to a separate protocol established with the dedicated analytical laboratory. 
For each subject, OPS201 plasma concentration will be measured. Each subject will have 10 
blood samples (2 mL each) collected at Cycle 1 only at the following time points: 
- 
Day 1: before the infusion (baseline), at the end of infusion of 177Lu-OPS201 (0), 
5±1 minutes, 30±5 minutes, 1 hour (±5 minutes) and 4 hours (±30 minutes), 6 
(±30 minutes), and 8 hours (±30 minutes) after the end of infusion. 
- 
Day 2: 24±2 hours after the end of infusion of 177Lu-OPS201. 
- 
Day 3: 48±2 hours after the end of infusion of 177Lu-OPS201. 
Blood samples should be collected from the arm opposite to that of the study drug infusion, or 
from another site. Subjects with breast surgery (and in particular lymphadenectomy) should not 
have any blood sampling in the corresponding arm. 
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. 


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Note that nominal sample collection times may be changed during the study based on available 
data. These changes will be decided by the sponsor: the total number may be decreased but it 
will not be increased.  
Residual plasma used for OPS201 PK analysis may also be used for exploratory analysis. This 
could include using leftover plasma for protein binding analysis, metabolite profiling or 
analysis of excipients. Plasma samples remaining from the analysis may be retained by the 
sponsor for additional investigations (i.e. long-term stability, reproducibility). 
9.3.2 
Urine Sample Collection 
To determine the renal excretion of OPS201, the concentration of OPS201 in urine will be 
determined using HPLC with MS/MS detection, according to a separate protocol established 
with the dedicated analytical laboratory. 
The samples for urine OPS201 concentration analysis will be taken from urine collected during 
four different periods at Cycle 1: from 0 to 4, 4 to 8, 8 to 24 and 24 to 48 hours (0 to 4 and 4 to 
8 hours only in US sites) after the start of infusion, with an initial void collection shortly before 
the infusion (0) and a final collection, 48 hours after the end of 177Lu-OPS201 infusion. 
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. 
Residual urine used for OPS201 PK analysis may also be used for exploratory analysis. This 
could include using leftover urine for metabolite profiling or analysis of excipients. Urine 
samples remaining from the analysis may be retained by the sponsor for additional 
investigations (i.e. long-term stability, reproducibility). 
Complete instructions for urine collection, processing, handling and shipment will be provided 
in the laboratory manual. 


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10 
EXPLORATORY BIOMARKERS AND BIOBANKING 
10.1 
DNA-DSB in Peripheral Lymphocytes 
Blood samples will be collected at specific time points as described in the schedule of 
assessments in Table 5. 
DNA-DSB in lymphocytes will be collected at selected sites. Blood samples should be collected 
from the arm opposite to that of the study drug infusion, or from another site. Subjects with 
breast surgery (and in particular lymphadenectomy) should not have any blood sampling in the 
corresponding arm. Lymphocyte preparation will be done immediately after each blood sample 
collection. The accurate time of sample collection must be recorded in the eCRF. 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 by the 
CRO in charge of the measurement. 
10.2 
DNA Repair Capacity in Peripheral Lymphocytes 
Blood samples will be collected at specific timepoints as described in the schedule of 
assessments in Table 5. 
DNA repair capacity in lymphocytes will be measured using an enzymatic method in selected 
sites. Blood samples should be collected from the arm opposite to that of the study drug 
infusion, or from another site. Subjects with breast surgery (and in particular 
lymphadenectomy) should not have any blood sampling in the corresponding arm. Lymphocyte 
preparation will be done immediately after each blood sample collection. The accurate time of 
sample collection must be recorded in the eCRF. 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 by the 
CRO in charge of the measurement. 
10.3 
Germinal Mutation in Blood 
Blood sample will be collected in a PAXgene-DNA tube at Cycle 1 Day 1 before infusion from 
the arm opposite to that of the study drug infusion or from another site. Subjects with breast 
surgery (and in particular lymphadenectomy) should not have any blood sampling in the 
corresponding arm. Complete instruction for sample collection, processing and handling will 
be provided by the CRO in charge of the measurement. 
10.4 
Tumour Biopsy 
Sequential biopsies will be obtained at Screening and EOCT or at disease progression, 
whichever occurs earlier. Baseline biopsy is mandatory and post-treatment biopsy is optional. 
If a historic biopsy is available and evaluable according to the requirements described below; 
it should not be older than 28 days prior the signature of the ICF, this biopsy can be used as 
baseline biopsy. The tissue material will be used for exploratory analysis to gain insight in the 
mechanism of action of the IRPP, the mechanism of resistance and association of sstr2 
expression with the tumour uptake of 177Lu-OPS201. 
The biopsy size will be at least 3 to 5 mm3. Two different tissue preparation will be done 
depending on the size of the collected biopsy: 1) in the case of the biopsy is smaller than 5 mm3, 
the biopsy will be formalin-fixed, paraffin‑embedded; 2) in case the biopsy is larger than 5 
mm3, one part will be formalin-fixed, paraffin-embedded while the extra-part will be frozen. 
Tumor biopsy has to be taken from the primary or metastatic lesion, whichever is accessible, 
ideally from a lesion which is positive for sstr2 on 68Lu-OPS202 scan following eligibility 


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criteria and can be accomplished with reasonable safety. Tumour biopsy assessments will be 
performed afterwards by a CRO since they are not part of the eligibility assessment. 
Tumour biopsies will be stored at the CRO during maximum 5 years after the end of the study. 
Complete instructions on processing, handling and shipping will be provided by the CRO in 
charge of the different assessments. 
10.4.1 
Tumour Micro-environment and Other Markers of Interest 
The biopsy will be used to evaluate tumour microenvironment and other markers of interest of 
the disease, such as: proliferative marker (ki-67), Tumour infiltrating immune cells (TIL/TME), 
DNA-DSB (gammaH2AX), target receptor evaluation (sstr2), tumour gene expression profile 
and gene mutations (targeted or TMB). 
Specific markers depending on the indication will also be assessed in tumour biopsy (i.e. for 
BC: ER, progesterone receptor and HER2 protein expression and for SCLC: p53, Rb1, MYC 
and DLL3 gene expression).  
10.4.2 
DNA Repair Capacity in Tumour Tissue 
DNA repair capacity will be measured in tumour tissue by a specialised laboratory in case 
sufficient material is available (biopsy larger than 5 mm3). No additional biopsy will be taken 
for this measurement since the extra part of the biopsy described in Section 10.4.1 will only be 
frozen for DNA repair capacity if this biopsy is larger than 5 mm3. 
Complete instructions for biopsy, processing and handling will be provided by the CRO in 
charge of the measurement. 
10.5 
 Biobanking 
Analysis of biobank samples will be performed outside the scope of the main study and will be 
reported separately. Therefore, this analysis is optional. 
For each subject who has signed a specific consent for the biobank samples, three biobanking 
sampling time points (see below). 
Instructions for collection, processing, handling and shipment of the samples banking will be 
outlined in the laboratory manual. 
Samples to be used for serum, cfDNA and blood for RNA, biobank storage will be taken at 
Day 1 (or Day -1) of Cycle 1 before infusion and at Day 1 of Cycle 2 before infusion and at 
EOCT/EOAC/EW.  
(a) 
Serum: 7 mL of whole blood will be collected on specific dry tubes for serum isolation 
and frozen for storage 
(b) 
Blood for RNA: 2.5 mL of whole blood will be collected in PAXgene RNA tubes. 
(c) 
Blood for cfDNA: 10 mL of whole blood will be collected in specific tubes 
 
Samples will be biobanked for future analysis of circulating markers, including proteins, 
pharmacogenetic and pharmacogenomic biomarkers and will only be collected for those 
subjects who have agreed to it by signing the specific informed consent form for the exploratory 
part of the study (see Section 14.2.1). 
The biobanked samples will be stored for up to 15 years from the end of the study, to be made 
available for future research towards further understanding of (i) treatment response including, 
but not limited to, the safety profile, (ii) drug treatment mode of actions and (iii) disease 
understanding. 
Samples will be archived in a central biorepository designated by the sponsor and according to 


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local administration regulations and/or the European Medicines Agency and will not carry 
personal identification (e.g. social security number or name). Analysis of additional biomarkers 
(including potential genetic research) from the biobank samples will be performed outside the 
scope of the main study and reported separately. 
Only people designated by the sponsor will be allowed access to the samples. All information 
collected will be kept strictly confidential and all clinical information will be de-identified. This 
means that no personally identifiable information will be retained with the results of the 
exploratory analyses, so that no individual or collective results will be linked to the individual 
subject whose sample was taken in the study. No individual genetic results will be 
communicated to the investigator or subject unless required by local regulation. 
The sponsor will comply with all local regulations related to the establishment, management 
and application of a human blood samples biobank.  


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11 
STATISTICS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP). 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)® (version 9.2 
or higher). 
Summary descriptive tables by treatment and over time (as applicable) will be provided.  
Continuous data will be summarised with the following items: frequency, median, range, mean, 
standard deviation (SD) and Coefficient of Variation (CV) if relevant. 
Categorical data will be presented in contingency tables with frequencies and percentages of 
each modality (including missing data modality). The 95% confidence interval (CI) will be 
calculated following the exact method. 
To describe time dependent parameters (PFS, OS), Kaplan-Meier curves and life tables will be 
provided. The 95% CI on the median will be given. 
Data from phase I and phase II will be analysed and reported separately. 
An overview of the main analysis strategy is provided in the following sections. 
11.1 
Analyses Populations 
The following population will be used during statistical analyses: 
• 
Eligibility screened population: All subjects screened (i.e. who signed the informed 
consent).  
• 
Safety population: All subjects who received at least one dose of 177Lu-OPS201 or 
68Ga-OPS202. 
• 
68Ga-OPS202 safety population: All subjects who received at least one dose of 
68Ga-OPS202. 
• 
177Lu-OPS201 safety population: All subjects who received at least one dose of 
177Lu-OPS201. 
• 
MTCA evaluable population: All subjects who received at least one dose of 
177Lu-OPS201 in the radioactivity escalation of the phase I of the study. The 
MTCA-evaluable population will be used to determine the MTCA/MTSA/MACA. 
• 
Intention to treat (ITT) population: All subjects who received at least one dose of 
177Lu-OPS201 in the phase II of the study. 
• 
Per protocol (PP) population: All subjects in the ITT population in the phase II of the 
study who have measurable disease at baseline, have at least one post baseline response 
assessment and no major protocol deviations occurred that could affect efficacy analysis. 
The PP population will be used for the analyses of ORR, DCR, PFS, OS, TTP, TTR and 
DoR. 
• 
Dosimetry population: All subjects who received at least one dose of 177Lu-OPS201 for 
whom at least one complete set of dosimetry imaging and dosimetry blood sample 
measurements is available. Dosimetry may be analysed separately for phase I and phase 
II. 
• 
Per protocol dosimetry population: All subjects in the dosimetry population for whom 
no major protocol violations occurred affecting dosimetry variables. Dosimetry may be 
analysed separately for phase I and phase II. 


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• 
Radiopharmaceutical pharmacokinetic population: All subjects who received at least 
one dose of 177Lu-OPS201 and have at least one measured radioactive concentration in 
blood. Radiopharmaceutical PK may be analysed separately for phase I and phase II. 
• 
OPS201 pharmacokinetic population: All subjects who received at least one dose of 
177Lu-OPS201 and have no major protocol deviations affecting the PK variables and who 
have a sufficient number of OPS201 concentrations to estimate the main PK parameters 
(i.e. Cmax, Tmax and AUC). OPS201 PK may be analysed separately for phase I and 
phase II. 
Subjects will be assigned to each analysis population prior to the statistical analysis. 
11.1.1 
Populations Analysed 
For the phase I of the study, the primary analysis based on the primary safety endpoint will be 
performed on the MTCA evaluable population. The analysis of pharmacokinetic data will be 
performed on the pharmacokinetic population. 
For the phase II of the study, the primary analysis based on the primary efficacy endpoint will 
be performed on the PP population. In addition, secondary/confirmatory analysis may be 
performed on the ITT population. 
The analyses of safety data will be performed based on the safety population. 
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 (ITT, PP and safety 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 interim analysis and database lock. The list may be updated, up to the 
point of interim analysis and database lock, to include any additional major protocol deviations 
impacting inclusion in the PP population. 
11.2 
Statistical Methodology for Phase I 
11.2.1 
Sample Size Determination 
This is primarily a descriptive safety and tolerability study. The total number of subjects is not 
based on a formal statistical sample size calculation.  
The actual sample size required to adequately determine the MTCA/MTSA during phase I 
depends on the initial activity, rate of radioactivity escalation and the observed 
radioactivity-toxicity and radioactivity/organ absorbed dose relationships. Simulation studies 
have been performed to quantify the operational characteristics (ie, precision of the 
MTCA/MTSA, sample size, number of subjects being over/under dosed) of the adaptive 
radioactivity-escalation design under a number of plausible escalation-DLT relationship 
scenarios. Results are provided in Appendix 1. Based on experience, the chosen sample size of 
3-5 subjects per cohort is considered to be sufficient to fulfil the objectives of the study. It is 
anticipated that between 15 and 30 subjects will be required to establish the MTCA or MACA. 
11.2.2 
Significance Testing and Estimations 
As this is a descriptive safety and tolerability study, no formal statistical testing of safety will 
be carried out. 
11.2.3 
Statistical Methods 
Statistical analyses will be performed by an external CRO, managed by the sponsor’s biometry 
department. 


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11.2.3.1 Demographic and Other Baseline Characteristics 
Summary statistics will be presented for the total study population and by cohort. Frequency 
tables for qualitative data will be provided. Medical and surgical history findings will be 
summarised using MedDRA terms. 
11.2.3.2 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. 
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, renal clearance) will be derived using the 
noncompartmental approach on the individual plasma concentration-time profiles of OPS201 
and on the individual urine concentrations. 
An attempt to build an integrated model taking into account PK, dosimetry as well as efficacy 
and safety data will be made if warranted by the data. The exploratory analysis will be captured 
in a separate data analysis plan and reported in a standalone report. 
11.2.3.3 Radiation Dosimetry of 177Lu-OPS201: 
The radiation dosimetry analysis of the radiopharmaceutical 177Lu-OPS201 will be performed 
under the responsibility of the sponsor’s Clinical PK department. 
Further details on dosimetry assessments and on dosimetry parameters will be provided in a 
separate data analysis plan. 
The dosimetry assessments will be performed and reported according to the criteria set by the 
EANM Dosimetry Committee guidance document: good practice of clinical dosimetry 
reporting (Lassmann 2011). 
Calculations will be conducted on the following parameters (only in organs showing uptake): 
- 
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) 
Cumulative absorbed organ doses (Gy)/Organs of highest radioactivity uptake will be identified 
visually. Regions of interest (ROI) will be placed over these organs to determine the relative 
radioactivity in the respective organs. TACs (time radioactivity curves), describing % IA/ROI 
of the radioactivity amount injected versus time, considering renal excretion radioactivity) will 
be derived. The absorbed organ doses of the dose-limiting organs (kidney, BM and liver) will 
be evaluated and reported to the investigator before the next administration of 177Lu-OPS201 
can be initiated to enable radioactivity adaptations in the event the next dose may exceed the 
organ limits for the kidney (23 Gy) and for the BM (1.5 Gy or up to 2 Gy during core trial and 
additional cycles, respectively). Of note, imaged-based dosimetry results associated to 


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overlying tumors/lesions resulting in absorbed dose overestimation will not be used for dose 
radioactivity adaptation. In this case, the dose radioactive adtaptaion will rely on an overall 
benefice/risk dosimetry evaluation. 
A Bayesian power model will be considered to relate the cumulative 177Lu-OPS201 
radioactivity during Cycles 1 and 2 of the dose escalation to the cumulative absorbed dose in 
the BM and kidney (see details in Appendix 1). Vague priors will be used. The posterior 
predictive distribution of the exposure will be summarised by radioactivity level. The maximum 
cumulative absorbed dose where the posterior predictive probability of remaining below the 
target organ limits (1.5 Gy for BM and 23 Gy for kidney) will be estimated from that model, as 
the radiation-safety component of the MTCA.  
The dosimetry for all organs other than BM and kidney will be assessed and finalised for the 
final clinical study report, whereas dosimetry data for BM and kidney must be available for the 
DRB meetings. These data can be reviewed at any time if a major safety issue occurs. 
11.2.3.4 Pharmacodynamics and Efficacy Evaluation 
Details for pharmacodynamic/efficacy evaluations are provided in Section 7. Tumour response 
will be evaluated by the ICL. Response and progression will be evaluated using the revised 
RECIST guideline v1.1 (see IRC), PERCIST guideline v1.0 (see IRC) as well as volumetric 
CT. Only subjects with measurable disease at baseline, who have received at least two 
administrations of study treatment and reach the end of EOCT visit will be considered evaluable 
for response. In addition, a mGa-RECIST and mGa-PERCIST using sstr2-positive lesions only, 
will be evaluated. Tumour volume and percentage change in tumour volume will be evaluated. 
Efficacy data, such as best tumour response, will be summarised using descriptive statistics and 
will be graphically displayed if appropriate. The 95% CI will be calculated for ORR and 
selected secondary efficacy endpoints by treatment. Time-to-event data will be analysed by 
using survival methods. The results will be presented both in summary tables and graphically 
in Kaplan-Meier plots. 
The association between pharmacodynamics parameters and selected safety, efficacy, or PK 
parameters may be graphically displayed. An attempt to build an integrated model taking into 
account PK, dosimetry as well as efficacy and safety data will be made, if warranted by the 
data. The exploratory analysis will be captured in a separate data analysis plan and reported in 
a standalone report. Further statistical analyses may be conducted. Details of the response 
evaluation will be given in a separate IRC. Details of the analysis will be specified in the SAP. 
11.2.3.5 Safety Evaluation 
For the overall study, descriptive statistics will be calculated for the safety parameters. No 
formal statistical analyses of safety data are planned. 
Summaries will be prepared by treatment group and, as needed, by timepoint. 
All AEs will be coded according to the latest version of the MedDRA and NCI-CTCAE.  
Study drug treatment-emergent AE (TEAE) summaries will include the overall incidence (by 
system organ class (SOC) and PT), events by maximum intensity, events by relationship to 
study drug, events leading to discontinuation of IIP/IRPP and SAEs. 
Physical examination findings, vital signs, 12-lead ECG, ECG Holter recordings and clinical 
laboratory parameters will be summarised descriptively at each timepoint. Actual and change 
from baseline data will be calculated and summarised where data are available. The 
investigator’s interpretation of 12-lead ECGs will be listed. 


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Concomitant medications will be coded using the latest version of the World Health 
Organisation drug dictionary (WHO-DD) and will be summarised by treatment group and 
overall with the number and percentage of subjects receiving concomitant medication by drug 
class and preferred drug name. 
The NCI-CTCAE version 5.0 classification will be used to classify all TEAEs and laboratory 
abnormalities. 
Maximum grade or severity will be tabulated by subject for each MedDRA SOC and PT. 
Analyses of AEs and SAEs will be performed in two different ways: regardless of the 
relationship to the IIP/IRPP and related to the IIP/IRPP. Moreover, all AEs excluding SAEs 
and SAEs only will be tabulated. 
For haematological and biochemical toxicities, the worst NCI-CTCAE grade 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. 
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 administration of 177Lu-OPS201; or  
• 
It was present prior to receiving the first administration of 177Lu-OPS201 but the intensity 
increased during the active phase of the study; or  
• 
It was present prior to receiving the first administration of 177Lu-OPS201, the intensity 
is the same but the drug relationship became related during the active phase of the study. 
11.2.3.6 Maximum Tolerated Single and Cumulative Activity 
Individual listings and treatment summaries of DLTs with CTCAE code and grade will be 
presented. 
The incidence of subjects with DLTs during Cycles 1 or 2 of the radioactivity escalation will 
be summarised by treatment and, if possible, modelled as a function of the cumulative 
radioactivity for Cycles 1 and 2 using Bayesian logistic regression. The moderately-informative 
independent priors used during the interim analysis (see Appendix 1 for details) as well as 
non-informative priors will be used for this analysis in order to assess sensitivity of the 
estimates. Parameter estimates and model predictions will be reported with 90% credibility sets. 
The DLT components of the MTCA will be computed as a derived function of model 
parameters. If possible, the same analysis will be repeated for the Cycle 1 DLTs in order to 
predict the MTSA. 
The posterior distribution of the MTCA and MTSA will be summarised in tabular and graphical 
formats. 
11.2.3.7 Interim Analyses 
Safety and radiation exposure data will be reviewed on an ongoing basis during the radioactivity 
escalation. A DRB will be set up for the radioactivity escalation decisions. For each cohort, the 
DRB is planned to review the safety and dosimetry data at the end of Cycle 2 of three subjects. 
Individual safety and organ absorbed dose data of Cycle 1 will also be reviewed at the end of 
Cycle 1 to determine the subject’s eligibility and maintenance dose for Cycle 2. 
At the time of DRB meeting, all cumulative available information will be reviewed.  
Bayesian radioactivity-response and/or PK/PD modelling of DLT rates and organ absorbed 
dose to target organs may be performed during the planned review meetings in order to generate 
additional relevant information for the adaptive dose selection decisions. The DRB will review 
all available data and make the final decision as to radioactivity escalation, de-escalation, or 


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cohort expansion during the adaptive radioactivity escalation and recommended phase II dose. 
This group will also determine when to implement predefined stopping rules. 
A specific charter will be developed to define roles and responsibilities, as well as the data set 
to be reviewed by the DRB. 
Full analysis will be performed on the entire dataset at the EOCT/EOAC/EW and at the end of 
the 24-month long-term follow-up. 
11.3 
Statistical Methodology for Phase II 
11.3.1 
Sample Size Determination 
The sample size is calculated using Simon's optimal two-stage design based on the ORR rate 
(CR + PR) following 177Lu-OPS201 treatment.  
For the Simon's optimal two-stage design, the hypotheses that will be tested for each cohort are: 
H0: ORR≤ORR0 versus the alternative H1: ORR>ORR0 where ORR is the true objective 
response rate following 177Lu-OPS201 treatment that warrants further clinical development, 
and ORR0 is the minimum objective response rate to be excluded from further clinical 
development. The thresholds for ORR and ORR0 may be updated based on results from phase 
I and the advances in scientific knowledge. 
ORR will be analysed at the end of Stage 1 (6 weeks after the second 177Lu-OPS201 
administration (Cycle 2) of the core treatment period of the last evaluable subject of the Stage 1 
cohort for each type of cancer). If the observed number of responders is below a predefined 
threshold, the respective study cohort will be stopped for futility. Otherwise, additional subjects 
will be treated to complete the planned enrolment. At the end of Stage 2, the null hypothesis 
will be rejected depending on the total observed number of responders based on a predefined 
threshold. 
For the SCLC cohort, with 69 response evaluable subjects, there will be 90% power to test a 
null hypothesis ORR rate of 23% and an alternative hypothesis ORR rate of 40% at one-sided 
significance level of α=0.05. The first stage consists of 29 subjects. If seven responses or less 
are seen in the first 29 subjects, then the trial is stopped. Otherwise accrual continues to a total 
of 69 response evaluable subjects. Approximately 76 subjects are planned to be enrolled to 
account for 10% study dropout. 
For the BC cohort, with 87 response evaluable subjects, there will be 90% power to test a null 
hypothesis ORR rate of 12% and an alternative hypothesis ORR rate of 25% at one-sided 
significance level of α=0.05. The first stage consists of 33 subjects. If four responses or less are 
seen in the first 33 subjects, then the trial is stopped. Otherwise accrual continues to a total of 
87 response evaluable subjects. Approximately 96 subjects are planned to account for 10% 
study dropout.  
11.3.2 
Significance Testing and Estimations 
The analysis will be descriptive and no formal statistical tests are planned for the primary and 
secondary endpoints. 
11.3.3 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external CRO, managed by the sponsor’s Biometry 
Department. 
A SAP describing the planned statistical analysis in detail with tables, figures and listings 
(TFLs) templates will be developed as a separate document. The SAP will be prepared before 
the first subject first visit. 


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Statistical evaluation will be performed using SAS® (version 9.2 or higher). 
11.3.3.1 Demographic and Other Baseline Characteristics 
Descriptive summary statistics (n, mean, SD, 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 and safety populations. 
11.3.3.2 Subject Disposition and Withdrawals 
The numbers and percentages of subjects enrolled and included in each of the ITT, PP and 
safety 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. 
11.3.3.3 Pharmacokinetic Data 
The pharmacokinetic data analysis, if collected in phase II, will be performed independently by 
a CRO under the supervision of the sponsor’s Clinical PK department as described in Section 
9.3. 
Individual listings and summary tables of OPS201 plasma concentrations and amount excreted 
in urine will be provided. 
11.3.3.4 Efficacy Evaluation 
At the end of phase II, descriptive summaries will be provided for all primary and secondary 
efficacy endpoints. For the primary endpoint, final analysis will take into account the sequential 
sampling procedure of the design and the underlying binomial distribution assumed by the 
Simon's optimal two-stage design. 
As indicated in Section 7.2.1, the primary efficacy variable is the ORR over the two treatment 
cycles of the core study measured by CT or MRI using RECIST version 1.1. ORR is defined as 
the percentage of subjects who have achieved a response of CR or PR. Exact 95% CIs based on 
the binomial distribution will be reported. Tumour response assessments are performed 6 weeks 
after each administration of 177Lu-OPS201 during the core study or at the time of occurrence of 
first clinical signs of disease progression as determined by the investigator. 
As indicated in Section 7.2.2, the secondary efficacy variables are the below listed variables 
measured after administration of study treatment: 
• 
DRR, defined as the percentage of subjects who have achieved a response of CR or PR 
lasting more than 6 months. 
• 
PFS as determined from start of study treatment until occurrence of event. PFS is defined 
as the time from the date of first dose of 177Lu-OPS201 to the date of first documented 
disease progression as determined by the investigator or death due to any cause, 
whichever occurs first. Rules for declaring PFS events versus censors will be described 
in the SAP. 
• 
OS is defined as the time from the date of first dose of 177Lu-OPS201 to the date of death 
due to any cause.  
- 
One-year and two-year survival are defined as the subject survival probability at 
1 year and 2 years, respectively, after the date of first dose of 177Lu-OPS201. 
• 
Other response endpoints as per RECIST version 1.1: 


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- 
disease control rate (DCR), defined as the percentage of subjects who have 
achieved a response of CR, PR or stable disease. 
- 
TTP, defined as the time from date of first dose of 177Lu-OPS201 to the date of 
first documentation disease progression as determined by the investigator. 
- 
TTR, defined as the time from the date of first dose of 177Lu-OPS201 to the date 
of the first documentation of a response (CR or PR whichever occurs first) in a 
subject who responded. 
- 
duration of response (DoR), defined as the time from date of first documentation 
of response (CR or PR whichever occurs first) to the date of disease progression 
or to death due to any cause, whichever occurs first. 
Time-to-event parameters will be graphically displayed using Kaplan-Meier estimates. Median 
event times and 2-sided 95% CIs will be reported on the graphs. Two-sided 95% CIs may be 
displayed for some other parameters.  
• 
Mean change (%) in tumour volume at 6 weeks after each 177Lu-OPS201 administration 
compared to baseline, as assessed by volumetric CT. 
• 
Correlation between tumour uptake on 68Ga-OPS202 PET/CT (assessed based on 
SUVmax and SUVmean) at screening with tumour response to 177Lu-OPS201 therapy from 
Screening to 6 weeks after second 177Lu-OPS201 administration (second cycle) 
• 
Correlation between the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 on 
PET/CT images and the uptake on 177Lu-OPS201 SPECT/CT 
• 
Change in 68Ga-OPS202 uptake on PET scan after the second 177Lu-OPS201 
administration (second cycle) as assessed by SUVmax and SUVmean in subjects screened 
for 177Lu-OPS201 treatment as compared to clinical response and ORR.  
• 
Proportion subjects with of sstr2-positive tumour lesions by 68Ga-OPS202 PET/CT scans 
as assessed by the identification of avid lesions in subjects screened for 177Lu-OPS201 
treatment at baseline. 
Subject Reported Outcomes (only Phase II) 
• 
Changes in health-related quality of life scores from baseline to EOCT measured by 
EQ-5D-5L and EORTC QLQ-C30. 
Exploratory endpoints  
• 
The association between the uptake on 68Ga-OPS202 PET/CT with sstr2 expression on 
tumours as determined by IHC. 
• 
Change in renal safety biomarkers compared to baseline. 
• 
Change from baseline in tumour microenvironment, transcriptomics, DNA repair, gene 
mutations and other disease markers of interest. 
• 
Change from baseline in DNA repair capacity in blood. 
11.3.3.5 Adjustment for Country/Centre Effect 
Not applicable, as no randomization or stratification will be performed in this study. 
11.3.3.6 Safety Evaluation 
All AEs will be coded according to the MedDRA version (latest version in use) and will be 
classified by MedDRA SOC and PT. AEs, SAEs, AEs leading to discontinuation of study 
treatment and AEs leading to death will be summarised and listed by subject, SOC class and 
PT. Adverse events reported by investigators using the NCI-CTCAE classification (version 5.0) 
will be coded using MedDRA dictionary (latest available version).  


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Incidence of all reported AEs and SAEs will be tabulated. In addition, summary tables will be 
presented by maximum intensity, drug relationship and AEs associated with premature 
withdrawal of study medication. 
Concomitant medication will be coded by using WHO-DD (latest available version) and will 
be summarised. 
Summary statistics (mean, median, SD and range as appropriate) will be presented for vital 
signs, blood pressure, heart rate, ECG parameters, clinical laboratory tests etc. at each 
assessment with change from Baseline. For laboratory data, abnormal values will be flagged in 
the data listings and a list of clinically significant abnormal values will be presented. Clinically 
significant ECG findings will also be flagged. Shift tables will be presented of the number and 
percentage of subjects with low, normal or high values and normal or abnormal exams. 
Summary incidence tables will be provided classified by SOC, 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 intensity (Grade 5 > Grade 4 > Grade 3 > Grade 2 > Grade 1 > missing 
> not applicable) will be chosen.  
Haematological and biochemistry toxicities will be recorded and graded according to the 
NCI-CTCAE criteria. The NCI-CTCAE Grade 3 and 4 haematology and biochemistry 
parameters by subject and by cycle will be listed. For WBC, neutrophils, platelets and 
haemoglobin, with associated Grade 3 or 4 toxicities, nadir and day to nadir will be calculated. 
11.3.4 
Subgroup Analyses 
Not applicable. 
11.3.5 
Interim / Futility Analyses and ISAC Safety Review Committees 
Phase II 
An interim analysis will be performed for futility based on the first stage of Simon's optimal 
two-stage design within each cohort.  
For the SCLC cohort, the first stage consists of 29 subjects. An analysis will be conducted after 
approximately 29 subjects have been assessed on the ORR. The ORR assessment cut-point for 
the 29th subject is 6 weeks after Cycle 2 dose. The probability of early termination (PET) after 
the first stage is 0.6555.  
For the BC cohort, the first stage consists of 33 subjects. An analysis will be conducted after 
approximately 33 subjects have been assessed on the ORR. The ORR assessment cut-point for 
the 33rd subject is 6 weeks after Cycle 2 dose. The probability of early termination (PET) after 
the first stage is 0.6374. 
The details of the interim analysis will be described in the SAP. 
An ISAC will be established to monitor the safety and progress of the study on a regular basis. 
The committee will operate independently from the sponsor and the clinical investigators. To 
minimise the potential introduction of bias, these individuals will not have any direct contact 
with the study site personnel or subjects. ISAC members will be selected for their expertise in 
oncology. 
The ISAC will be responsible for any adhoc assessments of safety and futility for each phase II 
cohort, and can meet as needed to recommend protocol modifications, or any other actions 
including but not limited to:  
• 
Changing the eligibility criteria if the risks of the intervention seem to be higher in a 
subgroup; 


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• 
Altering the drug product dosage and/or schedule if the AEs observed appear likely to be 
reduced by such changes;  
• 
Identifying information needed to inform current and future trial subjects of newly 
identified risks via changes in the consent form and, in some cases, obtaining reconsent 
of current subjects to continued trial participation. 
Further details regarding the ISAC and their requirements will be outlined in the ISAC charter. 
 
 


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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. 
Sponsor-delegated Clinical Research Associates will have access to source data and documents 
for source data verification purposes during monitoring visits. 
Auditors, study monitors 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, radiology department). 
In the event of the site being notified directly of a regulatory inspection, the investigator must 
notify the sponsor’s representative as soon as possible, to assist with preparations for the 
inspection. 


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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: 
• 
Non-substantial 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. 
• 
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: 
(1) 
The deviation has harmed or posed a significant or substantive risk of harm to the 
research subject. 
(2) 
The deviation compromises the scientific integrity of the data collected for the study. 
(3) 
The deviation is a wilful or knowing breach of human subject protection regulations, 
policies, or procedures on the part of the investigator(s). 
(4) 
The deviation involves a serious or continuing noncompliance with any applicable 
human subject protection regulations, policies, or procedures. 
(5) 
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. 


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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, they must immediately inform the sponsor. 
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 
give instruction on the protocol, the completion of the CRF 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 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor or delegate is responsible for monitoring these data to verify that the rights and 
wellbeing of subjects are protected, that study data are accurate (complete and verifiable to 
source data) and that the study is conducted in compliance with the protocol, GCP and 
regulatory requirements. 
Sponsor or delegate assigned monitors will conduct regular site visits. The investigator will 
allow direct access to all relevant files (for all subjects) and clinical study supplies (dispensing 
and storage areas) for the purpose of verifying entries made in the CRF/eCRF and assist with 
the monitor’s activities, if requested. Adequate time and space for monitoring visits should be 
made available by the investigator. 
The site must complete the eCRFs on an ongoing basis to allow regular review by the study 
monitor, both remotely by the internet and during site visits. The central study monitor at the 
sponsor will use functions of the electronic data capture (EDC) system to address any queries 
raised while reviewing the data entered by the study site personnel in a timely manner. 
Whenever a subject name is revealed on a document required by the sponsor (e.g. laboratory 
print outs) the name must be blacked out permanently by the site personnel, leaving the initials 
visible and annotated with the subject number as identification. 
A DRB will review data for the phase I of the study (refer to Section 3.1.4.1.4). 
An Operations Committee will be composed of investigator and sponsor representatives and, 
as appropriate, of representatives of a dedicated study specific management organisation to 


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efficacy and safety data at each interim analysis for the phase II. A specific charter may be 
developed to define roles and responsibilities.  
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 CRFs/eCRFs transferred from the investigational site to the assigned Data 
Management group will be reviewed (secondary monitoring) for completeness, consistency, 
legibility and protocol compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require additional 
electronic manual queries to be raised to the investigator by the monitor 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. 


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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 (Section 1.8). 
FDA, 21 CFR Part 11, Electronic Records, Electronic Signatures and FDA, Guidance for 
Industry: Computerized 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 person designated by the investigator, 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 IIP/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 
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. 
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 Biobanking  
This study has the option for subjects to consent to the collection of samples for biobanking for 
future exploratory analysis and storage for up to 15 years (where local regulations allow). A 


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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 ethics committee(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 assure that the privacy of the subjects, including their personal identity 
and all personal medical information, will be maintained at all times. In CRFs and other 
documents or image material submitted to the sponsor, subjects will be identified not by their 
names, but by an identification code (e.g. initials and identification number). 
Personal medical information may be reviewed for the purpose of verifying data recorded on 
the CRF. This review may be conducted by the study monitor, properly authorised persons on 
behalf of the sponsor, the quality assurance unit, or regulatory authorities. Personal medical 
information will always be treated as confidential. 


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15 
DATA HANDLING AND RECORD KEEPING 
15.1 
Data Recording of Study Data 
In compliance with GCP, the medical records/medical notes, etc., should be clearly marked and 
permit easy identification of a subject’s participation in the specified clinical study. 
The investigator must record all data relating to protocol procedures, IIP/IRPP administration, 
laboratory data, safety data and efficacy ratings on the CRFs/eCRFs provided for the study. The 
investigator, by completing the signature log, may formally designate authority to complete 
CRFs/eCRFs to appropriately qualified staff having certified user access to the eCRF. Subject 
completed diaries and questionnaires will be printed and entered by the site personnel into the 
eCRF. 
The investigator must, as a minimum, provide an electronic signature (e-signature) to each case 
report book to attest to the accuracy and completeness of all the data. If any changes are made 
to the eCRF, after a form has been locked and electronically signed, the investigator will be 
required to perform an additional e-signature authorising agreement with any new information 
or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is always 
required. In the eCRF, the audit trail function will allow the changes made to be viewed on each 
item entered. 
15.2 
Data Management 
EDC will be utilised for collecting subject data. Each site is required to have a computer and 
internet connection available for site entry of clinical data. All entries in the eCRF will be done 
under the electronic signature of the person performing the action. This electronic signature 
consists of an individual and confidential username and password combination. It is declared to be 
the legally binding equivalent of the handwritten signature. Only sponsor authorised users will 
have access to the eCRF as appropriate to their study responsibilities. Users must have successfully 
undergone software application training prior to entering data into the eCRF. 
Data management will be conducted by a CRO, directed by the sponsor’s data management 
department. All data management procedures will be completed in accordance with the sponsor 
and the contracted CRO SOPs. Prior to data being received in-house at the assigned CRO, they 
will be monitored at the investigator site, (for further details please see Section 13.3 Monitoring 
Procedures). 
The sponsor will ensure that an appropriate eCRF is developed to capture the data accurately 
and suitable queries are raised to resolve any missing or inconsistent data. At the end of the 
trial, the investigator will receive their data, from the clinical study, in an electronic format 
(PDF files) which will be an exact copy of the eCRF and will include the full audit trail, for 
archiving purposes and future reference. 
Any queries generated during the data management process will also be tracked by the 
contracted data management CRO/will be raised within the EDC system. It is the central study 
monitor’s responsibility to ensure that all queries are resolved by the relevant parties. 
The sponsor will also ensure that SAE data collected in the CRF/eCRF are consistent with 
information provided to the sponsor’s pharmacovigilance department (and vice versa).  
The coding of an AE, medical history, surgical procedures and concomitant medication terms 
will be performed by a CRO and reviewed and approved by the sponsor. Concomitant 
medications will be coded using WHODRUG and AEs/medical history terms will be coded 
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Only data from subjects who signed the trial informed consent form will be reported in the 
eCRFs and collected in the sponsor’s database. 
For screen failure subjects, at minimum the Unique Subject Identifier, the date of informed 
consent signature, the information that the subject failed screening and the potential AEs which 
occurred during the screening phase will be reported in the eCRFs and collected in the sponsor’s 
database. 
15.3 
Record Archiving and Retention 
During the prestudy and initiation visits, the monitor must ensure the archiving facilities are 
adequate and archiving/retention responsibilities of the investigator have been discussed.  
Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 15 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. The investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed by 
the monitor when closing out the site. The sponsor will inform the investigator, in writing, as to 
when these documents no longer need to be retained. 
If the principal investigator relocates or retires, or otherwise withdraws his/her responsibility 
for maintenance and retention of study documents, the sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 


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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. 
Financial Disclosure Statements will need to be completed, as requested by FDA 21 CFR 
Part 54. 
16.2 
Insurance, Indemnity and Compensation 
The sponsor will provide Product Liability insurance for all subjects included in the clinical 
study. Where required, a hospital specific indemnity agreement will be used. 


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17 
REPORTING AND PUBLICATIONS OF RESULTS 
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. 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. 
17.2 
Clinical Study Report 
A final clinical study report (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. 
An analysis will be performed on the final response data after the last subject has completed 
the treatment period. This analysis will be included in an interim study report/s. An addendum 
to the CSR will include the analysis of data from the follow-up period and will be prepared after 
the last subject completes the 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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SAP_001.pdf: 
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CONFIDENTIAL  
 
STATISTICAL AND ANALYSIS PLAN 
 
PROTOCOL TITLE: A MULTICENTRE, OPEN-LABEL PHASE I/II 
STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
BIODISTRIBUTION AND ANTI-TUMOUR ACTIVITY OF 177LU-OPS201 
WITH COMPANION IMAGING 68GA-OPS202 PET/CT IN PREVIOUSLY 
TREATED SUBJECTS WITH LOCALLY ADVANCED OR METASTATIC 
CANCERS EXPRESSING SOMATOSTATIN RECEPTOR 2 (SSTR2) 
 
PROTOCOL VERSION AND DATE: VERSION 2.0 – 07 MARCH 2019 
 
SAP Version 
Date 
Final Version 2.0 
03 January 2020 






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TABLE OF CONTENTS 
1 
INFORMATION TAKEN FROM THE PROTOCOL ............................................. 11 
1.1 
Study objectives ............................................................................................................. 11 
1.1.1 
Primary objective ......................................................................................... 11 
1.1.2 
Secondary objectives ................................................................................... 11 
1.1.3 
Exploratory Objectives ................................................................................ 12 
1.2 
Study design ................................................................................................................... 12 
1.2.1 
Study population ......................................................................................... 14 
1.2.2 
Study exposure ............................................................................................ 14 
1.3 
Methods and procedures .............................................................................................. 15 
1.3.1 
Subject identification and allocation to study treatment ........................... 15 
1.3.2 
Subjects assessments ................................................................................... 15 
1.3.2.1 
Pharmacodynamics/efficacy assessments .................................................... 15 
1.3.2.2 
Safety assessments ....................................................................................... 20 
1.3.2.3 
Physical Examination .................................................................................. 21 
1.3.2.4 
Vital Signs .................................................................................................... 21 
1.3.2.5 
Electrocardiography .................................................................................... 21 
1.3.2.6 
Clinical Laboratory Tests ............................................................................ 22 
1.3.2.7 
Nuclear Medicine Imaging for Dosimetry ................................................... 23 
1.3.2.8 
Pharmacokinetics of OPS201 ...................................................................... 23 
1.3.2.9 
Exploratory Biomarkers and Biobanking .................................................... 24 
1.3.2.10 
Withdrawal/discontinuation ......................................................................... 24 
1.3.3 
Schedule of assessments ............................................................................. 26 
1.3.4 
Planned sample size .................................................................................... 27 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) ...................................................... 27 
2.1 
Eligibility screened population .................................................................................... 27 
2.2 
Efficacy .......................................................................................................................... 28 
2.2.1 
Intention-To-Treat population (ITT) ......................................................... 28 
2.2.2 
Per Protocol population (PP) ..................................................................... 28 
2.2.3 
68Ga-OPS202 positive population ............................................................... 28 
2.2.4 
68Ga-OPS202 response evaluable population ............................................ 28 
2.3 
Safety .............................................................................................................................. 28 
2.4 
MTCA evaluable population ........................................................................................ 28 
2.5 
Dosimetry ....................................................................................................................... 28 
2.5.1 
Dosimetry population .................................................................................. 28 
2.5.2 
Per protocol dosimetry population ............................................................. 28 
2.6 
Pharmacokinetics .......................................................................................................... 29 
2.6.1 
Radiopharmaceutical pharmacokinetic population .................................. 29 
2.6.2 
OPS201 pharmacokinetic population ........................................................ 29 


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2.7 
Primary population ....................................................................................................... 29 
2.8 
Reasons for exclusion from the analyses ..................................................................... 29 
3 
STATISTICAL METHODS ........................................................................................ 29 
3.1 
Statistical analysis strategy .......................................................................................... 29 
3.1.1 
Primary endpoints ....................................................................................... 29 
3.1.2 
Secondary endpoints ................................................................................... 30 
3.1.3 
Safety endpoints .......................................................................................... 35 
3.1.4 
Exploratory endpoints ................................................................................. 35 
3.1.5 
Multiplicity .................................................................................................. 35 
3.1.6 
Significance testing and estimation ............................................................ 35 
3.2 
Analysis methods ........................................................................................................... 35 
3.2.1 
Efficacy ........................................................................................................ 35 
3.2.1.1 
Therapeutic Efficacy of 177Lu-OPS201 ........................................................ 35 
3.2.1.2 
Diagnostic Sensitivity of 68Ga-OPS202 (For Phase 1 and Phase 2): .......... 39 
3.2.2 
Safety ........................................................................................................... 42 
3.2.2.1 
Adverse events .............................................................................................. 42 
3.2.2.2 
Laboratory data ........................................................................................... 43 
3.2.2.3 
Maximum Tolerated Single and Cumulative Activity .................................. 44 
3.2.2.4 
Vital signs ..................................................................................................... 44 
3.2.2.5 
ECG .............................................................................................................. 44 
3.2.2.6 
Physical examination ................................................................................... 45 
3.2.3 
Exploratory biomarkers .............................................................................. 45 
3.2.4 
Missing data and outliers ............................................................................ 46 
3.2.4.1 
Missing data ................................................................................................. 46 
3.2.4.2 
Missing or incomplete dates ........................................................................ 46 
3.2.4.3 
Outliers ........................................................................................................ 46 
3.2.5 
Subject disposition and withdrawals .......................................................... 46 
3.2.6 
Demographic and baseline characteristics ................................................ 47 
3.2.7 
Medical and surgical history ...................................................................... 48 
3.2.8 
Subject compliance ..................................................................................... 48 
3.2.9 
Prior and concomitant therapies ................................................................ 48 
3.2.10 
Pharmacokinetics ........................................................................................ 49 
3.2.11 
Radiation Dosimetry of 177Lu-OPS201....................................................... 49 
3.2.12 
Derived data ................................................................................................. 50 
3.2.13 
Visit windows ............................................................................................... 50 
3.2.14 
Rules and data formats ............................................................................... 50 
3.2.15 
Pooling of Centres ....................................................................................... 51 
3.2.16 
Interim/futility analysis ............................................................................... 51 
3.2.17 
Role of data review board (DRB) ............................................................... 52 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS . 52 


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4.1 
Software ......................................................................................................................... 52 
4.2 
Validation programs ..................................................................................................... 53 
4.3 
Restitution of the programs ......................................................................................... 53 
5 
CHANGES FROM PROTOCOL ................................................................................ 53 
6 
REFERENCES .............................................................................................................. 53 
7 
APPENDICES ............................................................................................................... 54 
Appendix 1: Derived Data ..................................................................................................... 54 
 
LIST OF FIGURES 
Figure 1 
Phase I Study Design Scheme (Without Additional Cycles) ............................ 26 
Figure 2 
Phase I Study Design Scheme (With Additional Cycles) ................................. 26 
 
LIST OF TABLES 
Table 1 
Secondary Tumour Activity Endpoints and Evaluations in Phase I (Core 
Treatment) ........................................................................................................... 15 
Table 2 
Primary and Secondary Tumour Activity Endpoints and Evaluations ......... 18 
Table 3 
Scoring EORTC QLQ-C30 version 3.0 ............................................................. 20 
Table 4 
Date of Progression or Censoring for PFS ........................................................ 32 
Table 5 
Date of Progression or Censoring for TTP ....................................................... 33 
Table 6 
Date of Progression or Censoring for DOR ...................................................... 34 
Table 7 
Diagnostic performance of 68Ga-OPS202 PET/CT compared to RECIST as 
the SOT ................................................................................................................. 39 
Table 8 
Diagnostic performance of 68Ga-OPS202 PET/CT compared to mGa-
RECIST* as the SOT .......................................................................................... 40 
Table 9 
Diagnostic performance of 68Ga-OPS202 PET/CT compared to SOT of 
ceCT (or ceMRI) .................................................................................................. 41 
Table 10 
Diagnostic performance of 68Ga-OPS202 compared to SOT of 177Lu-
OPS201 SPECT/CT ............................................................................................. 41 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
Wording Definition 
Ae 
Cumulative amount (of unchanged drug) excreted into the urine 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate amino transferase 
AUC 
Area under the curve  
BC 
Breast cancer 
BM 
Bone marrow 
BOR 
Best overall response 
Bq 
Becquerel, SI unit of radioactivity 
CDK 
Cyclin-dependent kinase 
ceCT 
Contrast enhanced CT 
ceMRI 
Contrast enhanced MRI 
CI 
Confidence interval  
Cmax 
Maximum observed concentration 
CMR 
Complete metabolic response 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organisation 
CRP 
C-reactive protein 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria Adverse Event 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DNA-DSB 
Deoxyribonucleic acid-double strand breaks 
DOM 
Dosimetry operational manual 
DoR 
Duration of response 
DOTA 
Tetraxetan (INN), a chemical chelator group 
DRB 
Data review board 
DRR 
Durable response rate 
EANM 
European Association of Nuclear Medicine  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ED 
Extensive disease 
eCRF 
Electronic case report form 


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ABBREVIATION 
Wording Definition 
eGFR 
Estimated glomerular filtration rate 
EOAC 
End of additional cycles 
EOCT 
End of core trial 
EORTC QLQ-C30 
The European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 
EQ-5D-5L 
EuroQoL 5-dimension 5-level 
EU 
European Union 
EW 
Early withdrawal 
FDG 
Fluorodeoxyglucose 
GCP 
Good Clinical Practice 
Gy 
Gray, SI unit of absorbed radiation dose 
GST 
Alpha-glutathione S-transferase 
GSTP1 
Glutathione S-transferase P1 
HCG 
Human chorionic gonadotrophin 
HER2- 
Human epidermal growth factor receptor 2 negative 
HR+ 
Hormone receptor positive 
KIM-1 
Kidney injury molecule-1 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonisation 
ICL 
Imaging core laboratory 
IHC 
Immunohistochemistry 
IIP 
Investigational Imaging Product 
IRPP 
Investigational radiopharmaceutical product 
ITT 
Intent to treat 
i.v. 
Intravenous 
LD 
Limited disease 
MACA 
Maximum administrable cumulative activity 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
mL 
Millilitre 
mGa-PERCIST 
Modified gallium PERCIST 
mGa-RECIST 
Modified gallium RECIST 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 


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ABBREVIATION 
Wording Definition 
MRI 
Magnetic resonance imaging 
MTCA 
Maximum tolerated cumulative activity 
MTSA 
Maximum tolerated single activity 
NCI 
National Cancer Institute 
NET 
Neuroendocrine tumours 
OPS301 
Ipsen’s amino acid solution 
ORR 
Objective response rate 
OS 
Overall survival 
PARP 
Poly adenosine diphosphate ribose polymerase 
PERCIST 
Positron emission tomography response criteria in solid tumours 
PET 
Positron emission tomography 
PFS 
Progression free survival  
PMD 
Progressive metabolic disease 
PMR 
Partial metabolic response 
PP 
Per protocol 
PR 
Partial response 
PRRT 
Peptide receptor radionuclide therapy 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred term 
QC 
Quality control 
QoL 
Quality of life 
RBC 
Red blood cell(s) 
RECIST 
Response evaluation criteria in solid tumours  
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS® 
Statistical Analysis System® 
SD 
Standard deviation 
SCLC 
Small cell lung cancer 
SMD 
Stable metabolic disease 
SNMMI 
Society of Nuclear Medicine and Molecular Imaging 
SoC 
Standard-of-care 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
SOT 
Standard-of-Truth 


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ABBREVIATION 
Wording Definition 
SPECT 
Single Photon Emission CT 
sstr2 
Somatostatin receptors subtype 2 
SUL 
SUV normalised by lean body mass 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUV 
Standardised uptake volume 
t½ 
Elimination half life 
TEAE 
Treatment emergent adverse event 
tmax 
Time to maximum observed concentration 
TTP 
Time to progression 
TTR 
Time to response 
ULN 
Upper limit of normal 
Vd 
Apparent volume of distribution 
WBC 
White blood cell(s) 
μg 
Microgram 
68Ga 
Gallium-68, positron-emitting isotope of gallium 
68Ga-OPS202 
Study medication; 68Ga-radiolabelled somatostatin analogue for 
diagnostic imaging 
177Lu  
Lutetium-177, beta- and gamma-emitting isotope of lutetium 
177Lu-OPS201 
Study medication; 177Lu-radiolabelled somatostatin analogue for 
PRRT 
 
 
 


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1 
INFORMATION TAKEN FROM THE PROTOCOL 
1.1 
Study objectives  
1.1.1 
Primary objective 
Phase I 
To evaluate the safety and tolerability and to define the maximum tolerated cumulative activity 
(MTCA) of fractionated intravenous (i.v.) administration over two cycles of 177Lu-OPS201 in 
previously treated subjects with locally advanced or metastatic cancers expressing somatostatin 
receptors (sstr2) as identified by 68Ga-OPS202 positron emission tomography (PET)/computed 
tomography (CT) scans.  
Phase II 
To evaluate the objective response rate (ORR) of fractionated i.v. administration of 177Lu-
OPS201 in previously treated subjects with locally advanced or metastatic cancers expressing 
sstr2 as identified by 68Ga-OPS202 PET/CT scans. 
1.1.2 
Secondary objectives 
Phase I 
• 
To determine the whole-body distribution and pharmacokinetics (PK) of 177Lu-OPS201 
after each administration. 
• 
To determine the radiation dosimetry of 177Lu-OPS201 (organ exposure to radiation) 
after each administration. 
• 
To determine the PK of OPS201 in plasma and urine. 
• 
To describe the preliminary anti-tumour activity of 177Lu-OPS201. 
• 
To evaluate progression free survival (PFS) until Long-term Follow-up Visits up to 2 
years after the End of Core Trial (EOCT) Visit. 
• 
To determine the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 on PET/CT 
images and estimate its correlation with the uptake on 177Lu-OPS201 SPECT/CT. 
• 
To evaluate the association between uptake on 68Ga-OPS202 PET/CT and tumour 
response to 177Lu-OPS201. 
Phase II 
• 
To evaluate the efficacy of 177Lu-OPS201 using Response Evaluation Criteria In Solid 
Tumours (RECIST) v1.1 and/or Positron Emission Tomography Response Criteria In 
Solid (PERCIST) v1.0 criteria, volumetric CT and modified PERCIST using 68Ga-
OPS202 PET scans and modified RECIST using the 68Ga-OPS202 avid lesions. 
• 
To evaluate PFS until long-term follow-up visits up to 2 years after the EOCT Visit. 
• 
To estimate the 1-year overall survival (OS) rate. 
• 
To further evaluate the safety profile of 177Lu-OPS201. 
• 
To evaluate the association between uptake on 68Ga-OPS202 PET/CT with tumour 
response to 177Lu-OPS201 therapy. 
• 
To determine the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 on PET/CT 
images and estimate its correlation with the uptake on 177Lu-OPS201 SPECT/CT. 
• 
To evaluate the impact of 177Lu-OPS201 on the health-related quality of life of treated 
subjects. 


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• 
To estimate the proportion of sstr2-positive tumour lesions by 68Ga-OPS202 PET/CT 
scans as assessed by standardised uptake volume (SUV) in subjects screened for 177Lu-
OPS201 treatment. 
• 
To further assess some PK and dosimetry parameters of 177Lu-OPS201 based on the 
phase I results. 
1.1.3 
Exploratory Objectives 
Phase I/II 
• 
To explore renal and haematological safety by measuring urinary specific biomarkers 
and deoxyribonucleic acid-double strand breaks (DNA-DSB) and DNA repair in 
peripheral lymphocytes (at selected centres). 
• 
To evaluate the tumour microenvironment, transcriptomics, DNA repair, gene mutation 
in tumour as compared to germinal mutation and other markers of interest through 
assessment of tumour biopsies. 
• 
To collect biobank samples for future analysis of circulating markers (optional, 
additional informed consent required). 
• 
To evaluate the association between the tumour uptake of 68Ga-OPS202 and sstr2 
expression on tumours as determined by immunohistochemistry (IHC). 
• 
To generate a model integrating PK, pharmacodynamics, dosimetry, anti-tumour activity 
and safety data if warranted by the data. 
1.2 
Study design 
 
This study is a phase I/II, multicentre, open-label study of 177Lu-OPS201 therapy with 
companion diagnostic imaging product 68Ga-OPS202 PET/CT in previously treated subjects 
with locally advanced or metastatic solid tumour expressing sstr2 who progressed under or 
after, failed to respond to, or are intolerant or having a contraindication to available standard-
of-care (SoC) treatment options and are deemed suitable for treatment with 177Lu-OPS201 as 
per the investigator’s clinical assessment and/or their individual disease state. More 
specifically: 
• 
Subjects who had extensive disease-small cell lung cancer (ED-SCLC) at presentation 
who have progressed on or after one line of standard chemotherapy. If a subject had 
limited disease-small cell lung cancer (LD-SCLC) at presentation and received surgery 
and/or radiotherapy as first line treatment (with or without chemotherapy) and has 
localised relapse, further local treatment (such as surgery) should be considered in 
addition to the chemotherapy options.  
For subjects with either ED-SCLC or LD-SCLC, if subjects relapse more than 6 months 
after first-line treatment, re-treatment with their initial regimen is recommended. 
Subjects may have received prior immunotherapy. 
• 
Subjects with hormone receptor positive/human epidermal growth factor receptor 2 
negative (HR+/HER2-) metastatic breast cancer (BC) after failure of prior standard-of-
care treatments and who have received, if indicated, at least one line of hormonal therapy, 
cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for advanced or metastatic disease and 
at least one line of chemotherapy for metastatic disease; subjects with BRCA-mutated 
metastatic disease who may have received a poly adenosine diphosphate ribose 
polymerase (PARP) inhibitor, if available, are eligible; prior adjuvant hormonal 
treatment and prior adjuvant chemotherapy are allowed. 


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Once the maximum tolerated cumulative radioactivity is reached and the appropriate peptide 
mass determined, additional subjects may be treated at this radioactivity/peptide dose, per 
tumour type cohort. 
A clinical research Master Protocol in selected indications (basket design) will encompass this 
biomolecular target study protocol together with other study protocols targeting the same 
receptor (sstr2) and will describe the overall background, rationale, objectives, design, 
methodology and organisation of the overall sstr2-positive cancer research project for OPS201 
and OPS202.  
Pre-treatment Period 
A subject that qualifies will receive 68Ga-OPS202 and will be imaged on PET/CT. Subjects 
with at least two sstr2 avid lesions of ≥20 mm in the longest diameter on 68Ga-OPS202 PET/CT 
scan, confirmed by central read and having ≥50% matching between the lesions detected on 
68Ga-OPS202-PET/CT and on 18F-FDG-PET/CT as confirmed by central reader will then be 
treated with 177Lu-OPS201. 
Treatment Period - Phase I 
Phase I is a multicentre, open-label, single-arm study designed to primarily investigate the 
safety and tolerability of 177Lu-OPS201 following fractionated i.v. administrations in pretreated 
subjects with locally advanced or metastatic cancers expressing sstr2 as identified by 68Ga-
OPS202 PET/CT scans. This phase will encompass both radioactivity escalation and peptide 
mass dose evaluation. 
Treatment Period - Phase II 
Phase II is a multicentre study with open-label multiple single arm cohorts using Simon's 
optimal two-stage design to evaluate the efficacy, as assessed by ORR, of treatment with 177Lu-
OPS201 in subjects with locally advanced or metastatic SCLC, or metastatic HR+/HER2- BC 
expressing sstr2, as identified by 68Ga-OPS202 PET/CT scans. 
Approximately 76 subjects with locally advanced or metastatic SCLC and approximately 96 
subjects with metastatic HR+/HER2- BC deemed sstr2-positive on 68Ga-OPS202 PET/CT 
scans will receive the 177Lu-OPS201 treatment regimen recommended based on the results of 
the phase I. It is expected that two cycles of 177Lu-OPS201 will be administered in subjects 
enrolled in phase II.  
For phase I and phase II studies, up to four additional cycles might be administered in subjects 
who tolerate the treatment well and show clinical benefit (CR, PR, or stable disease) after the 
first two cycles. 
These additional cycles will be administered at radioactivity adjusted based on dosimetry 
results, provided limiting organ radiation dose levels have not been exceeded. 
Additional cohorts could be added to the study according to evidence based on preclinical and 
clinical work and data on 68Ga-OPS202 and 177Lu-OPS201, sstr2 expression and candidate 
diseases. 
Post-treatment Period 
Subjects in each phase of the study will have 2-year follow-up after the end of the last 177Lu-
OPS201 Cycle, with a visit every 3 until 24 months, disease progression, death or withdrawal 
of full consent, whichever occurs first. 
The phase I schedule of assessment during the study is summarised in Table 4 of the protocol 
for the core treatment phase and in Table 5 of the protocol for the additional cycles. The phase 


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II schedule of assessment will be based on the phase I results and documented as part of a 
protocol amendment. 
1.2.1 
Study population 
This study will be conducted at approximately 30 global clinical sites. Eight of these sites will 
participate in phase I and all sites in phase II. Participating regions are planned to be North 
America, Europe and Asia-Pacific. Additional sites may be added. 
During phase I, up to 30 subjects will be enrolled for treatment with 177Lu-OPS201. Based on 
the current knowledge on the proportion of subjects presenting with sstr2-positive tumours, it 
is anticipated that approximately 55 to 60 subjects will need to be administered 68Ga-OPS202. 
Should, at the start of the study, 20 consecutive subjects fail screening due to 68Ga-OPS202 
PET/CT negative for sstr2 with all the other inclusion/criteria met, the administration of 68Ga-
OPS202 and subsequent PET imaging will be stopped. Selection of sstr2-positive tumours for 
the treatment with 177Lu-OPS201 will be revised in a protocol amendment. 
During phase II, approximately 172 subjects (76 subjects with SCLC and 96 with BC) are 
planned to be enrolled for the Simon's optimal two-stage design. In this study phase, it is 
anticipated that approximately 340 subjects will need to be administered 68Ga-OPS202 for PET 
imaging screening. However, recruitment will be stopped once the number of required 
evaluable subjects (i.e. 76 subjects with SCLC and 96 with BC) is reached. 
Further cohorts of subjects with other tumours expressing sstr2 could be added in this protocol 
according to the advances in the preclinical and clinical knowledge on 68Ga-OPS202 and 177Lu-
OPS201 and emerging published data on the diseases. In this case, the additional number of 
subjects will be estimated based on standard of care historical response (e.g. ORR/best overall 
response (BOR)) of the corresponding disease. 
1.2.2 
Study exposure 
In phase I, for subjects receiving only two treatment cycles of 177Lu-OPS201, this study will 
consist of up to 3-week screening period and a 12-week dosing period (+ up to additional 4 
weeks in case of adverse events (AEs) that need to be adequately recovered). A treatment cycle 
is defined as the timeframe of 6 (up to 10) weeks between two administrations or the timeframe 
of 6 weeks following the last administration. In case of logistical issues, the cycle could be 
extended by up to additional 2 weeks. Dosing period can be extended up to 36 weeks in case 
subjects receive up to four additional cycles. Subjects are thus expected to participate in this 
study for a minimum of 15 weeks and up to 39 weeks (+ up to additional 4 weeks in case of 
AEs that need to be adequately recovered). In all cases, a long-term follow-up lasting 24 months 
will start after the end of the last 177Lu-OPS201 cycle. 
For phase II, it is anticipated that the duration of the study will be identical to the duration in 
phase I; however, pending the results of phase I on recommended treatment regimen (doses and 
intervals) the study duration will be refined. 
The subject’s participation in the treatment period of the study will be considered to have ended 
at the end of core trial (EOCT) or end of additional cycles (EOAC) visit. The subject’s 
participation in the 24-month follow-up period of the study will be considered to have ended 
when the subject dies, withdraws consent to the follow-up period, or ends the 24-month follow-
up, whichever occurs first. 
The overall duration of the study will be approximately 5.5 years. The study will be considered 
to have started when the first site has been initiated. 
The study will be considered to have ended after the last subject has completed the last follow-
up visit in the study. 


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1.3 
Methods and procedures 
1.3.1 
Subject identification and allocation to study treatment 
This is an open-label, single arm trial. After informed consent is obtained, subjects who are 
screened will be allocated a subject number.  All screened subjects must be identifiable 
throughout the study. Following confirmation of eligibility for the treatment, subjects will be 
considered as enrolled and allocated to one of the cohorts. Evaluable subjects will be enrolled 
in cohorts to receive 177Lu-OPS201 therapy at a nominal radioactivity level and peptide mass 
dose.  
1.3.2 
Subjects assessments 
1.3.2.1 
Pharmacodynamics/efficacy assessments 
Phase I 
Secondary tumour activity endpoints and evaluations planned in phase I are summarised in 
Table 1. All tumour endpoints will be evaluated by a central imaging core laboratory (ICL). 
Table 1 
Secondary Tumour Activity Endpoints and Evaluations in Phase I (Core Treatment) 
Measure 
Timepoints 
Variable 
Endpoint 
Tumour size 
(longest 
diameter) 
Screening[a] and 6 
weeks after each 
177Lu-OPS201 
administration (each 
cycle) 
Tumour response according 
to RECIST v1.1 
ORR 
BOR 
DCR 
PFS 
 
Tumour size 
(longest 
diameter) 
 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration 
(second cycle) 
Tumour response according 
to mGa-RECIST*; 
Metabolic tumour response 
by 18F-FDG-PET using 
PERCIST v1.0 and 68Ga-
OPS202 by mGa-PERCIST* 
ORR 
BOR 
 
Tumour 
volume 
Screening[a] and 6 
weeks after each 
177Lu-OPS201 
administration (each 
cycle) 
Mean change (%) in tumour 
volume assessed by 
Volumetric CT (or MRI) 
% change from baseline in 
tumour volume 
Event of 
death 
1 and 2 years 
Death count 
OS 
SULmax and 
SULmean 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration 
(second cycle) 
Tumour-to-background ratio 
by 18F-FDG-PET using 
PERCIST v1.0  
Quantitative changes in 
tumour-to-background 18F-
FDG-PET uptake 
SUVmax and 
SUVmean 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration 
(second cycle) 
sstr2 targeted tumour uptake 
by 68Ga-OPS202 PET/CT. 
Changes in tumour uptake 
on 68Ga-OPS202 PET/CT 
 


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Measure 
Timepoints 
Variable 
Endpoint 
SUVmax and 
SUVmean 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration 
(second cycle) 
68Ga-OPS202 uptake and 
177Lu-OPS201 therapy 
response 
Change in 68Ga-OPS202 
uptake on PET scan in 
subjects screened for 
177Lu-OPS201 treatment as 
compared to clinical 
response and BOR 
SUVmax and 
SUVmean 
Screening[a] for 
68Ga-OPS202 
PET/CT; 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration 
(second cycle) 
Uptake on 68Ga-OPS202-
PET/CT and 177Lu-OPS201 
therapy response (using 
ceCT/MRI – RECIST v1.1) 
Correlation between 
change (%) in tumour 
uptake on 68Ga-OPS202 
PET/CT at screening[a] 
with tumour response to 
177Lu-OPS201 therapy. 
Lesion count 
For 68Ga-OPS202 at 
screening  
For 177Lu-OPS201 at 
24 hours after first 
administration 
(Cycle 1) 
Uptake on 68Ga-OPS202-
PET/CT and uptake on 
177Lu-OPS201 SPECT/CT 
Correlation between the 
uptake of 68Ga-OPS202 in 
tumour lesions expressing 
sstr2 on PET/CT images 
and the uptake on 177Lu-
OPS201 SPECT/CT 
Abbreviations: BOR=Best overall response; ce= Contrast enhanced; CT=Computed tomography; DCR=Disease control rate; 
FDG=Fluorodeoxyglucose; mGa= Modified gallium; MRI=Magnetic resonance imaging; ORR=Objective response rate; 
OS=Overall survival; PERCIST=Positron emission tomography response criteria in solid tumours; PFS= Progression free 
survival; PET= Positron emission tomography; RECIST=Response evaluation criteria in solid tumours; SUL=SUV normalised 
by lean body mass; SUV=Standardised uptake volume. 
a. Screening=Baseline scan 
 
Imaging Assessments and Evaluations 
Expression of the target receptor (sstr2) will be determined using PET/CT imaging with the 
companion diagnostic imaging product 68Ga-OPS202. Radiographic response and disease 
progression will be determined using RECIST v1.1 (CT/MRI) and PERCIST v1.0 (18F-FDG-
PET), tumour volume (as assessed by volumetric analysis from CT/MRI), “mGa-RECIST” 
(CT/MRI and OPS202 PET scan) and mGa-PERCIST evaluating PET 68Ga-OPS202 for sstr2-
positive lesions (see details in the IRC). 
For each subject, the same imaging methods should be used throughout the study (e.g. ceCT or 
ceMRI for RECIST v1.1 tumour response assessment). Imaging parameters and approach used 
at screening should remain consistent throughout the study. 
The same PET scanner for all the 68Ga-OPS202 and scans must be used for each subject and 
likewise for the 18F-FDG-PET.  
68Ga-OPS202 scans are anticipated to be identified on lesions that may or may not be seen by 
FDG-PET scans due to the different metabolic pathways. Therefore, PERCIST, which is based 
on evaluating the most avid lesion, is likely to be different than one selected by 68Ga-OPS202 
and hence the need for evaluation by the modification (mGa-PERCIST). Likewise, RECIST 
requires the identification of the five largest lesions, which are generally selected by ceCT and 
a fused PET image. 68Ga-OPS202 may provide an alternative radiological interpretation, which 
will be evaluated using the modification (mGa-RECIST). 
Tumour Response Using RECIST v1.1 
For phase I, tumour response will be evaluated using the revised RECIST guideline v1.1 (see 
IRC). Only subjects with measurable disease at baseline, who have received at least two 


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administrations of 177Lu-OPS201 and reached the end of Cycle 2 or EOCT visit would 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. 
A modified version of RECIST (“mGa-RECIST”) will also be assessed. In this second 
evaluation, tumours will be assessed for reading based on 68Ga-OPS202 and CT. There will be 
a tumour mapping, so that RECIST can be determined on 68Ga-OPS202 positive lesions. Since 
there is a possibility for a different set of lesions to be identified by 68Ga-OPS202, this provides 
the direct response of 177Lu-OPS201 on these tumours to be evaluated. 
Tumour response of each subject will be graded as complete response, partial response, stable 
disease or progressive disease and unevaluable according to RECIST version 1.1. Based on this 
classification, the following endpoint will be calculated as defined by RECIST v1.1 and “mGa-
RECIST”: 
• 
ORR: proportion of subjects with a BOR characterised as either CR or PR relative to the 
total number of evaluable subjects. 
• 
DCR: proportion of subjects with a BOR characterised as CR, PR or stable disease 
relative to the total number of evaluable subjects. 
• 
PFS will be evaluated as defined per RECIST version 1.1. 
• 
Tumour response using volumetric CT/MRI assessment 
The same tumours identified as target lesions and assessed by “mGa-RECIST” will also be 
evaluated by the percentage change in volume. 
Tumour Response Using PERCIST v1.0 
For phase I, tumour response will be evaluated using the PERCIST guideline v1.0 (see IRC). 
Only subjects with measurable disease at baseline, who have received at least two 
administrations of 177Lu-OPS201 and reached EOCT visit will be considered evaluable for 
response. 
Key elements of PERCIST include performance of PET scans in a method consistent with the 
NCI recommendations (UPICT) and those of The Netherlands multicentre trial group on well 
calibrated and well-maintained scanners. A baseline PET scan will be obtained at 
approximately 1 hour (50 to 70 minutes) after 18F-FDG injection. At EOCT, the PET scan will 
be obtained with the same interval (between 18F-FDG-injection and acquisition time) reported 
at baseline ±15 minutes, but never less than 50 minutes from the injection. All scans will be 
performed on the same PET scanner with the same injected dose ±20% of radioactivity. 
A PERCIST evaluation will also be performed using the 68Ga-OPS202 scans (mGa-PERCIST). 
This will provide a different set of analyses and support the possibility of using 68Ga-OPS202 
as a surrogate endpoint in future studies. 
Tumour metabolic response of each subject will be defined based on quantitative changes 
(SULmax and SULmean) in tumour-to-background after two cycles versus baseline and will be 
graded as complete metabolic response (CMR), partial metabolic response (PMR), stable 
metabolic disease (SMD) or progressive metabolic disease (PMD) or unevaluable according to 
PERCIST v1.0. The grading scale for “mGa-PERCIST” will be evaluated. 
Sstr2 Targeted Tumour Uptake 
Sstr2 targeted tumour uptake will be determined using PET/CT molecular imaging with the 
companion diagnostic imaging product 68Ga-OPS202. 


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The change in 68Ga-OPS202 PET/CT tumour uptake will be computed as a change in SUVmax 
and SUVmean from baseline to EOCT/EOAC visit. These changes will also be compared to 
clinical outcome and ORR and to 177Lu-OPS201 tumour uptake on SPECT/CT. 
Phase II 
The primary endpoint is ORR over the two treatment cycles of the core study. Objective 
response is defined using RECIST v1.1 measured by CT or magnetic resonance imaging (MRI). 
Tumour response assessments are performed 6 weeks after each administration of 
177Lu-OPS201 during the core study or at the time of occurrence of first clinical signs of disease 
progression as determined by the investigator. Radiological interpretation for subject 
management will be performed at the site, whereas efficacy evaluation will be conducted by 
the ICL. 
 
Primary and secondary tumour activity endpoints and evaluations are summarised in Table 2. 
Table 2 
Primary and Secondary Tumour Activity Endpoints and Evaluations 
Measure 
Timepoint 
Variable 
Endpoint 
Tumour size 
(longest diameter) 
Screening[a] and 6 
weeks after each 
177Lu-OPS201 
administration 
(each cycle) 
Tumour response 
according to 
RECIST v1.1 
x 
ORR 
x 
BOR 
x 
PFS (complemented with 
events of death)  
x 
DRR (CR or PR lasting ≥6 
months)  
x 
DCR  
x 
TTP  
x 
TTR 
x 
DoR 
Tumour size 
(longest diameter) 
 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration 
(second cycle) 
Tumour response 
according to mGa-
RECIST; 
Metabolic tumour 
response by 18F-
FDG-PET – 
PERCIST v1.0 and 
68Ga-OPS202 by 
mGa-PERCIST* 
x 
ORR 
x 
BOR 
 
Tumour volume 
Screening[a] and 6 
weeks after each 
177Lu-OPS201 
administration 
(each cycle) 
Mean change (%) 
in tumour volume 
assessed by 
volumetric CT/MRI 
% change from baseline in 
tumour volume 
Event of death 
1 and 2 years 
Death count 
OS 
SUVmax and 
SUVmean 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration 
(second cycle) 
sstr2 targeted 
tumour uptake by 
68Ga-OPS202-
PET/CT 
Change in tumour uptake on 
68Ga-OPS202 PET/CT scan 
 


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Measure 
Timepoint 
Variable 
Endpoint 
SULmax and 
SULmean 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration 
(second cycle) 
Tumour-to-
background ratio by 
18F-FDG-PET using 
PERCIST v1.0 
Quantitative changes in tumour-
to-background 18F-FDG-PET 
uptake 
SUVmax and 
SUVmean 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration 
(second cycle) 
68Ga-OPS202 
uptake and 
177Lu-OPS201 
therapy response 
Change in 68Ga-OPS202 uptake 
on PET scan in subjects 
screened for 177Lu-OPS201 
treatment as compared to 
clinical response and ORR 
SUVmax and 
SUVmean 
 
 
Screening[a] for 
68Ga-OPS202 
PET/CT; 
Screening[a] and 6 
weeks after second 
177Lu-OPS201 
administration 
(second cycle) 
Uptake on 68Ga-
OPS202 PET/CT 
and 177Lu-OPS201 
therapy response 
(using ceCT/MRI – 
RECIST v1.1) 
Correlation between the uptake 
on 68Ga-OPS202 PET/CT at 
baseline[a] with tumour 
response to 177Lu-OPS201 
therapy  
Lesion count 
For 68Ga-OPS202 at 
screening  
For 177Lu-OPS201 
at 24 hours after 
first administration 
(Cycle 1) 
Uptake on 68Ga-
OPS202-PET/CT 
and uptake on 
177Lu-OPS201 
SPECT/CT 
Correlation between the uptake 
of 68Ga-OPS202 in tumour 
lesions expressing sstr2 on 
PET/CT images and the uptake 
on 177Lu-OPS201 SPECT/CT 
Identification of 
avid lesions 
Screening[a] 
Number of subjects 
with avid lesions 
Proportion of subjects with 
sstr2-positive tumour lesions by 
68Ga-OPS202 PET/CT 
Abbreviations: ce= Contrast enhanced; CR=Complete response; CT=Computed tomography; DCR=Disease control rate; 
DoR=Duration of response; DRR=Durable response rate; FDG=Fluorodeoxyglucose; MRI=Magnetic resonance imaging; 
OS=Overall survival; PERCIST=Positron emission tomography response criteria in solid tumours; PET=Positron emission 
tomography; PFS=Progression free survival; PR=Partial response; RECIST=Response evaluation criteria in solid tumours; 
SUL=SUV normalised by lean body mass; SUV=Standardised uptake volume; TTP=Time to progression; TTR=Time to 
response. 
[a] Screening=Baseline scan 
 
Patient Reported Outcomes (PROs) will be assessed in phase II using the following 
questionnaires: the EuroQoL 5-dimension 5-level (EQ-5D-5L) and European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).  
The EQ-5D-5L questionnaire is a 2-page, generic preference-based Quality of Life (QoL) 
measure comprised of a 5-item health status measure and a visual analogue scale and is used to 
generate two scores. The EQ-5D utility score is based on answers to five questions to evaluate 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension 
has 5 levels: no problem, slight problems, moderate problems, severe problems, unable 
to/extreme.  
The EQ-5D-5L visual analogue scale generates a single health status index, the analogue scale 
ranges from 0 to 100 in which subjects are asked to rate their current health state by drawing a 
line from a box marked. 
The EORTC QLQ-C30 is a 2-page, self-reporting 30-item generic instrument for use in cancer 
subjects across tumour types. It assesses 15 domains consisting of five functional domains 
(physical, role, emotional, cognitive, social), nine symptom domains (fatigue, nausea and 


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vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, financial difficulties) 
and a global health status or QoL scale as shown below. Missing data will be handled using the 
method described in the scoring guidelines for EORTC QLQ-C30. If at least half of the items 
from a scale are answered, it is assumed that the missing items have values equal to the average 
of those items that are present for that respondent. 
Table 3 
Scoring EORTC QLQ-C30 version 3.0 
 
Number of items 
Item range 
Item numbers 
Global health status/QoL 
 
 
 
  Global health status/QoL 
2 
6 (1-7) 
29, 30 
 
 
 
 
Functional scales 
 
 
 
  Physical functioning 
5 
3 (1-4) 
1-5 
  Role functioning 
2 
3 (1-4) 
6, 7 
  Emotional functioning 
4 
3 (1-4) 
21-24 
  Cognitive functioning 
2 
3 (1-4) 
20, 25 
  Social functioning 
2 
3 (1-4) 
26, 27 
 
 
 
 
Symptom scales / items 
 
 
 
  Fatigue 
3 
3 (1-4) 
10, 12, 18 
  Nausea and vomiting 
2 
3 (1-4) 
14, 15 
  Pain 
2 
3 (1-4) 
9, 19 
  Dyspnoea 
1 
3 (1-4) 
8 
  Insomnia 
1 
3 (1-4) 
11 
  Appetite loss 
1 
3 (1-4) 
13 
  Constipation 
1 
3 (1-4) 
16 
  Diarrhoea 
1 
3 (1-4) 
17 
  Financial difficulties 
1 
3 (1-4) 
28 
 
The PK of 177Lu-OPS201 and OPS201, as well as the dosimetry assessments and timepoints are 
related to the phase I of the study. PK and dosimetry assessments will also be included in phase 
II. However, the timepoints might be revised based on the phase I results and document as part 
of a protocol amendment. 
1.3.2.2 
Safety assessments 
The primary safety variable is the occurrence of Dose-Limiting Toxicities (DLTs) during Cycle 
1 or Cycle 2. 
The DLTs are defined for any of the following Investigational Radio-Pharmaceutical Product-
related (IRPP-related) AEs according to National Cancer Institute Common Terminology 
Criteria Adverse Event (NCI-CTCAE) scale version 5.0 that occur during the defined DLT 
assessment period (from the first administration of 177Lu-OPS201 to 6 weeks after the second 
administration): 
• 
Grade 4 neutropenia lasting for seven or more consecutive days. 
• 
Grade 3 and 4 febrile neutropenia. 
• 
Grade 4 thrombocytopenia for seven or more consecutive days. 
• 
Grade 3 thrombocytopenia complicated by a bleeding event. 
• 
Grade 4 anaemia. 


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• 
Grade 3 anaemia requiring transfusion. 
• 
Grade 3 or higher laboratory abnormalities of aspartate amino transferase/alanine amino 
transferase (AST/ALT) and/or bilirubin, with the following exceptions: 
for subjects with Grade 1 AST/ALT at baseline (>upper limit of normal (ULN) to 
3xULN), a AST/ALT level of >7.5xULN will be considered a DLT. 
for subjects with Grade 2 AST/ALT at baseline (>3xULN to 5xULN), a AST/ALT level 
> 10xULN will be considered a DLT. 
• 
any Grade 3 or higher acute kidney injury (creatinine >3x baseline or >4.0 mg/dL). 
• 
Grade 3 or higher non-haematological toxicity excluding: 
- 
Grade 3 nausea, vomiting or diarrhoea for less than 72 hours with adequate 
supportive care 
- 
Grade 3 fatigue lasting less than a week 
- 
Grade 3 or higher electrolyte abnormality that lasts for less than 72 hours, is not 
clinically complicated and resolves spontaneously or with conventional medical 
interventions 
- 
Grade 3 or higher amylase or lipase not associated with symptoms or clinical 
manifestations of pancreatitis 
• 
any toxicity related to 177Lu-OPS201 resulting in a treatment delay of more than 4 weeks 
due to delayed recovery to baseline or resolution of any AE of Grade 2 or more 
(exception of alopecia and lymphopenia). 
• 
Grade 5 toxicity (death) 
DLT Assessment: During the DLT assessment period (from first administration of 177Lu-
OPS201 to 6 weeks after the second administration), two assessments over 6 weeks each will 
be performed. The first, between first and second administration and the second, between 
second administration and EOCT visit. 
DLT Population: Subjects will be evaluable for DLT if received Cycle 1 and Cycle 2 
administrations and completed DLT assessment period (i.e. 6 weeks after second 
administration) or stopped treatment because of a DLT during DLT assessment period. 
Other safety assessments include clinical laboratory haematology, serum chemistry, urinalysis 
and pregnancy tests, physical examination, vital signs, electrocardiography.   
1.3.2.3 
Physical Examination 
Physical examinations, including body weight will be conducted at Screening, Day 1, Day 15 
of Cycle 1 and Cycle 2 and EOCT. 
1.3.2.4 
Vital Signs 
Supine and standing systolic and diastolic blood pressure, heart rate, body temperature, 
respiratory rate will be measured at Screening, Day 1, Day 2, Day 3, Day 15, Day 22, Day 29, 
Day 36 of each cycle and EOCT.  
For the day of infusion vital signs will be measured prior to infusion and at infusion completion 
(0 minutes), 30±5 minutes, 60±10 minutes, 4 hours ±10 minutes after the end of infusion. 
1.3.2.5 
Electrocardiography 
An ECG analysis will be included as a safety evaluation/endpoint in this study. Twelve lead-
ECG will be recorded at Screening, Day 1 of each cycle and EOCT and 6-hour Holter ECG 


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will be recorded at Day 1 of each cycle. Twelve lead ECGs will be recorded so that the different 
ECG intervals (RR, PR, QRS, QT, QTcF) will be measured. 
1.3.2.6 
Clinical Laboratory Tests 
Haematology 
Blood samples will be collected to assess the following parameters: RBC count, haemoglobin, 
haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean 
corpuscular haemoglobin concentration (MCHC), WBC count with differential (neutrophils, 
lymphocytes, monocytes, eosinophils and basophils) and platelet count. 
Blood Biochemistry 
Blood samples will be collected to assess the following parameters: 
• 
urea, uric acid, creatinine, creatinine clearance, total bilirubin, conjugated bilirubin 
• 
chloride, bicarbonate, sodium, potassium, calcium, phosphate 
• 
alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma 
glutamyl transferase 
• 
albumin and total protein, total cholesterol, triglycerides, fasting glucose 
• 
C-reactive protein (CRP) 
Estimated glomerular filtration rate (eGFR) will be calculated based on serum creatinine levels 
using MDRD formula. 
Urinalysis 
Urine samples will be collected to assess the following parameters: pH, protein, ketones, 
bilirubin, blood, urobilinogen, nitrites, leukocytes, glucose. Proteinuria will be performed with 
dipsticks, in case of positivity, a proteinuria over 24 hours will be performed. 
Pregnancy Test 
A β human chorionic gonadotrophin (HCG) serum test will be performed for all female subjects 
of childbearing potential at Screening (visit 1) and if clinically indicated thereafter. Moreover, 
a HCG urine test will be performed at Day 1 of each cycle before each 177Lu-OPS201 
administration. 
Hypothalamic-Pituitary-Adrenal Axis Biomarkers 
Sample for hormone analysis will be collected at predose Day 1 of each Cycle and at 
EOCT/EOAC visit. These samples include analysis of cortisol, TSH, parathyroid hormone 
(PTH), luteinising hormone (LH), follicle-stimulating hormone (FSH), free thyroxine (FT4) 
and IGF-1. 
Hormone analyses will only be analysed in subjects who do not have substitution or therapy 
impacting one of the respective pituitary axis (e.g. no cortisol sampling in subjects who receive 
corticosteroids, no thyroid-stimulating hormone and free thyroxine sampling in subjects who 
have thyroxine substitution. 
TSH, cortisol and IGF-1 will be measured at baseline and at end of core trial. 
Specific Renal Safety Biomarkers 
Renal safety biomarkers include markers specific of the different renal tubule regions toxicity: 
alpha-glutathione S-transferase (GST), glutathione S-transferase P1 (GSTP1), kidney injury 
molecule-1 (KIM-1), clusterin, cystatin-C, calbindin, beta-2 microglobulin and creatinine. 
Urine samples will be collected at the following timepoints: 
• 
Cycle 1: 


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- 
Day 1: early morning, before the infusion (baseline) 
- 
Day 3: early morning (48 hours after the end of 177Lu-OPS201 infusion at the 
latest) 
• 
End of core trial Visit/Early Withdrawal Visit: early morning. 
Specific Pancreatic Function Biomarker 
Samples for specific pancreatic function biomarker will include glycosylated haemoglobin 
HbA1c and glucose. Blood will be collected at Day 1 of each visit before infusion and End of 
core trial visit / Early Withdrawal. 
Testicular Function Biomarkers 
Samples for Testicular Function Biomarkers will include testosterone, Inhibin B and sex 
hormone-binding globulin SHBG. Blood will be collected at Day 1 of each visit before infusion 
and End of core trial visit / Early Withdrawal. 
1.3.2.7 
Nuclear Medicine Imaging for Dosimetry 
All images will be centralised and analysed by independent readers for dosimetry analysis of 
the dose limiting organs and tumour lesions. 
To determine the biokinetics and perform an absolute quantification, whole body scans (planar 
scintigraphy) and SPECT/CT will be performed at each cycle at the following timepoint ranges 
just after the end of 177Lu-OPS201 infusion: 
- 
Day 1: 2 to 4 hours 
- 
Day 2: 16 to 24 hours 
- 
Day 3: 40 to 48 hours 
- 
Day 4 to Day 5: 72 to 96 hours 
- 
Day 6 to Day 7: 144 to 168 hours. 
At the timepoint between 16 to 24 hours, SPECT/diagnostic CT will be performed. For all other 
time points, SPECT/low dose CT will be performed. 
For subjects receiving additional administrations (up to four additional cycles), dosimetry 
assessments will be performed after each additional administration with nuclear medicine 
imaging described above. 
1.3.2.8 
Pharmacokinetics of OPS201 
Blood Sample Collection 
For each subject, OPS201 plasma concentration will be measured. Each subject will have blood 
samples collected at Cycle 1 only at the following time points: 
- 
Day 1: before the infusion (baseline), at the end of infusion of 177Lu-OPS201 (0), 
5±1 minutes, 30±5 minutes, 1 hour (±5 minutes) and 4 hours (±30 minutes), 6 (±30 
minutes), and 10±1 hours after the end of infusion. 
- 
Day 2: 24±2 hours after the end of infusion of 177Lu-OPS201. 
- 
Day 3: 48±2 hours after the end of infusion of 177Lu-OPS201. 
Urine Sample Collection 
The samples for urine OPS201 concentration analysis will be taken from urine collected during 
four different periods at Cycle 1: from 0 to 4, 4 to 8, 8 to 24 and 24 to 48 hours (0 to 4 and 4 to 
8 hours only in US sites) after the start of infusion, with an initial void collection shortly before 
the infusion (0) and a final collection, 48 hours after the end of 177Lu-OPS201 infusion. 


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1.3.2.9 
Exploratory Biomarkers and Biobanking 
DNA-DSB in Peripheral Lymphocytes 
DNA-DSB in lymphocytes will be measured using an immunofluorescent method in selected 
sites. DNA-DSB will be measured in lymphocytes (n=6 per cycle) before the infusion 
(baseline), at 1, 4, 24, 48 and 72 to 96 hours after the end of 177Lu-OPS201 infusion (Cycle 1 
and Cycle 2). 
DNA Repair Capacity in Peripheral Lymphocytes 
DNA repair capacity in lymphocytes will be measured using an enzymatic method in selected 
sites. 
Germinal Mutation in Blood 
Blood sample will be collected in a Paxgen-DNA tube at Cycle 1 Day 1 before infusion from 
the arm opposite to that of the study drug infusion or from another site. 
Tumour Biopsy 
Sequential biopsies will be obtained at Screening and EOCT or at disease progression, 
whichever occurs earlier. Baseline biopsy is mandatory and post-treatment biopsy is optional. 
Tumour Micro-environment and Other Markers of Interest 
The biopsy will be used to evaluate tumour microenvironment and other markers of interest of 
the disease, such as: proliferative marker (ki-67), Tumour infiltrating immune cells (TIL/TME), 
DNA-DSB (gammaH2AX), target receptor evaluation (sstr2), tumour gene expression profile 
and gene mutations (targeted or TMB). 
Specific markers depending on the indication will also be assessed in tumour biopsy (i.e. for 
BC: ER, progesterone receptor and HER2 protein expression and for SCLC: p53, Rb1, MYC 
and DLL3 gene expression). 
DNA Repair Capacity in Tumour Tissue 
DNA repair capacity will be measured in tumour tissue by a specialised laboratory in case 
sufficient material is available (biopsy larger than 5 mm3). 
Biobanking 
Analysis of biobank samples will be performed outside the scope of the main study and will be 
reported separately. Therefore, this analysis is optional. 
1.3.2.10 Withdrawal/discontinuation 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each subject is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a subject from the study in the event of concurrent illness, AEs, or 
other reasons concerning the health or wellbeing of the subject, or in the case of lack of 
cooperation.  
A subject (or a legal representative) has the right to withdraw from the study at any time and 
for any reason without prejudice to their future medical care by the investigator at the 
institution. 
The investigator and/or sponsor can decide to withdraw a subject from investigational product 
and/or other protocol-required therapies, protocol procedures, or the study as a whole at any 
time prior to study completion for the following reasons: 
• 
Subject no longer experiences clinical benefit as determined by the investigator. If study 
treatment is withdrawn for this reason, the date this decision is to be recorded and every 


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effort should be made to continue safety evaluations, tumour assessments, and collection 
of subsequent anticancer treatment information and follow-up information for survival. 
• 
The investigator feels it is not in the best interest of the subject to continue on study. 
• 
Subject participation in another clinical study using an investigational agent or 
investigational medical device. 
• 
Necessity for treatment with other systemic anticancer therapy (non-protocol defined). 
• 
Necessity for withholding study drug for greater than 6 weeks for study-treatment related 
AEs. 
• 
Refusal of sexually active fertile subjects (excluding subjects who have been sterilised) 
to use medically accepted methods of contraception. 
• 
Female subjects who become pregnant. 
• 
Request by the sponsor. 
• 
Subject request to discontinue study treatment (with or without concurrent withdrawal of 
informed consent). 
• 
Significant noncompliance with the protocol schedule in the opinion of the investigator 
or the sponsor 
• 
Unacceptable side effects the investigator feels may be due to study treatment.  
In addition, if any of the following occur, no further treatment will be administered: 
• 
Cumulative kidney absorbed dose exceeds 23 Gy. 
• 
Cumulative BM absorbed dose exceeds 1.5 Gy during core trial or up to 2 Gy during 
additional cycles, as determined by dosimetry of peripheral blood samples and imaging. 
• 
Subject has not sufficiently recovered from an adverse event despite extension of the 
dosing interval by 4 weeks (such as delayed grade 3-4 haematotoxicity) 
• 
Hypersensitivity to the active substance or to any of the excipients of the study drugs  
• 
Radiological disease progression 
All cases of discontinuation will be discussed between the investigator and the sponsor. 
A subject can also withdraw their consent to the treatment period but agree to take part in 24-
month follow-up period. 
If a subject is considered Not Evaluable for DLT due to withdrawal during DLT assessment 
period, he/she will be replaced by another subject.  
In phase I, a cohort will be considered as completed once three subjects of the cohort complete 
Cycle 2 or discontinue early during Cycle 2. If subjects discontinue for any reason other than a 
DLT (e.g. disease progression) before end of Cycle 2, they might be replaced. 
The phase I will be terminated once the MTCA has been determined. The phase II is designed 
with early stopping criteria, allowing any cohort to be closed early in case of futility. 
A specific site or a given cohort can also be discontinued or the entire study may be terminated 
at any time if the sponsor judges it necessary for any reason. In that case, all scheduled 
procedures and assessments for subjects who are still in the study will be performed. Some 
possible reasons for the closure of a study site may include: 
• 
failure of the investigator staff to comply with the protocol or with the Good Clinical 
Practice (GCP) guidelines. 
• 
safety concerns. 
• 
inadequate subject recruitment. 


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In case of premature discontinuation of a site or the complete study, depending on the reason(s) 
for the discontinuation, the sponsor will notify the investigator(s) affected in writing as to 
whether the ongoing subjects should continue the remaining IRPP dose administration(s). 
Should, at the start of the study, 20 consecutive subjects fail screening due to 68Ga-OPS202 
PET/CT negative for sstr2 with all the other inclusion/criteria met, the administration of 68Ga-
OPS202 and subsequent PET imaging will be stopped. Selection of sstr2-positive tumours for 
the treatment with 177Lu-OPS201 will be revised in a protocol amendment. 
1.3.3 
Schedule of assessments 
The phase I study design with and without additional cycles are shown in Figure 1 and Figure 
2. 
Figure 1 Phase I Study Design Scheme (Without Additional Cycles) 
 
 
Figure 2 Phase I Study Design Scheme (With Additional Cycles) 
Pharmacokinetics, biodistribution and dosimetry endpoints and measurement timepoints for 
phase II will be defined according to the phase I results. 
The current protocol may be amended at the end of the phase I to define the phase II design. 


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1.3.4 
Planned sample size 
Sample Size Determination for Phase I 
This is primarily a descriptive safety and tolerability study. The total number of subjects is not 
based on a formal statistical sample size calculation. 
The actual sample size required to adequately determine the MTCA/MTSA during phase I 
depends on the initial activity, rate of radioactivity escalation and the observed radioactivity-
toxicity and radioactivity/organ absorbed dose relationships. Simulation studies have been 
performed to quantify the operational characteristics (ie, precision of the MTCA/MTSA, 
sample size, number of subjects being over/under dosed) of the adaptive radioactivity-
escalation design under a number of plausible escalation-DLT relationship scenarios. Based on 
experience, the chosen sample size of 3-5 subjects per cohort is considered to be sufficient to 
fulfil the objectives of the study. It is anticipated that between 15 and 30 subjects will be 
required to establish the MTCA or maximum administered cumulative activity (MACA). 
Sample Size Determination for Phase II 
The sample size is calculated using Simon's optimal two-stage design based on the ORR rate 
(complete response (CR) + partial response (PR)) following 177Lu-OPS201 treatment. 
For the Simon's optimal two-stage design, the hypotheses that will be tested for each cohort are: 
H0: ORR≤ORR0 versus the alternative H1: ORR>ORR0 where ORR is the true objective 
response rate following 177Lu-OPS201 treatment that warrants further clinical development, and 
ORR0 is the minimum objective response rate to be excluded from further clinical development. 
The thresholds for ORR and ORR0 may be updated based on results from phase I and the 
advances in scientific knowledge. 
ORR will be analysed at the end of Stage 1 (6 weeks after the second 177Lu-OPS201 
administration (Cycle 2) of the core treatment period of the last evaluable subject of the Stage 
1 cohort for each type of cancer). If the observed number of responders is below a predefined 
threshold, the respective study cohort will be stopped for futility. Otherwise, additional subjects 
will be treated to complete the planned enrolment. At the end of Stage 2, the null hypothesis 
will be rejected depending on the total observed number of responders based on a predefined 
threshold. 
For the SCLC cohort, with 69 response evaluable subjects, there will be 90% power to test a 
null hypothesis ORR rate of 23% and an alternative hypothesis ORR rate of 40% at one-sided 
significance level of α=0.05. The first stage consists of 29 subjects. If seven responses or less 
are seen in the first 29 subjects then the trial is stopped. Otherwise accrual continues to a total 
of 69 response evaluable subjects. Approximately 76 subjects are planned to be enrolled to 
account for 10% study dropout. 
For the BC cohort, with 87 response evaluable subjects, there will be 90% power to test a null 
hypothesis ORR rate of 12% and an alternative hypothesis ORR rate of 25% at one-sided 
significance level of α=0.05. The first stage consists of 33 subjects. If four responses or less are 
seen in the first 33 subjects then the trial is stopped. Otherwise accrual continues to a total of 
87 response evaluable subjects. Approximately 96 subjects are planned to account for 10% 
study dropout. 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) 
2.1 
Eligibility screened population 
All subjects screened (i.e. who signed the informed consent). 


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2.2 
Efficacy 
2.2.1 
Intention-To-Treat population (ITT) 
All subjects who received at least one dose of 177Lu-OPS201 in the phase II of the study. 
2.2.2 
Per Protocol population (PP) 
All subjects in the ITT population in the phase II of the study who have measurable disease at 
baseline, have at least one post baseline response assessment and no major protocol deviations 
occurred that could affect efficacy analysis. 
The PP population will be used for the analyses of ORR, DCR, PFS, OS, TTP, TTR and DoR. 
2.2.3 
68Ga-OPS202 positive population 
All subjects who received 68Ga-OPS202 with at least one readable screening 68Ga-OPS202 
PET, at least one readable screening ceCT scan, at least one readable screening 18F-FDG-PET 
scan, and have at least one lesion identified by central readers on screening 68Ga-OPS202 PET. 
This population encompasses subjects with sstr2 positive lesion(s) (i.e., avid lesion with 68Ga-
OPS202). 
2.2.4 
68Ga-OPS202 response evaluable population 
All subjects in the 68Ga-OPS202 positive population with the following 6 weeks post second 
177Lu-OPS201 administration (second cycle): a readable 68Ga-OPS202 PET, a readable ceCT 
scan, and a readable 18F-FDG-PET scan.  
 
The 68Ga-OPS202 positive and 68Ga-OPS202 response evaluable populations will be used for 
the analyses of diagnostic endpoints of 68Ga-OPS202. 
2.3 
Safety 
Safety population is all subjects who received at least one dose of 177Lu-OPS201 or 68Ga-
OPS202. 
• 
68Ga-OPS202 safety population: All subjects who received at least one dose of 68Ga-
OPS202. 
• 
177Lu-OPS201 safety population: All subjects who received at least one dose of 177Lu-
OPS201. 
2.4 
MTCA evaluable population  
MTCA evaluable population is all subjects who received at least one dose of 177Lu-OPS201 in 
the radioactivity escalation of the phase I of the study. The MTCA-evaluable population will 
be used to determine the MTCA/MTSA/MACA for phase I of the study.  
2.5 
Dosimetry 
2.5.1 
Dosimetry population 
All subjects who received at least one dose of 177Lu-OPS201 for whom at least one complete 
set of dosimetry imaging and dosimetry blood sample measurements is available. Dosimetry 
may be analysed separately for phase I and phase II. 
2.5.2 
Per protocol dosimetry population 
All subjects in the dosimetry population for whom no major protocol violations occurred 
affecting dosimetry variables. Dosimetry may be analysed separately for phase I and phase II. 


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2.6 
Pharmacokinetics 
2.6.1 
Radiopharmaceutical pharmacokinetic population 
All subjects who received at least one dose of 177Lu-OPS201 and have at least one measured 
radioactive concentration in blood. Radiopharmaceutical PK may be analysed separately for 
phase I and phase II. 
2.6.2 
OPS201 pharmacokinetic population 
All subjects who received at least one dose of 177Lu-OPS201 and have no major protocol 
deviations affecting the PK variables and who have a sufficient number of OPS201 
concentrations to estimate the main PK parameters (i.e. maximum observed concentration 
(Cmax), time to maximum observed drug concentration (tmax) and area under curve (AUC)). 
OPS201 PK may be analysed separately for phase I and phase II. 
2.7 
Primary population 
For the phase I of the study, the primary analysis based on the primary safety endpoint will be 
performed on the MTCA evaluable population. 
For the phase II of the study, the primary analysis based on the primary efficacy endpoint will 
be performed on the PP population. In addition, secondary/confirmatory analysis may be 
performed on the ITT population. 
The primary dosimetry analysis will be based on the dosimetry population. A supportive 
analysis will be based on per protocol dosimetry population.  
The assessment of safety and tolerability will be based on the safety population. 
The assessment of PK will be based on the radiopharmaceutical pharmacokinetic population 
and OPS201 pharmacokinetic population. 
2.8 
Reasons for exclusion from the analyses 
Any major protocol deviation will be described and its impact on inclusion in each analysis 
population for any subject will be specified. The final list of protocol deviations impacting each 
analysis population will be reviewed prior to interim analysis and database lock. The list may 
be updated, up to the point of interim analysis and database lock, to include any additional 
major protocol deviations impacting inclusion in each analysis population. 
3 
STATISTICAL METHODS 
3.1 
Statistical analysis strategy 
The statistical analyses will be performed in accordance with ICH E9 guideline and will be 
based on the pooled data from the individual study sites, unless otherwise stated. 
Statistical analyses will be performed by 
 
 managed by the sponsor’s biometry 
department.  
Data from phase I and phase II will be analysed and reported separately.  Phase I analyses will 
be performed by cohort and in total for the applicable population. Phase II analyses will be 
performed by cancer type for efficacy analyses and by cancer type and in total for safety 
analyses for the applicable population.  
3.1.1 
Primary endpoints 
Phase I 
The primary endpoint is the MTCA or the MACA if the MTCA is not identified during the 
phase I. The primary variables determining the MTCA will be the incidence of DLTs and the 
cumulative organ absorbed doses (Gy) during two cycles of treatment. The DLT assessment 
CCI


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period for the determination of the primary endpoint starts from the first administration of 177Lu-
OPS201 and ends 6 weeks after the second administration. 
The MTCA is defined as the maximum cumulative radioactivity that may be administered 
following fractionated i.v. administrations of at least 6 weeks apart, so that: 
• 
no more than 33% of the subjects experience a DLT after first or second administration 
of 177Lu-OPS201 and/or 
• 
no more than 10% of the subjects have cumulative absorbed dose in each target organ 
exceeding the acceptability limits (1.5 Gy in BM and 23 Gy in kidney) after second 
administration of 177Lu-OPS201. 
The MTSA is defined as the highest single radioactivity that can be given so that no more than 
33% of the subjects experience a DLT during Cycle 1. The MTSA will be determined in case 
of unacceptable toxicity seen after first administration of 177Lu-OPS201. 
The MACA will be determined if the MTCA is not reached during the dose escalation. 
Phase II 
Phase II primary endpoint is to evaluate the ORR of fractionated i.v. administration of 177Lu-
OPS201 in previously treated subjects with locally advanced or metastatic cancers expressing 
sstr2 as identified by 68Ga-OPS202 PET/CT scans. The primary endpoint is ORR measure by 
RECIST 1.1 over the two treatment cycles of the core study. Objective response is defined as 
the sum of PR and CR measured by CT or MRI using RECIST version 1.1. Tumour response 
assessments are performed 6 weeks after each administration of 177Lu-OPS201 during the core 
study or at the time of occurrence of first clinical signs of disease progression as determined by 
the investigator. All images will be sent to an ICL for evaluation and confirmation of response. 
3.1.2 
Secondary endpoints 
All imaging endpoints will be assessed by blinded independent readers managed by the ICL. 
Phase I 
Pharmacokinetics, biodistribution and dosimetry 
For PK, biodistribution and dosimetry of 177Lu-OPS201, the endpoints are: 
• 
Cmax, tmax, maximal uptake (%), AUC at the target lesions, discernible organs and blood 
and elimination half-life (t½) of radioactivity concentrations in blood. 
• 
Highest absorbed dose, Specific absorbed dose to the target lesions (Gy/GBq), Specific 
absorbed dose per organ (Gy/GBq) and Cumulative absorbed organ doses (Gy). 
For PK of OPS201, the endpoints are: 
• 
Pharmacokinetic parameters including, but not limited to, Cmax, AUC, t1/2, total plasma 
clearance (CL), apparent volume of distribution (Vd), cumulative amount (of unchanged 
drug) excreted into the urine (Ae), renal clearance, as measured in plasma and urine at 
defined timepoints. 
Pharmacodynamic/efficacy 
• 
Mean change (%) in tumour volume at 6 weeks after each 177Lu-OPS201 administration 
compared to Screening as assessed by CT or MRI: 
- 
RECIST version 1.1 (tumour size is defined as the sum of the diameters of the 
target lesion in subjects who received 177Lu-OPS201) 
- 
volumetric CT 
• 
PFS as determined from start of study treatment until occurrence of tumour progression 
or death. 


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• 
BOR defined as the best response recorded from the start of the treatment until disease 
progression/recurrence. 
• 
ORR defined as proportion of subjects with a BOR characterised as either CR or PR 
relative to the total number of evaluable subjects. 
• 
DCR defined as proportion of subjects with a BOR characterised as CR, PR or stable 
disease relative to the total number of evaluable subjects. 
• 
PFS will be evaluated as defined per RECIST version 1.1. 
• 
OS at 1-year and 2-year follow-up as determined from start of study treatment until 
occurrence of death of any cause. 
• 
Quantitative changes (SUV normalised by lean body mass (SUL)max and SULmean) in 
tumour-to-background 18F-FDG-PET uptake using PERCIST version 1.0, from 
Screening to 6 weeks after second 177Lu-OPS201 administration (second cycle). 
• 
Changes in tumour uptake (assessed based on SUVmax and SUVmean) on 68Ga-OPS202 
PET/CT from Screening to 6 weeks after second 177Lu-OPS201 administration (second 
cycle) as compared to clinical response and BOR.  
• 
Correlation between change (%) in tumour uptake on 68Ga-OPS202 PET/CT (assessed 
based on SUVmax and SUVmean) at screening with tumour response to 177Lu-OPS201 
therapy from Screening to 6 weeks after second 177Lu-OPS201 administration (second 
cycle) using ceCT/MRI – RECIST v1.1. 
• 
Correlation between the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 on 
PET/CT images and the uptake on 177Lu-OPS201 SPECT/CT.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging using RECIST by subject-based 
analysis. 
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging using mGa-RECIST by subject-based 
analysis. 
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by subject-based, organ-based and 
lesion-based analysis compared to standard-of-truth (SOT) of ceCT (or ceMRI). 
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by both organ-based and lesion-based 
analysis compared to standard-of-truth (SOT) of 177Lu-OPS201 SPECT/CT. 
Phase II 
Efficacy 
• 
Durable response rate (DRR: CR or PR lasting ≥6 months) 
• 
Progression free survival (PFS) as determined from start of study treatment until 
occurrence of tumour progression or death. Progression will be radiologically assessed 
by RECIST v1.1 and “mGa-RECIST” as two separate endpoints; for RECIST it will be 
measured at Screening and 6 weeks after each 177Lu-OPS201 administration (each cycle); 
for “mGa-RECIST” it will be measured at Screening and 6 weeks after the second 177Lu-
OPS201 administration (second cycle). 
PFS (months) = (event or censoring date – first dose date + 1)/30.4375 
PFS will be right-censored for subjects who met one or more of the following conditions:  
- 
no baseline disease assessment or no evaluable post baseline disease assessments 
unless death occurred prior to the first planned assessment at post baseline (in 
which case death will be considered a PFS event).  


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- 
amputation or surgical resection of tumour in the absence of documented disease 
progression.  
- 
subsequent anticancer therapy in the absence of documented disease progression. 
- 
died or documented disease progression after missing two or more consecutively 
scheduled disease assessment visits 
- 
alive and without documented disease progression on or before the data cutoff date 
If a subject meets more than one of these conditions, then the scenario that occurs first will be 
used for analysis. The progression or censoring date will be determined based on the 
conventions listed in Table 4: 
Table 4 
Date of Progression or Censoring for PFS 
Situation 
Date of progression or 
censoring 
Outcome 
Death before first planned 
disease assessment 
Date of death 
Event 
Death or disease progression 
between planned disease 
assessments 
Date of death or first disease 
assessment showing disease 
progression, whichever occurs 
first 
Event 
No baseline disease assessment 
or no evaluable post-baseline 
disease assessments 
Date of first dose of 
177Lu-OPS201 
Censored 
Surgical resection or 
subsequent anticancer treatment 
started before disease 
progression or death (without 
disease progression beforehand) 
Date of last disease assessment 
prior to surgery or start of 
subsequent anticancer treatment 
Censored 
Death or disease progression 
after missing two or more 
consecutively scheduled disease 
assessments 
Date of last disease assessment 
visit without documentation of 
disease progression before the 
first missed visit 
Censored 
Alive and without disease 
progression 
Date of last disease assessment 
Censored 
• 
Other response endpoints (same timepoints as for PFS): 
- 
disease control rate (DCR) 
- 
time to progression (TTP) 
- 
time to response (TTR) 
- 
duration of response (DoR) 
TTP or TTR (months) = (event or censoring date – first dose date + 1)/30.4375 
TTP does not include deaths. Deaths are censored, either at the time of death or at an earlier 
visit representing informative censoring.  
The progression or censoring date will be determined based on the conventions listed in Table 
5: 


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Table 5 
Date of Progression or Censoring for TTP 
Situation 
Date of progression or 
censoring 
Outcome 
Death before or after first 
planned disease assessment 
Date of death 
Censored 
Disease progression between 
planned disease assessments 
Date of first disease assessment 
showing disease progression 
Event 
No baseline disease assessment 
or no evaluable post-baseline 
disease assessments 
Date of first dose of 177Lu-
OPS201 
Censored 
Surgical resection or 
subsequent anticancer treatment 
started before disease 
progression (without disease 
progression beforehand) 
Date of last disease assessment 
prior to surgery or start of 
subsequent anticancer treatment 
Censored 
Disease progression after 
missing two or more 
consecutively scheduled disease 
assessments 
Date of last disease assessment 
visit without documentation of 
disease progression before the 
first missed visit 
Censored 
Alive and without disease 
progression 
Date of last disease assessment 
Censored 
DOR will be calculated as follows for subjects who have a BOR of CR or PR: 
DOR (months) = (Event/Censoring Date – Response Start Date + 1) / 30.4375 
Subjects who meet one or more of the following conditions will be right-censored for DOR: 
- 
amputation or surgical resection of tumour in the absence of documented disease 
progression. 
- 
subsequent anticancer therapy in the absence of documented disease progression 
- 
died or documented disease progression after missing two or more consecutively 
scheduled disease assessment visits 
- 
alive and without documented disease progression on or before the data cut-off 
date 
If a subject meets more than one of these conditions, then the scenario that occurs first will be 
used for the analysis. The progression or censoring date will be determined based on the 
conventions listed in Table 6. 


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Table 6 
Date of Progression or Censoring for DOR 
Situation 
Date 
of 
progression 
or 
censoring 
Outcome 
Death or disease progression 
between planned disease 
assessments 
Date of death or first disease 
assessment showing disease 
progression, whichever occurs 
first 
Event 
Surgical resection or 
subsequent anticancer treatment 
started before disease 
progression or death (without 
disease progression beforehand) 
Date of last disease assessment 
prior to surgery or start of 
subsequent anticancer treatment 
Censored 
Death or disease progression 
after missing two or more 
consecutively scheduled disease 
assessments 
Date of last disease assessment 
visit without documentation of 
disease progression before the 
first missed visit 
Censored 
Alive and without disease 
progression 
Date of last disease assessment 
Censored 
• 
Mean change (%) in tumour volume at 6 weeks after each 177Lu-OPS201 administration 
(each cycle) compared to baseline, as assessed by volumetric CT/MRI. 
• 
OS at 1-year and 2-year follow-up as determined from start of study treatment until 
occurrence of death of any cause. Subjects who were lost to follow-up or who were still 
alive at the time of analysis will be censored at the last day the subject was known to be 
alive or data cut-off date, whichever occurs first. OS will be calculated as follows: 
• 
OS (months) = (Death or Censoring Date – First Dose Date + 1)/30.4375  
• 
Quantitative changes (SUV normalised by lean body mass (SUL)max and SULmean) in 
tumour-to-background 18F-FDG-PET uptake using PERCIST version 1.0, from 
Screening to 6 weeks after second 177Lu-OPS201 administration (second cycle). 
• 
Change in 68Ga-OPS202 uptake on PET scan after the second 177Lu-OPS201 
administration (second cycle) as assessed by SUVmax and SUVmean in subjects screened 
for 177Lu-OPS201 treatment as compared to clinical response and ORR. 
• 
Correlation between tumour uptake on 68Ga-OPS202 PET/CT (assessed based on 
SUVmax and SUVmean) at screening with tumour response to 177Lu-OPS201 therapy from 
Screening to 6 weeks after second 177Lu-OPS201 administration (second cycle). 
• 
Correlation between the uptake of 68Ga-OPS202 in tumour lesions expressing sstr2 on 
PET/CT images and the uptake on 177Lu-OPS201 SPECT/CT. 
• 
Proportion of subjects with sstr2-positive tumour lesions by 68Ga-OPS202 PET/CT scans 
as assessed by the identification of avid lesions in subjects screened for 177Lu-OPS201 
treatment at baseline.  
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging using RECIST by subject-based 
analysis. 
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by using mGa-RECIST by subject-based 
analysis. 
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by subject-based, organ-based and 
lesion-based analysis compared to standard-of-truth (SOT) of ceCT (or ceMRI). 
• 
Diagnostic sensitivity of 68Ga-OPS202 imaging by both organ-based and lesion-based 
analysis compared to standard-of-truth (SOT) of 177Lu-OPS201 SPECT/CT. 


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Subject Reported Outcomes 
Changes in health-related quality of life scores from baseline to EOCT measured by EQ-5D-
5L and EORTC QLQ-C30. 
3.1.3 
Safety endpoints 
Safety and tolerability measured by the type, nature, severity, expectedness and frequency of 
AEs overall and per grade according to the current version of the NC-CTCAE (version 5.0) and 
significant laboratory abnormalities. 
Pharmacokinetics, biodistribution and dosimetry endpoints and measurement timepoints for 
phase II will be defined according to the phase I results.  
3.1.4 
Exploratory endpoints  
Phase I/II 
Biomarkers  
• 
Association between the uptake on 68Ga-OPS202 PET/CT with sstr2 expression on 
tumours as determined by IHC. 
• 
Change in renal safety biomarkers compared to baseline. 
• 
Change from baseline in tumour microenvironment, transcriptomics, DNA repair, gene 
mutations and other disease markers of interest. 
• 
Change from baseline in DNA repair capacity in blood.  
Biobanking  
The exploratory endpoint comprises biobanking of samples for future analysis, among subjects 
who consent. Analysis of additional biomarkers from the biobank samples will be performed 
outside the scope of the main study and reported separately. 
Serum and whole blood ribonucleic acid (RNA) samples will be collected during 
screening, on Day 1 of Cycle 2 and at EOCT visit. 
Instructions for collection, processing, handling and shipment of the banking samples will be 
outlined in the laboratory manual.  
3.1.5 
Multiplicity 
No multiple testing will be performed in this study. 
Therefore, type I error will not be adjusted. 
3.1.6 
Significance testing and estimation 
As this is a descriptive safety and tolerability study, no formal statistical testing of safety will 
be carried out. 
3.2 
Analysis methods 
3.2.1 
Efficacy 
3.2.1.1 
Therapeutic Efficacy of 177Lu-OPS201 
Tumour response will be evaluated by the ICL. Phase I analyses on tumour responses will be 
using the MTCA evaluable population. Phase II analyses on tumour responses will be using the 
ITT population and the PP population. 
Phase I 
• 
The summaries of BOR will include number and percentage of subjects in each of these 
categories (CR, PR, SD, PD, NE, NA). BOR will be assessed based on RECIST v1.1 


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(Eisenhauer EA, 2009). BOR by 68Ga-OPS202 PET mGa-RECIST, will also be analysed 
similarly. BOR by 18F-FDG-PET PERCIST v1.0 and by mGa-PERCIST will be analysed 
similarly as BOR by RECIST 1.1 using each of these categories (CMR, PMR, SMD, 
PMD, NE, NA). 
• 
ORR over the two treatment cycles of the core study measured by the ICL. Objective 
response is defined as the percentage of subjects with BOR as PR and CR measured by 
CT or MRI using RECIST version 1.1. Tumour response assessments are performed 6 
weeks after each administration of 177Lu-OPS201 during the core study or at the time of 
occurrence of first clinical signs of disease progression as determined by the investigator. 
The point estimates of the ORR will be calculated   and accompanied by a 95% exact 
binomial confidence interval (CI) using the Clopper-Pearson method. ORR by 68Ga-
OPS202 PET, mGa-RECIST will also be analysed similarly. ORR of CMR and PMR by 
PERCIST 1.0 and by mGa-PERCIST will be analysed similarly as ORR by RECIST 1.1. 
• 
DCR by RECIST v1.1 defined as the percentage of subjects who have achieved a 
response of CR, PR or stable disease, will be analysed and summarised in the same 
manner as ORR. 
• 
PFS by RECIST v1.1 will be summarised descriptively using the Kaplan-Meier method. 
The Kaplan-Meier estimates of the median PFS, and the corresponding 2-sided 95% 
confidence intervals calculated using Greenwood’s formula will be presented.  
• 
OS is defined as the time from the date of first dose of 177Lu-OPS201 to the date of death 
due to any cause. Subjects who have not died will be censored at the date of last contact 
which may be identified from a visit date or any study assessment (physical examination, 
vital signs, ECOG performance status, ECG, study drug record, radiological evaluation, 
laboratory sampling, concomitant or follow-up procedures), AE, medication, or 
disposition information. OS will be calculated using the Kaplan-Meier method. One-year 
and two-year survival are defined as the subject survival probability at 1 year and 2 years, 
respectively, after the date of first dose of 177Lu-OPS201. One-year and two-year survival 
probability along with the associated 2-sided 95% confidence intervals, will be provided. 
If there are a sufficient number of OS events (i.e., deaths), median OS time, first and 
third quartiles and associated 95% 2-sided confidence intervals, will be estimated using 
the Brookmeyer-Crowley method (Brookmeyer, 1982). Kaplan-Meier OS curves also 
will be provided. 
• 
Change (%) in tumour volume from volumetric CT (or MRI) and sum of the diameters 
of the target lesion per RECIST version 1.1 from Screening to 6 weeks after each 
177Lu-OPS201 administration (each cycle) will be summarised descriptively. Waterfall 
plots will be used to depict graphically for individual subjects of their best change (%) 
or largest reduction (%) from Screening in the sum of the diameters in target lesions. 
Spider and swimmer plots will be used to display the change in tumour burden over time 
for individual subjects and the occurrence of clinical outcomes of interest (e.g., tumour 
response, disease progression, treatment discontinuation, death).  
• 
Quantitative changes (%) (SUV normalised by lean body mass (SUL)max and 
SULmean) in tumour-to-background 18F-FDG-PET uptake from Screening and 6 weeks 
after second 177Lu-OPS201 administration from the second cycle will be summarised 
descriptively. Waterfall plots will be used to depict graphically for individual subjects of 
their best change (%) or largest reduction (%) from Screening in SULmax and SULmean 
in target lesions. Spider and swimmer plots will be used to display the change in tumour 
burden over time for individual subjects and the occurrence of clinical outcomes of 


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interest (e.g., tumour response, disease progression, treatment discontinuation, death). 
Numbers and percentages of CMR (complete metabolic response), PMR (partial 
metabolic response), SMD (stable metabolic disease), and PMD (progressive metabolic 
disease) using PERCIST v1.0 criteria will be summarised.  
• 
Change (%) in tumour uptake (assessed based on SUVmax and SUVmean) on 
68Ga-OPS202 PET/CT from Screening and 6 weeks after second 177Lu-OPS201 
administration (second cycle) will be summarised descriptively. Waterfall plots will be 
used to depict graphically for individual subjects of their change (%) from Screening in 
tumour uptake to 6 weeks after second 177Lu-OPS201 administration (second cycle).  
• 
Change (%) in tumour uptake (assessed based on SUVmax and SUVmean) on 68Ga-
OPS202-PET/CT from Screening to 6 weeks after second 177Lu-OPS201 administration 
(second cycle) will be summarised descriptively by BOR tumour response according to 
RECIST v1.1. 
• 
Correlation between change (%) in tumour uptake on 68Ga-OPS202 (assessed based on 
SUVmax and SUVmean) PET/CT at baseline with tumour response to 177Lu-OPS201 
therapy using ceCT/MRI RECIST v1.1 will be assessed. Spearman correlation 
coefficient and its p-value will be reported for change (%) in tumour uptake (assessed 
based on SUVmax and SUVmean) on 68Ga-OPS202-PET/CT from Screening and tumor 
response 6 weeks after second 177Lu-OPS201 administration (second cycle)  
• 
Correlation between the number of lesion counts from 68Ga-OPS202 in tumour lesions 
expressing sstr2 on PET/CT images at screening and the number of lesion counts from 
177Lu-OPS201 SPECT/CT at 24 hours after the first 177Lu-OPS201 administration 
(Cycle 1) will be assessed by Pearson correlation coefficient and its p-value.  
Phase II 
• 
ORR over the two treatment cycles of the core study measured by the ICL. Objective 
response is defined as the sum of PR and CR measured by CT or MRI using RECIST 
version 1.1. Tumour response assessments are performed 6 weeks after each 
administration of 177Lu-OPS201 during the core study or at the time of occurrence of first 
clinical signs of disease progression as determined by the investigator. The point 
estimates of the ORR will be calculated and accompanied by a 95% exact binomial 
confidence interval (CI) using the Clopper-Pearson method. ORR by 68Ga-OPS202 PET 
mGa-RECIST, will also be analysed similarly. ORR of CMR and PMR by PERCIST 1.0 
and by mGa-PERCIST will be analysed similarly as ORR by RECIST 1.1. 
• 
The summaries of BOR will include number and percentage of subjects in each of these 
categories (CR, PR, SD, PD, NE, NA). BOR will be assessed based on RECIST v1.1 
(Eisenhauer EA, 2009). BOR by 68Ga-OPS202 mGa-RECIST will also be analysed 
similarly. BOR by 18F-FDG-PET PERCIST v1.0 and by mGa-PERCIST will be analysed 
similarly as BOR by RECIST 1.1 using each of these categories (CMR, PMR, SMD, 
PMD, NE, NA). 
• 
DRR by RECIST v1.1 defined as the percentage of subjects who have achieved a 
response of CR, PR or stable disease, will be analysed and summarised in the same 
manner as ORR. 
• 
PFS by RECIST v1.1 will be summarised descriptively using the Kaplan-Meier method. 
The Kaplan-Meier estimates of the median PFS, and the corresponding 2-sided 95% 
confidence intervals calculated using Greenwood’s formula will be presented.  


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• 
OS is defined as the time from the date of first dose of 177Lu-OPS201 to the date of death 
due to any cause. Subjects who have not died will be censored at the date of last contact 
which may be identified from a visit date or any study assessment (physical examination, 
vital signs, ECOG performance status, ECG, study drug record, radiological evaluation, 
laboratory sampling, concomitant or follow-up procedures), AE, medication, or 
disposition information. OS will be calculated using the Kaplan-Meier method. One-year 
and two-year survival are defined as the subject survival probability at 1 year and 2 years, 
respectively, after the date of first dose of 177Lu-OPS201. One-year and two-year survival 
probability along with the associated 2-sided 95% confidence intervals, will be provided. 
If there are a sufficient number of OS events (i.e., deaths), median OS time, first and 
third quartiles and associated 95% 2-sided confidence intervals, will be estimated using 
the Brookmeyer-Crowley method (Brookmeyer, 1982). Kaplan-Meier OS curves also 
will be provided. 
• 
DCR by RECIST v1.1, defined as the percentage of subjects who have achieved a 
response of CR, PR or stable disease, will be analysed and summarised in the same 
manner as ORR. 
• 
TTP by RECIST v1.1, defined as the time from date of first dose of 177Lu-OPS201 to the 
date of first documentation disease progression as determined by the investigator, will 
be analysed and summarised in the same manner as PFS. 
• 
TTR by RECIST v1.1, defined as the time from the date of first dose of 177Lu-OPS201 
to the date of the first documentation of a response (CR or PR whichever occurs first) in 
a subject who responded, will be analysed and summarised in the same manner as PFS. 
• 
DoR by RECIST v1.1, defined as the time from date of first documentation of response 
(CR or PR whichever occurs first) to the date of disease progression or to death due to 
any cause, whichever occurs first, will be analysed and summarised in the same manner 
as PFS. 
• 
Change (%) in tumour volume from volumetric CT (or MRI) and sum of the diameters 
of the target lesion per RECIST version 1.1 from Screening to 6 weeks after each 
177Lu-OPS201 administration (each cycle) will be summarised descriptively. Waterfall 
plots will be used to depict graphically for individual subjects of their best change (%) 
or largest reduction (%) from Screening in the sum of the diameters in target lesions. 
Spider and swimmer plots will be used to display the change in tumour burden over time 
for individual subjects and the occurrence of clinical outcomes of interest (e.g., tumour 
response, disease progression, treatment discontinuation, death).  
• 
Quantitative changes (%) (SUV normalised by lean body mass (SUL)max and 
SULmean) in tumour-to-background 18F-FDG-PET uptake from Screening and 6 weeks 
after second 177Lu-OPS201 administration from the second cycle will be summarised 
descriptively. Waterfall plots will be used to depict graphically for individual subjects of 
their best change (%) or largest reduction (%) from Screening in SULmax and SULmean 
in target lesions. Spider and swimmer plots will be used to display the change in tumour 
burden over time for individual subjects and the occurrence of clinical outcomes of 
interest (e.g., tumour response, disease progression, treatment discontinuation, death). 
Numbers and percentages of CMR (complete metabolic response), PMR (partial 
metabolic response), SMD (stable metabolic disease), and PMD (progressive metabolic 
disease) using PERCIST v1.0 criteria will be summarised.  
• 
Change (%) in tumour uptake (assessed based on SUVmax and SUVmean) on 
68Ga-OPS202 PET/CT from Screening and 6 weeks after second 177Lu-OPS201 


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administration (second cycle) will be summarised descriptively. Waterfall plots will be 
used to depict graphically for individual subjects of their change (%) from Screening in 
tumour uptake to 6 weeks after second 177Lu-OPS201 administration (second cycle).  
• 
Change (%) in tumour uptake (assessed based on SUVmax and SUVmean) on 68Ga-
OPS202-PET/CT from Screening to 6 weeks after second 177Lu-OPS201 administration 
(second cycle) will be summarised descriptively by ORR tumour response according to 
RECIST v1.1. 
• 
Correlation between change (%) in tumour uptake on 68Ga-OPS202 (assessed based on 
SUVmax and SUVmean) PET/CT at baseline with tumour response to 177Lu-OPS201 
therapy using ceCT/MRI RECIST v1.1 will be assessed. Spearman correlation 
coefficient and its p-value will be reported for change (%) in tumour uptake (assessed 
based on SUVmax and SUVmean) on 68Ga-OPS202-PET/CT from Screening and tumor 
response 6 weeks after second 177Lu-OPS201 administration (second cycle)  
• 
Correlation between the number of lesion counts from 68Ga-OPS202 in tumour lesions 
expressing sstr2 on PET/CT images at screening and the number of lesion counts from 
177Lu-OPS201 SPECT/CT at 24 hours after the first 177Lu-OPS201 administration (Cycle 
1) will be assessed by Pearson correlation coefficient and its p-value.  
• 
Proportion of subjects with sstr2-positive tumour lesions by 68Ga-OPS202 PET/CT scans 
as assessed by the identification of avid lesions in subjects screened for 177Lu-OPS201 
treatment at baseline will be summarised and analysed in the same manner as ORR.  
• 
Changes in health-related quality of life scores from baseline to EOCT measured by EQ-
5D-5L will be summarised descriptively. Frequency tables will be used to display the 
number and percentage of subjects of reported problems for each level and each 
dimension of the EQ-5D-5L by scheduled time point. Shift tables presenting the 2-way 
frequency tabulation from baseline to the worst post-baseline values will be presented 
for each dimension of the EQ-5D-5L.  
• 
Changes in health-related quality of life scores (global health status/QoL and each 
functional scale) from baseline to EOCT measured by EORTC QLQ-C30 will be 
summarised descriptively. 
 
3.2.1.2 
Diagnostic Sensitivity of 68Ga-OPS202 (For Phase 1 and Phase 2): 
a) 
Diagnostic sensitivity of 68Ga-OPS202 imaging at baseline using RECIST as the SOT by 
subject-based analysis. The SOT is the results on RECIST from the contrast enhanced 
CT (or contrast enhanced MRI) scan images performed 6 weeks after second 
177Lu-OPS201 administration (second cycle). Complete response (CR), partial response 
(PR) and stable disease (SD) will be considered as positive response, while progressive 
disease (PD) will be considered as negative response. 
Diagnostic sensitivity between 68Ga-OPS202 at baseline and SOT will be assessed using 
performance specified in Table 7. 
Table 7 
Diagnostic performance of 68Ga-OPS202 PET/CT compared to RECIST as the SOT 
68Ga-OPS202 PET/CT scan results 
SOT results (using RECIST) 
Positive (CR + PR + SD) 
6 weeks post 2nd 177Lu OPS201 
Negative (PD) 
6 weeks post 2nd 177Lu OPS201 
Subjects with lesions detected by 
Ga-OPS202 at baseline 
Positive Response 
Negative Response 


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The sensitivity corresponds to the probability of positive response from 177Lu-OPS201 based 
on lesions identified with ceCT (or ceMRI). Sensitivity will be computed using following 
formula, for overall subjects (subject-based approach): 
 
ܵ݁݊ݏ݅ݐ݅ݒ݅ݐݕൌ
ܲ݋ݏ݅ݐ݅ݒ݁ ܴ݁ݏ݌݋݊ݏ݁
ܲ݋ݏ݅ݐ݅ݒ݁ ܴ݁ݏ݌݋݊ݏ݁൅ܰ݁݃ܽݐ݅ݒ݁ ܴ݁ݏ݌݋݊ݏ݁ 
 
For Phase 1 subjects only, the above analysis will be repeated using volumetric RECIST as 
SOT. 
 
b) 
Diagnostic sensitivity of 68Ga-OPS202 imaging at baseline using mGa-RECIST as the 
SOT by subject-based analysis. The SOT is the results from mGa-RECIST from the 
contrast enhanced CT (or contrast enhanced MRI) scan images performed 6 weeks after 
second 177Lu-OPS201 administration (second cycle). Complete response (CR), partial 
response (PR) and stable disease (SD) will be considered as positive response, while 
progressive disease (PD) will be considered as negative response.  
Diagnostic sensitivity between 68Ga-OPS202 at baseline and SOT will be assessed using 
performance specified in Table 8. 
Table 8 
Diagnostic performance of 68Ga-OPS202 PET/CT compared to mGa-RECIST* as the SOT  
68Ga-OPS202 PET/CT scan results 
SOT results (using mGa-RECIST) 
Positive (CR + PR + SD) 
6 weeks post 2nd 177Lu OPS201 
Negative (PD) 
6 weeks post 2nd 177Lu OPS201 
Subjects with lesions detected by 
68Ga-OPS202 PET/CT at baseline 
Positive Response 
Negative Response 
*modified Ga-RECIST using RECIST criteria on only those lesions which are 68Ga-OPS202 avid at baseline 
 
The sensitivity corresponds to the probability of positive response from 177Lu-OPS201 based 
on lesions identified with 68Ga-OPS202-PET/ceCT (or ceMRI). Sensitivity will be computed 
using following formula, for overall subjects (subject-based approach): 
 
ܵ݁݊ݏ݅ݐ݅ݒ݅ݐݕൌ
ܲ݋ݏ݅ݐ݅ݒ݁ ܴ݁ݏ݌݋݊ݏ݁
ܲ݋ݏ݅ݐ݅ݒ݁ ܴ݁ݏ݌݋݊ݏ݁൅ܰ݁݃ܽݐ݅ݒ݁ ܴ݁ݏ݌݋݊ݏ݁ 
For Phase 1 subjects only, the above analysis will be repeated using volumetric mGa-RECIST 
as SOT. 
 
c) 
Diagnostic sensitivity of 
68Ga-OPS202 imaging at baseline by subject-based, 
organ-based and lesion-based analysis compared to standard-of-truth (SOT). The SOT is 
the contrast enhanced CT (or contrast enhanced MRI) scan images acquired at baseline. 
Diagnostic sensitivity between 68Ga-OPS202 at baseline and SOT at baseline will be assessed 
using performance specified in Table 9. 


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Table 9 
Diagnostic performance of 68Ga-OPS202 PET/CT compared to SOT of ceCT (or ceMRI) 
68Ga-OPS202 PET/CT scan results 
SOT results (ceCT/ceMRI) 
Lesions detected 
at baseline 
Lesions not detected 
at baseline 
Lesions detected at baseline 
True Positive (TP) 
False Positive (FP) 
Lesions not detected at baseline 
False Negative (FN) 
True Negative (TN)* 
[will remain unknown] 
*True negative will remain unknown at the lesion level 
 
The sensitivity corresponds to the probability that the 68Ga-OPS202 scan at baseline detects the 
lesions, given that the lesions are detected (positive) by SOT at baseline.  This measurement 
refers to the ability of the test to correctly identify those lesions with the outcome of interest.  
Sensitivity is defined as the proportion of lesions with a positive ‘standard’ test response who 
also have a positive ‘experimental’ test response. 
For each assessment, the sensitivity will be computed using following formula, for each subject, 
for each organ and overall lesions: 
ܵ݁݊ݏ݅ݐ݅ݒ݅ݐݕൌ
ܶܲ
ܶܲ൅ܨܰ 
 
d) 
Diagnostic sensitivity of 68Ga-OPS202 imaging at baseline by both organ-based and 
lesion-based analysis compared to the SOT of 177Lu-OPS201 SPECT/CT after first 
administration. The contrast enhanced CT (or contrast enhanced MRI) scan images 
acquired at baseline will be used for anatomical location and lesion mapping between the 
two imaging techniques. 
Diagnostic sensitivity between 68Ga-OPS202 at baseline and 177Lu-OPS201 SPECT/CT as SOT 
will be assessed using performance specified in Table 10. 
Table 10 Diagnostic performance of 68Ga-OPS202 compared to SOT of 177Lu-OPS201 SPECT/CT 
68Ga-OPS202 scan results  
SOT results (177Lu-OPS201 SPECT/CT) 
Lesions detected after first 
administration of 177Lu-OPS201 
 
Lesions not detected after first 
administration of 177Lu-OPS201 
 
Lesions detected at baseline  
True Positive (TP) 
False Positive (FP) 
Lesions not detected at baseline  
False Negative (FN) 
True Negative (TN) 
[will remain unknown]* 
*True negative will remain unknown at the lesion level 
 
The sensitivity corresponds to the probability that the 68Ga-OPS202 detects the lesion identified 
on the 177Lu-OPS201 SPECT/CT scan after first administration.  This measurement refers to 
the ability of the test to correctly identify those lesions with the outcome of interest.  Sensitivity 
is defined as the proportion of lesions with a positive ‘standard’ test response who also have a 
positive ‘experimental’ test response. 
For each assessment, the sensitivity will be computed using following formula, for each organ 
and overall lesions: 
ܵ݁݊ݏ݅ݐ݅ݒ݅ݐݕൌ
ܶܲ
ܶܲ൅ܨܰ 


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3.2.2 
Safety 
All safety data will be included in the data listings and summary tables will be based on the 
safety population.  
For phase I study, continued monitoring of DLTs and toxicities will be performed. At the time 
of each data review board (DRB), the available safety data, including DLTs, toxicities, 
physiological parameters, ECG, laboratory test results and selected organ absorbed radiation 
doses (kidney and BM) will be tabulated to guide the radioactivity selection during the dose 
escalation. 
For the overall study, descriptive statistics will be calculated for the safety parameters. No 
formal statistical analyses of safety data are planned. 
Summaries will be prepared by cohort and, as needed, by timepoint. 
The NCI-CTCAE version 5.0 classification will be used to classify all TEAEs and laboratory 
abnormalities. 
3.2.2.1 
Adverse events 
Adverse events will be coded initially using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 21.0 and updated regularly.  
Listings will be presented and sorted by cohort and within cohort sorted by cancer type for 
phase I and by cancer type for phase II, with subject id, start time of AEs, primary system organ 
class, preferred term and verbatim text for all adverse events recorded during the study. Listings 
sorted by primary system organ class, preferred term, verbatim, subject id, start time of AEs 
may be also required. 
Listings of serious adverse events (SAE), adverse events leading to discontinuation of study 
treatment 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 AE that occurs during the active phase of the study if: 
• 
It was not present prior to receiving the first administration of 177Lu-OPS201; or 
• 
It was present prior to receiving the first administration of 177Lu-OPS201 but the intensity 
increased during the active phase of the study; or 
• 
It was present prior to receiving the first administration of 177Lu-OPS201, the intensity 
is the same but the drug relationship became related during the active phase of the study.  
A 68Ga-OPS202 TEAE is defined as any AE that occurs if: 
• 
It was not present prior to receiving the administration of 68Ga-OPS202; or 
• 
It was present prior to receiving the administration of 68Ga-OPS202 but the intensity 
increased after the administration of 68Ga-OPS202; or 
• 
It was present prior to receiving the administration of 68Ga-OPS202, the intensity is the 
same but the drug relationship became related after the administration of 68Ga-OPS202.  
TEAE period for 68Ga-OPS202 will be from the administration of 68Ga-OPS202 to one day 
after the administration. All 68Ga-OPS202 TEAE will be summarized together. 
An overall summary table of all adverse events will be presented, which will summarise the 
following information: 
• 
Any TEAEs,  
- 
177Lu-OPS201-related TEAEs,  


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- 
68Ga-OPS202-related TEAEs,  
- 
OPS301-related TEAEs,  
• 
NCI CTCAE grade 3/4/5 TEAEs,  
- 
177Lu-OPS201-related NCI CTCAE grade 3/4/5 TEAEs,  
- 
68Ga-OPS202-related NCI CTCAE grade 3/4/5 TEAEs,  
- 
OPS301-related NCI CTCAE grade 3/4/5 TEAEs,  
• 
DLT TEAEs,  
• 
Deaths due to TEAEs,  
• 
Treatment-emergent SAEs,  
- 
177Lu-OPS201-related treatment-emergent SAEs,  
- 
68Ga-OPS202-related treatment-emergent SAEs,  
- 
OPS301-related treatment-emergent SAEs, 
• 
Discontinuation of study treatment due to TEAEs,    
- 
Discontinuation of study treatment due to 177Lu-OPS201-related TEAEs,  
- 
Discontinuation of study treatment due to 68Ga-OPS202-related TEAEs,  
- 
Discontinuation of study treatment due to OPS301-related TEAEs,  
• 
Dose reduction due to TEAEs,  
- 
Dose reduction due to 177Lu-OPS201-related TEAEs,  
- 
Dose reduction due to 68Ga-OPS202-related TEAEs,  
- 
Dose reduction due to OPS301-related TEAEs,  
• 
Dose interruption due to TEAEs, and   
- 
Dose interruption due to 177Lu-OPS201-related TEAEs, 
- 
Dose interruption due to 68Ga-OPS202-related TEAEs, 
- 
Dose interruption due to OPS301-related TEAEs, 
• 
Dose increased due to TEAEs, and   
- 
Dose increased due to 177Lu-OPS201-related TEAEs, 
- 
Dose increased due to 68Ga-OPS202-related TEAEs, 
- 
Dose increased due to OPS301-related TEAEs 
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 NCI/CTC 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) will be chosen. Maximum grade or severity will be tabulated by subject for 
each MedDRA SOC and PT. Analyses of AEs and SAEs may be performed: regardless of the 
relationship to the IIP/IRPP and related to the IIP/IRPP. Moreover, all AEs including SAEs and 
SAEs only will be tabulated. 
68Ga-OPS202 TEAEs occurred during TEAE period for 68Ga-OPS202 will be summarized 
following the same manners and flagged in all adverse events data listings. 
3.2.2.2 
Laboratory data 
Laboratory data must be listed in Standard International (SI) units and also be listed in local 
units.  


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A separate listing of normal ranges for SI units will be provided by gender and age where 
relevant. 
Laboratory data will be listed in SI units and abnormal values will be flagged (High, [H], Low 
[L], clinically significant [C], NCI-CTC grade (G)) where applicable. Any unscheduled 
laboratory assessments will be flagged [U] in the listings. 
A listing will be presented of all values for a subject with at least a clinically significant 
abnormal value. 
Haematological and biochemistry toxicities will be recorded and graded according to the NCI-
CTC criteria, version 5.0. The NCI CTC grade (0 to 4) of haematology and biochemistry by 
cycle and by subject and will be listed in the Section 16.2.8. Listings of the laboratory 
parameters in section 14.3.4 & 14.3.5 will include listings of NCI-CTC Grade 3 and 4 
haematological toxicities, listings of NCI-CTC Grade 3 and 4 biochemical toxicities and listings 
of out of range biochemistry parameters that could not be graded using NCI-CTC grade (below 
LLN – normal – above ULN).   
For white blood cells (WBC), neutrophils, platelets and haemoglobin, with associated grade 3 
or 4 toxicities, nadir and day to nadir will be calculated (refer to Appendix 1, Derived data).   
For categorical urinalysis data (normal/abnormal) frequency tables, by cohort and/or cancer 
type 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 may 
be presented for the number and percentage of subjects with [normal, abnormal]. 
For continuous urinalysis data, summary statistics, by -cohort and/or cancer type, will be 
presented at each scheduled assessment for actual values and changes from baseline. 
3.2.2.3 
Maximum Tolerated Single and Cumulative Activity 
Individual listings and treatment summaries of DLTs with CTCAE code and grade will be 
presented. The incidence of subjects with DLTs during Cycles 1 or 2 of the radioactivity 
escalation will be summarised by cohort and/or cancer type and, if possible, modelled as a 
function of the cumulative radioactivity for Cycles 1 and 2 using Bayesian logistic regression.  
Details for the Bayesian logistic regression is described in a separate analysis plan and protocol 
Appendix 1. 
3.2.2.4 
Vital signs 
Vital signs will be listed at each assessment by cohort and/or cancer type and subject. Any 
unscheduled vital signs 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 by cohort and/or cancer type will be presented at each scheduled assessment 
for actual values and changes from baseline. 
For interpretation of clinical significance (normal / abnormal, not clinically significant / 
abnormal, clinically significant / not evaluable), a frequency table will be presented, by cohort 
and/or cancer type, at each post-dose assessment and for the worst value between post-dose 
assessments (abnormal, clinically significant > abnormal, not clinically significant > not 
evaluable). 
3.2.2.5 
ECG 
ECG results will be listed at each assessment by cohort and/or cancer type and subject. Any 
unscheduled ECG will be flagged [U] in the listings. 


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Baseline will be defined as the last ECG measurement collected prior to the first dose of study 
drug. 
For continuous ECG parameters, summary statistics, by cohort and/or cancer type, will be 
presented at each scheduled assessment for actual values and changes from baseline. 
For sinus rhythm, a frequency table by cohort and/or cancer type, will be presented at each 
scheduled assessment. 
For interpretation of clinical significance (normal / abnormal, not clinically significant / 
abnormal, clinically significant / not evaluable), a frequency table will be presented, by cohort 
and/or cancer type, at each post-dose assessment and for the worst value between post-dose 
assessments (abnormal, clinically significant > abnormal, not clinically significant > not 
evaluable). 
3.2.2.6 
Physical examination  
For physical exam assessments (abnormal, not clinically significant / abnormal, clinically 
significant /normal), a frequency table will be presented, by cohort and/or cancer type, at each 
post-dose assessment and for the worst value between post-dose assessments (abnormal, 
clinically significant > abnormal, not clinically significant > normal > not evaluable). 
3.2.3 
Exploratory biomarkers  
• 
The association between the uptake on 68Ga-OPS202 PET/CT with sstr2 expression on 
tumours as determined by IHC will be explored. 
• 
Immunohistochemistry staining of sstr2 of the primary tumour is defined by three 
parameters: 
- 
% of positive tumour cells (at the membrane compartment) ranging from 0% to 
100% 
- 
Intensity of staining with score of 0, 1, 2 or 3  
- 
H score=% of positive cells ×Intensity of staining. H score ranges from 0 to 300. 
68Ga-OPS202 PET/CT uptake will be measured by SUVmean at screening.  
Pearson’s correlation coefficient will be used to estimate the correlation between SUVmean and 
% of positive cells.  
The correlations between SUVmean and the intensity of staining as well as between SUVmean and 
H score will be examined using Spearman’s correlation coefficient.  
Additionally, H score will be split into two categories as follows: negative if H score < 50 or 
positive if H score ≥ 50. As for SUVmean, a sample will be considered positive if SUVmean is > 
0 and negative is SUVmean is 0.  
H score (positive/negative) and SUVmean (positive/negative) will be described in a 2x2 table 
using descriptive statistics (frequencies and percentage). 
Individual values of H score (positive/negative) and SUVmean (positive/negative) will be listed 
by subject.  
• 
Change in renal biomarkers compared to baseline (Day 1) will be summarised 
descriptively. 
• 
Change in pancreatic function biomarkers compared to baseline (Day 1) will be 
summarised descriptively. 
• 
Change in testicular function biomarkers compared to baseline (Day 1) will be 
summarised descriptively. 


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• 
Change from baseline (Cycle 1 Day 1 before infusion) in DNA-DSB in peripheral 
lymphocytes, and DNA repair in blood and in tumour tissue will be summarised 
descriptively. 
• 
Change from screening in tumour microenvironment, transcriptomics, and other disease 
markers of interest will be summarised descriptively. 
• 
Germinal mutations in blood measured before infusion will be summarised descriptively. 
3.2.4 
Missing data and outliers 
3.2.4.1 
Missing data 
Missing data will not be imputed. Only observed data will be used in the summaries and 
analyses. 
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: 
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 phase (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. For other identified outliers, the impact should be assessed by performing 
the statistical analysis with the actual values and at least one other analysis eliminating or 
reducing the outlier effect. 
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. 
A search of outliers by 
 should be performed before database lock and actions with 
the sponsor should be defined. 
3.2.5 
Subject disposition and withdrawals 
A listing of dates of assessments (relative day) and number of cycles will be presented by 
subject for each cohort and cancer type. 
The numbers and percentages of subjects enrolled and included in each of the ITT, PP and 
safety 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 
CCI


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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. 
3.2.6 
Demographic and baseline characteristics 
All demographic and baseline characteristics will be listed for the total study population and by 
cohort, cancer type and subject. 
Summary statistics will be provided for demographic and baseline characteristics for the total 
study population and by cohort.  
Demographic characteristics will include 
• 
age (years),  
• 
sex (male, female), 
• 
ethnicity (Hispanic or Latino, Not Hispanic or Latino, not reported), 
• 
race (Asian, American Indian or Alaska Native, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, not reported, Other), 
• 
country, 
• 
weight (kg), 
• 
height (cm), and 
• 
body mass index (BMI) in kg/m2, 
• 
body surface area (m2) 
• 
ECOG Performance Status (0, 1, 2, 3, 4) 
Baseline disease characteristics will include  
• 
cancer type (breast cancer, small cell lung cancer) 
• 
time from initial diagnosis of primary disease until the informed consent date (months) 
• 
time from first relapse after last treatment until the informed consent date (months) 
• 
TNM Classification of Malignant Tumours (TNM) Staging for tumour, node, metastasis 
• 
breast cancer history 
- 
primary tumour site (left, right) 
- 
primary tumour histopathological type (invasive carcinoma, carcinoma in situ) 
 
Invasive carcinoma (ductal, lobular, not otherwise specified, other) 
 
Carcinoma in situ (ductal, not otherwise specified) 
- 
Scarff-Bloom-Richardson histological grade (SBR I, SBR II, SBR III) 
- 
Estrogen receptor status (positive, negative, not done) 
- 
Progesterone receptor status (positive, negative, not done) 
- 
HER2 receptor status(positive, borderline, negative, not done) 
- 
BRCA 1 or 2 mutation (positive, negative, not done) 
• 
small cell lung cancer history 
- 
anatomical stage - limited disease (0, IA1, IA2, IA3, IB, IIA, IIB, IIIA, IIIB, IIIC) 
- 
anatomical stage - extensive disease (IVA, IVB) 
- 
primary tumour site (upper right lobe, middle right lobe, lower right lobe, upper 
left lobe, lower left lobe, hilar lymph nodes, right bronchus, left bronchus) 
• 
prior chemotherapy for cancer (yes, no) 


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• 
prior hormonal therapy for cancer (yes, no) 
• 
prior immunotherapy for cancer (yes, no) 
• 
prior CDK4/6 inhibitors for breast cancer (yes, no) 
• 
prior targeted agents for cancer (yes, no) 
• 
prior radiotherapy for cancer (yes, no) 
• 
prophylactic cranial irradiation for cancer (yes, no) 
• 
prior surgical procedures for cancer (yes, no) 
• 
Best response from prior chemotherapy, hormonal, immunotherapy, CDK4/6 inhibitors, 
targeted agents (CR, PR, stable disease (SD), progressive disease (PD), inevaluable (NE), 
not available (NA)) 
3.2.7 
Medical and surgical history 
Medical and surgical history will be coded initially using MedDRA Version 21.0 and updated 
regularly. 
Listings will present the preferred term and verbatim text. The listings will be sorted by cohort, 
cancer type, subject, primary system organ class, preferred term and verbatim text.  
A frequency table of the number and percentage of subjects will be provided for medical and 
surgical history by primary system organ class and preferred term for each cohort and cancer 
type. 
3.2.8 
Subject compliance 
Number of treatment cycles completed by each subject will also be summarised by cohort and 
cancer type. Planned 177Lu-OPS201 dose and planned peptide mass dose will be summarised 
descriptively by cycle, and by cohort and cancer type and in total. 
A listing will be presented for 177Lu-OPS201 infusion administration (site, side, planned and 
actual 177Lu-OPS201 dose, planned and actual peptide mass dose, radioactivity measurement 
before and after injection, start/end date and time) by subject for each cohort and cancer type. 
Deviations from planned and actual dose will be presented.  
A listing will be presented for 68Ga-OPS202 administration (actual radioactivity dose, 
radioactivity dose and volume before and after administration, and date and time) by subject 
for each cohort and cancer type. 
Other information collected on eCRF for 177Lu-OPS201 and 68Ga-OPS202 administration will 
also be listed. 
All the protocol deviations identified prior to database lock will be also listed by subject for 
each cohort and cancer type.  
The impact of major protocol deviation on the phase II primary efficacy analysis and phase I 
and phase II dosimetry analysis will be investigated by comparing the results of the ITT and PP 
population analyses. 
3.2.9 
Prior and concomitant therapies 
Prior and concomitant therapies will be coded initially using WHO-Drug Dictionary Version 
Mar 2018 B3 and updated regularly. The therapeutic class will correspond to the second level 
of ATC code, which is, corresponding to the first 3 figures of ATC code. 
Listings will be presented for the therapeutic class, preferred term and verbatim text. The 
listings will be sorted by cohort and cancer type, subject, chronological start 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 
therapies by therapeutic class and preferred name for each cohort and cancer type. 
Prior, concomitant, and post-treatment medications will be summarised separately. 
Categorization will be defined as follows: 
• 
Prior medications will include medications which started prior to the start date and time 
of the first 177Lu-OPS201 administration.  
• 
Concomitant medications will include medications taken any time from the start date and 
time of the first 177Lu-OPS201 administration through 30 days following end date and 
time of the last 177Lu-OPS201administration or until the start of a subsequent anticancer 
therapy, whichever is earlier. Medications that started prior to the first dose of study drug 
but continued into treatment are considered concomitant. 
• 
Post-treatment medications will include medications taken any time after from the start 
date and time of the first 177Lu-OPS201 administration through 30 days following end of 
study drug administration or until the start of a subsequent anticancer therapy, whichever 
is earlier. 
Anticancer Treatment received during follow-up period be summarised separately. 
3.2.10 
Pharmacokinetics  
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. 
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, renal clearance) will be derived using the 
noncompartmental approach on the individual plasma concentration-time profiles of OPS201 
and on the individual urine concentrations. 
An attempt to build an integrated model taking into account PK, dosimetry as well as efficacy 
and safety data will be made if warranted by the data. The exploratory analysis will be captured 
in a separate data analysis plan and reported in a standalone report. 
3.2.11 
Radiation Dosimetry of 177Lu-OPS201 
The radiation dosimetry analysis of the radiopharmaceutical 177Lu-OPS201 will be performed 
under the responsibility of the sponsor’s Clinical PK department. 
Further details on dosimetry assessments and on dosimetry parameters will be provided in a 
separate data analysis plan. 
The dosimetry assessments will be performed and reported according to the criteria set by the 
EANM Dosimetry Committee guidance document: good practice of clinical dosimetry 
reporting (Lassmann 2011). 


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Calculations will be conducted on the following parameters (only, but not limited to, in organs 
showing uptake): 
- 
Maximal uptake (%) 
- 
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) 
Cumulative absorbed organ doses (Gy)/Organs of highest radioactivity uptake will be identified 
visually. Regions of interest (ROI) will be placed over these organs to determine the relative 
radioactivity in the respective organs. TACs (time radioactivity curves), describing % IA/ROI 
of the radioactivity amount injected versus time, considering renal excretion radioactivity) will 
be derived. The absorbed organ doses of the dose-limiting organs (kidney, BM and liver) will 
be evaluated and reported to the investigator before the next administration of 177Lu-OPS201 
can be initiated to enable radioactivity adaptations in the event the next dose may exceed the 
organ limits  
for the kidney (23 Gy) and for the BM (1.5 Gy or up to 2 Gy during core trial and additional 
cycles, respectively). Of note, imaged-based dosimetry results associated to overlying 
tumors/lesions resulting in absorbed dose overestimation will not be used for dose radioactivity 
adaptation. In this case, the dose radioactive adaptation will rely on an overall benefice/risk 
dosimetry evaluation. 
A Bayesian power model will be considered to relate the cumulative 177Lu-OPS201 
radioactivity during Cycles 1 and 2 of the dose escalation to the cumulative absorbed dose in 
the BM and kidney. Vague priors will be used. The posterior predictive distribution of the 
exposure will be summarised by radioactivity level. Detailed Bayesian power model for phase 
I dose escalation is documented in a separate analysis plan. 
The maximum cumulative absorbed dose where the posterior predictive probability of 
remaining below the target organ limits (1.5 Gy for BM and 23 Gy for kidney) will be estimated 
from that model, as the radiation-safety component of the MTCA. 
The dosimetry for all organs other than BM and kidney will be assessed and finalised for the 
final clinical study report, whereas dosimetry data for BM and kidney must be available for the 
DRB meetings. These data can be reviewed at any time if a major safety issue occurs. 
3.2.12 
Derived data 
The derived data are variables which are calculated from the raw data in the CRF and not 
included in the database. 
3.2.13 
Visit windows  
No study visit windows will be used for analyses. Within CRFs each unscheduled visit will be 
linked to a scheduled visit which will be used to identify visits. 
3.2.14 
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).  


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For summary statistics, the following will be presented n, number of missing values, 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 all subjects in a specified population. The 
denominator will be specified in a footnote to the tables for clarification if necessary.  
Lower and upper confidence interval values should 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% or first quartile, 75% third quartile) should be presented to one decimal 
place more than the raw/derived data.  
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 must 
be decimal justified.  Dates will be presented in the format [ddmmmyyyy] and times in the 
format [hh:mm]. 
3.2.15 
Pooling of Centres 
It is not planned to perform a subgroup analysis on individual or groups of centres. 
3.2.16 
Interim/futility analysis 
Phase I 
Safety and radiation exposure data will be reviewed on an ongoing basis during the radioactivity 
escalation.  
Proceeding to the Next Cohort  
The DRB meeting for radioactivity and peptide mass escalation will take place after three 
subjects of the radioactivity escalation cohort have completed two cycles of 177Lu-OPS201. The 
DRB will review all available safety and dosimetry data from the study to decide if the 
escalation can proceed as planned If DLTs are reported, a statistical Bayesian modelling 
approach will be implemented to produce more precise radioactivity-DLT and organ absorbed 
doses curves to guide the radioactivity selection and predict a radioactivity not exceeding the 
predicted MTCA/MTSA that could be tested in the next cohort of radioactivity escalation. 
If the starting cumulative radioactivity of 9 GBq is not well tolerated, another cohort with a 
decreased cumulative radioactivity will start. In this case, the cumulative radioactivity could be 
determined using the statistical Bayesian approach, for example, 7.5 GBq (one administration 
of 4.5 GBq followed by an administration of 3 GBq, 6 weeks apart (+ up to additional 4 weeks 
in case of AEs that need to be adequately recovered)). 
Stopping Rules for Dose Escalation 
The radioactivity escalation will be stopped as soon as: 
• 
the MTCA and/or MTSA have been defined with good precision; or 
• 
the maximum planned radioactivity of 12.9 GBq, fractionated into two administrations 
separated by 6 weeks, is administered without safety concerns and is thus defined as the 
MACA. 


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Once the radioactivity escalation has been completed, the MTCA level may be repeated based 
on the results of the Bayesian model in a last cohort of three to five subjects with the same 
peptide mass dose to confirm the safety profile. If the MTCA is not reached and if limiting 
organ absorbed doses are not exceeded at the highest planned radioactivity (12.9 GBq) and if 
no individual withdrawal criteria are met, the inclusion of an additional cohort with a higher 
cumulative radioactivity will be evaluated. 
Peptide Mass Dose Evaluation 
In parallel with the radioactivity escalation phase, once the first cycle of a radioactivity level is 
considered acceptably tolerated by the DRB, the radioactivity level will be repeated with a 
higher peptide mass dose (700 μg (±15%)). Three additional cohorts of three to five subjects 
will thus be enrolled in the peptide mass dose evaluation.  
The DRB for peptide mass dose escalation will meet after the third subject of each cohort has 
received the first cycle of 177Lu-OPS201 with DLT assessments performed. 
The DRB will review all safety and dosimetry data and allow the peptide mass dose escalation. 
The cohort with the high peptide mass dose (700 μg) will thus only start when the first cycle of 
the corresponding radioactivity level tested with 300 μg peptide mass dose has been evaluated 
by the DRB and has been considered acceptably tolerated. 
Moreover, the administration of the second cycle of the peptide mass dose evaluation cohorts 
can only proceed once the second cycle of the corresponding radioactivity level has been 
considered acceptably tolerated. The same subject cannot participate in the radioactivity 
escalation cohort and the peptide mass dose cohort. 
At the time of DRB meeting, all cumulative available information will be reviewed. 
Phase II  
An interim analysis will be performed for futility based on the first stage of Simon's optimal 
two-stage design within each cohort. 
For the SCLC cohort, the first stage consists of 29 subjects. An analysis will be conducted after 
approximately 29 subjects have been assessed on the ORR. The ORR assessment cut-point for 
the 29th subject is 6 weeks after Cycle 2 dose. The probability of early termination (PET) after 
the first stage is 0.6555. If seven responses or less are seen in the first 29 subjects then the trial 
is stopped. Otherwise accrual continues to a total of 69 response evaluable subjects. 
For the BC cohort, the first stage consists of 33 subjects. An analysis will be conducted after 
approximately 33 subjects have been assessed on the ORR. The ORR assessment cut-point for 
the 33rd subject is 6 weeks after Cycle 2 dose. The probability of early termination (PET) after 
the first stage is 0.6374. If four responses or less are seen in the first 33 subjects then the trial 
is stopped. Otherwise accrual continues to a total of 87 response evaluable subjects. 
3.2.17 
Role of data review board (DRB)  
The data review board (DRB) for radioactivity escalation, consisting of a team of “permanent” 
decision makers (the core team), including selected principal investigators and Ipsen personnel, 
will review the safety and dosimetry data and jointly decide with the sponsor whether to proceed 
with the enrolment of the next cohort. Details of roles and responsibilities of DRB are described 
in the DRB charter. 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS 
4.1 
Software 
All tables, listings and figures will be produced and statistical analysis performed using SAS® 
version 9.3 or higher.  All outputs will be in Microsoft Word Format. 




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7 
APPENDICES  
Appendix 1: Derived Data 
The following derived data will be calculated and included in the listings: 
(1) 
Age (specified DEMOG table) 
Subject age (years) will be derived as (screening date – birth date)/365.25 and truncated to the 
largest integer that is less than or equal to the calculated result. 
(2) 
BMI (specified VSIGN table) 
BMI (kg/m2) will be derived as Weight (kg)/[Height(cm)/100]2 and rounded to the nearest 
decimal. 
(3) 
Body Surface Area (specified VSIGN table) 
Body Surface Area (m2) will be derived as (Weight (kg)
0.425 × Height(cm)
0.725 × 71.84)/10000 
and rounded to the nearest decimal. 
(4) 
Changes from baseline  
Changes from baseline will be calculated as a difference from baseline (e.g. assessment at the 
visit – assessment at baseline). 
(5) 
Percent change from baseline  
Percent reduction from baseline will be calculated as a percentage of decrease from baseline 
(e.g. 100×(1-(assessment at the visit)/(assessment at baseline))).  
If assessment at baseline is zero, percent change will not be calculated. Unless when both 
assessment at baseline and assessment at the visit are zero, percent change will not be set as 
zero. 
(6) 
Adverse event duration 
If the start date of the adverse event is identical to the date of last administration, then”<1” day 
will be presented, otherwise 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.  
(7) 
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. 


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(8) 
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).  
(9) 
Relative phase  
Relative phase variables describe the event date as pre, during and or post treatment relative to 
the first study medication intake date.  There are two-phase variables: 
1. 
VAR_SPH describes the start phase of an event relative to the first and the last 
date of study medication intake 
2. 
VAR_EPH describes the end phase of an event relative to the first and the last date 
of study medication intake. 
The phase code list consists of  
0.5 = indeterminate 
1    = pre 
2    = during 
3    = post 
If the event start date is before the start date of study medication or before the start time of study 
medication, then  
VAR_SPH  = 1 (pre). 
If the event start date is on or after the start date of study medication and on or before the end 
date of study medication, then VAR_SPH  = 2 (during) 
If the event start date is after the end date of study medication, then VAR_SPH  = 3 (post) 
If the event end date is before the start date of study medication, then VAR_EPH = 1 (pre) 
If the event end date is on or after the start date of study medication and on or before the end 
date of study medication, then VAR_EPH = 2 (during) 
If the event end date is after the end date of study medication, then VAR_EPH = 3 (post) 
As a general rule, relative phase variables should be calculated for all date variables in a panel 
unless otherwise indicated (e.g.: AE, medical history, prior and concomitant medications, 
disease related histories, lab data). If dates are incomplete or completely missing, then 
information on cycle numbers should be used to complete the phases. 
Relative phase variables should not be left indeterminate for adverse events, medical history 
and concomitant medications. It should be completed even in the case where dates are partial 
or completely missing by using worst-case scenario. 
 
 
 
Worst Case Scenarios for Phase Variables 
Item 
Worst case scenario for the 
start phase _SPH 
Worst case scenario for the 
end phase   _EPH 
Adverse events 
During 
During 
Medical history  
Pre 
Pre 
Concomitant 
medication 
Pre 
During 
 
Phase variable should be left as Indeterminate.(0.5), only when no reasonable assumptions can 
be made due to missing or incomplete dates. 


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(10) Relative days 
Relative days based on the very first study medication infusion/intake date (D1, Cycle 1) and 
the very last study medication infusion/intake date (D1, Cycle n) or first day of a given Cycle. 
Four types of relative days (VAR_SrS, VAR_SrE, VAR_ErS and VAR_ErE) will be calculated 
for any event defined with start and stop dates (e.g.: AE, Prior and Concomitant medication, 
Medical history etc.) and three types of relative days (VAR_ArS, VAR_ArE and 
VAR_ArCxD1) will be calculated for assessments (e.g.: lab parameters, ECG, vitals etc.) unless 
otherwise specified.  
For example: if VAR=AE then 
AE_SrS: Relative days from start of the event to start of study drug administration. 
AE_SrS will be calculated by using either of the following two formula: 
• 
If AE onset was on or after initiation of study medication then 
AE_SrS = event start date – first study drug administration date + 1 
• 
If AE onset was before initiation of study medication then  
AE_SrS = event start date – first study drug administration date  
AE_ErS: Relative days from end of the event to start of study drug administration  
AE_ErS will be calculated by using either of the following two formula: 
• 
If AE end date was on or after initiation of study medication then AE_ErS = event end 
date – first study drug administration date + 1 
• 
If AE end date was before initiation of study medication then AE_ErS = event end date 
– first study drug administration date  
Relative assessment days based on the first drug administration will be calculated as 
following:  
• 
If LAB sample date was on or after first drug administration then 
• 
LAB_ArS = LAB sample date –first date of study drug administration + 1 
• 
If LAB sample date was before first drug administration then 
• 
LAB_ArS = LAB sample date –first date of study drug administration  
Relative assessment days based on the last drug administration will be calculated in a 
similar fashion.  
• 
If LAB sample date was on or after last drug administration then  
LAB_ArE = LAB sample date –last date of study drug administration + 1 
• 
If LAB sample date was before last drug administration then 
LAB_ArE = LAB sample date –last date of study drug administration  
Relative assessment cycle days based on the Day 1 of cycle X will be calculated in the 
similar fashion.  
• 
LAB_ArCxD1: Relative assessment cycle days from lab sample date  to D1 of cycle X 
(CxD1)  will be calculated by using formula 
• 
LAB_ ArCxD1 = lab sample date –CxD1 + 1 
(Note : the relative assessment cycle days based on the day one of cycle one  (C1D1) is the 
equal to relative assessment days based on first drug administration (i.e.: VAR_ArS).  


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(11) AE duration 
AE duration will be set equal to the value recorded on the CRF if the duration is less than 24 
hours. If the duration is not specified, then it will be calculated by using “AE_ErS - AE_SrS” 
recorded in days. If the end date is missing because the adverse event was ongoing then the 
duration will be listed as “ongoing”. 
(12) A nadir for a subject is defined as the lowest laboratory value or tumor evaluation 
(volume or longest diameter) 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 or tumor evaluation (volume or longest diameter) 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. 
(13) The time to recovery will be calculated for WBC, neutrophils, haemoglobin and 
platelets with toxicities grade 3 or 4. Recovery is defined as the return to grade 0, 1 or 
baseline level. The time to recovery is the number of days between the nadir and the date 
of first assessment of the recovery.   
For the calculation of the nadir, day to nadir and time to recovery of haematological events, the 
cycles where G-CSF  or red blood cell packs or platelets units have been given will be censored 
for the related parameter as following: WBC and neutrophils will be  censored when G-CSF or 
total blood products are given, haemoglobin will be censored when red blood cell packs or total 
blood products or erythropoietin products are given and platelets when platelets units or total 
blood products are given. If the haematological supporting drugs were started before the nadir 
then any following assessment of this nadir such as day to nadir and time to recovery will be 
censored. If this therapy was initiated after the nadir is reached, only time to recovery will be 
censored.  A listing detailing the censoring will be provided. 
(14) Neutrophils values 
In some cases, lab data may not be reported as they may be difficult to detect.  When the White 
Blood Cells counts (WBC) are recorded,  and if WBC < 0.5*109/L, then neutrophils value will 
be imputed as zero and thus will be considered to be in NCI grade 4.  
(15) Laboratory values grades 
Laboratory values grades will be assigned toxicity grades when available using the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) scale 
(Version 5.0). Laboratory toxicity grades are “0”, “1”, “2”, “3”, “4”. Some laboratory tests provide 
two sets of grades – one set for values that are too low and another set for values that are too high. 
For these parameters, both directions will be derived, i.e. one record with parameter decreased and 
one record with parameter increased. If more than one grade can be assigned, due to the high and 
low normal range values overlapping more than 1 grade, then the worst grade should be assigned. 
(16) Tumour assessments 
In case of missing tumour assessment at cycle n, it should be kept missing as long as the next 
evaluation at cycle n+1 is a Progressive Disease (PD). The best overall response in this case is 
‘not evaluable’ if there are no previous assessments. Otherwise, the best overall response will 
be assessed by using tumour assessments up to cycle n-1. 
On the other hand, if the assessment at cycle n+1 does not show any progression, this missing 
assessment (at cycle n) will be derived by using the assessment from previous cycle n-1 (last 
observation carried forward method). In this case the best overall response will be assessed as 
defined. 
 
P